HK1083339B

HK1083339B - Chirale oxazole-arylpropionic acid derivatives and their use as prar agonists

Info

Publication number: HK1083339B
Application number: HK06104701.6A
Authority: HK
Inventors: 艾弗雷德‧宾格尼; 马科斯‧波林格; 乌伟‧格雷斯; 汉斯‧黑普特; 乔治‧赫斯; 汉斯-皮特‧马克; 马科斯‧梅尔; 皮特‧墨尔; 法比尼‧雷克林
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2002-10-07
Filing date: 2003-10-06
Publication date: 2008-11-14

Description

Chiral oxazole-arylpropionic acid derivatives and their use as PPAR agonists

The present invention relates to novel oxazole derivatives, their manufacture and their use as pharmaceuticals. In particular, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof,

wherein

R¹Is aryl or heteroaryl;

R²is hydrogen, lower alkyl, or fluoro lower alkyl;

R³and R⁴Independently of one another, hydrogen, hydroxy, halogen, lower alkyl, fluoro lower alkyl, hydroxy lower alkyl, lower alkoxy, fluoro lower alkoxy, hydroxy lower alkoxy, lower alkoxy, or lower alkenyl,

wherein R is³And R⁴At least one of which is not hydrogen;

R⁵is lower alkoxy, fluoro-lower alkoxy, lower alkenyloxy, fluoro-lower alkenyloxy, aryloxy, aryl-lower alkoxy, or arylfluoro-lower alkoxy;

R⁶is hydrogen or lower alkyl;

n is 1, 2 or 3.

Peroxisome proliferator-activated receptors (PPAR's) are members of the nuclear hormone receptor superfamily, which are ligand-activated transcription factors that regulate gene expression. Different subtypes of these have been identified and cloned. These different subtypes include PPAR α, PPAR β (also known as PPAR δ) and PPAR γ. There are at least two major isoforms of PPAR γ. Although PPAR γ 1 is ubiquitously expressed in most tissues, the longer isoform, PPAR γ 2, is found almost exclusively in adipocytes. In contrast, PPAR α is mainly expressed in the liver, kidney and heart. PPAR's modulate a variety of bodily responses including glucose and lipid homeostasis, cell differentiation, inflammatory responses and cardiovascular events.

Diabetes is a disease in which a patient's ability to control blood glucose levels is impaired because the patient has partially lost the ability to respond appropriately to the action of insulin. In type II diabetes (T2D), commonly referred to as non-insulin dependent diabetes mellitus (NIDDM) and afflicting 80-90% of all diabetic patients in developed countries, the islets of langerhans in the pancreas still produce insulin. However, the target organs, mainly muscle, liver and adipose tissue, exhibit profound resistance to insulin stimulation and the body compensates by producing unphysiologically high levels of insulin. In the advanced stages of the disease, insulin secretion is reduced due to pancreatic failure. In addition, T2D is a metabolic-cardiovascular disease syndrome. Among the complications (comorbidities) associated with T2D are, for example, insulin resistance, dyslipidaemia (dyslipemia), hypertension, endothelial dysfunction and inflammatory atherosclerosis.

Current first-line therapies for diabetes typically involve low fat and low glucose diets and exercise. However, compliance is limited and as the disease progresses, treatment with hypoglycemic agents such as sulfonylureas or metformin becomes essential. A promising new class of drugs (insulin sensitizers) has been introduced to restore sensitivity to their own insulin in patients, thereby restoring blood glucose and triglyceride levels to normal and eliminating, or at least reducing, the need for exogenous insulin. Pioglitazone (pioglitazone) (Actos)^TM) And rosiglitazone (rosiglitazone) (Avandia)^TM) Belong to the Thiazolidinedione (TZD) class of PPAR γ -agonists and are approved for NIDDM in several countriesFirst representative drug batch. However, these compounds present various side effects, including rare but severe hepatotoxicity (as observed with troglitazone), and they increase body weight in humans. Therefore, there is an urgent need for new, better and more effective drugs for the treatment of NIDDM. Recent studies provide evidence that co-agonism of PPAR α and PPAR γ (coadonisms) can produce compounds with enhanced therapeutic potential, i.e., improved lipid profile in addition to normalizing glucose and insulin levels (Keller and Wahli:. Trends Endocrin. Metab. 1993; 4: 291. 296, Macdonald and Lane:. newest Biology (Current Biology) Vol.5 pp.618-621 (1995)). Recent observations further suggest that there is an independent PPAR α mediated effect on insulin-sensitization which may in turn lead to lipid reduction (Guerre-Millo et al; J Biol Chem 2000; 275: 16638-16642). Therefore, it is desirable to incorporate PPAR α activity into PPAR γ agonists to produce a more effective medicament for the treatment and/or prevention of diabetes.

The novel compounds of the present invention are superior to the compounds known in the art because they can bind to and activate PPAR α and PPAR γ simultaneously and very efficiently. Thus, these compounds combine the hypoglycemic (anti-gylcemic) effect of PPAR γ activation with the antilipidemic (anti-dyslipidemic) effect of PPAR α activation. Thus, blood glucose and insulin are reduced (insulin sensitization), triglycerides are lowered, and HDL cholesterol is increased (improved lipid profile). In addition, such compounds may also lower LDL cholesterol, lower blood pressure and combat inflammatory atherosclerosis. As various aspects of the T2D disease syndrome are addressed by PPAR α and PPAR γ co-agonists (coagonists), they have enhanced therapeutic capabilities compared to compounds known in the art.

The compounds of the invention further exhibit improved pharmacological properties compared to known compounds.

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention.

In the present specification, the term "lower" is used to refer to a group consisting of 1 to 7, preferably 1 to 4 carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "protecting group" refers to a group that serves to temporarily block the activity of a functional group, such as, for example, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a silyl group, or an imine derivative. Well-known protecting groups are, for example, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or diphenylmethylene which may be used for protecting amino groups, or lower alkyl-, beta-trimethylsilylethyl-and beta-trichloroethyl-esters which may be used for protecting carboxyl groups.

The term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms.

The term "lower alkyl" alone or in combination with other groups refers to a branched or straight chain monovalent alkyl group of 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. The term is further exemplified by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.

The term "fluorinated lower alkyl" refers to a lower alkyl group that is mono-or poly-substituted with fluorine. Examples of fluorinated lower alkyl are e.g. CF₃，CF₃CH₂And (CF)₃)₂CH。

The term "alkoxy" refers to the group R '-O-, wherein R' is alkyl. The term "lower alkoxy" refers to the group R '-O-, wherein R' is lower alkyl. Examples of lower alkoxy are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy.

The term "fluoro-lower-alkoxy" denotes the group R "-O-, wherein R "is fluoro lower alkyl. Examples of fluoro-lower alkoxy are e.g. CF₃-O，CF₃CH₂-O and (CF)₃)₂CH-O。

The term "lower alkenyl", alone or in combination, denotes a straight-chain or branched hydrocarbon residue containing an olefinic bond and up to 8, preferably up to 6, particularly preferably up to 4, carbon atoms. Examples of alkenyl are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.

The term "lower alkenyloxy" refers to the group R "-O-, where R" is lower alkenyl. Examples of lower alkenyloxy are butenyloxy, especially but-3-enyloxy.

The term "fluoro lower alkenyloxy" refers to a lower alkenyloxy group as defined above, which is mono-or poly-substituted with fluorine. Examples of lower alkenyloxy are, for example, (Z) or (E)4, 4, 4-trifluoro-but-2-en-1-yl.

The term "aryl" refers to phenyl or naphthyl, preferably phenyl, which may be optionally mono-or polysubstituted, in particular mono-, di-or trisubstituted, by: halogen, hydroxy, CN, CF₃、NO₂、NH₂N (H, lower alkyl), N (lower alkyl)₂Carboxy, aminocarbonyl, lower alkyl, fluoro lower alkyl, lower alkoxy, phenyl and/or phenoxy. Preferred substituents are halogen, lower alkyl, fluoro lower alkyl and/or lower alkoxy.

The term "heteroaryl" refers to a 5-or 6-membered aromatic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur, such as furyl, pyridyl, 1, 2-diazinyl, 1, 3-diazinyl and 1, 4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl or pyrrolyl. The term "heteroaryl" further refers to: bicyclic aromatic radicals containing two 5-or 6-membered rings, where one or both rings may contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulfur,such as indole or quinoline; or partially hydrogenated bicyclic aromatic groups such as, for example, indolinyl. Heteroaryl groups may have substitution as described above in connection with the term "aryl". Preferred heteroaryl groups are, for example, optionally substituted as described above, preferably by halogen, CF₃Lower alkyl and/or lower alkoxy substituted thienyl and furyl.

The term "pharmaceutically acceptable salts" includes salts of the compounds of formula (I) with pharmaceutically acceptable bases such as alkali metal salts, e.g. Na-and K-salts, alkaline earth metal salts, e.g. Ca-and Mg-salts, and ammonium or substituted ammonium salts, such as e.g. trimethylammonium salts.

The compounds of formula (I) may also be solvated, e.g. hydrated. The solvation may be carried out during the preparation or may for example be carried out due to the hygroscopic nature of the initially anhydrous compound of formula (I) (hydration). The term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.

The term "pharmaceutically acceptable ester" includes derivatives of the compounds of formula (I) wherein the carboxyl group has been converted to an ester. Examples of suitable esters are lower alkyl esters, hydroxy lower alkyl esters, lower alkoxy lower alkyl esters, amino-lower alkyl esters, mono-or di-lower alkyl-amino-lower alkyl esters, morpholino-lower alkyl esters, pyrrolidine-lower alkyl esters, piperidino-lower alkyl esters, piperazino-lower alkyl esters, lower alkyl-piperazino-lower alkyl esters and aralkyl esters. Methyl, ethyl, propyl, butyl and benzyl esters are preferred. Methyl and ethyl esters are particularly preferred. The term "pharmaceutically acceptable esters" additionally includes compounds of formula (I) wherein the hydroxyl groups have been converted to the corresponding esters with inorganic or organic acids, such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are non-toxic to living organisms.

In detail, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof,

wherein

R¹Is aryl or heteroaryl;

R²is hydrogen, lower alkyl, or fluoro lower alkyl;

wherein R is³And R⁴At least one of which is not hydrogen;

R⁶is hydrogen or lower alkyl;

n is 1, 2 or 3.

Preferred are compounds of formula (I) and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof,

wherein

R¹Is aryl or heteroaryl;

R²is hydrogen, lower alkyl, or fluoro lower alkyl;

R³and R⁴Independently of one another hydrogen, hydroxy, halogen, lower alkyl, fluoro lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkylLower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, or lower alkenyl,

wherein R is³And R⁴At least one of which is not hydrogen;

R⁶is hydrogen or lower alkyl;

n is 1.

The compounds of the formula (I) above contain⁵Adjacent asymmetric carbon atoms. According to the Cahn-Ingold-Prelog specification, R⁵The attached carbon atom is in the S configuration.

Preferably wherein R is¹A compound of formula (I) as defined above which is aryl. Also preferred is where R¹Is phenyl optionally substituted with 1-3 substituents independently selected from lower alkyl, lower alkoxy, halogen and fluoro-lower alkyl, more preferably R¹Are those compounds which are phenyl optionally substituted with 1-2 substituents independently selected from lower alkyl, lower alkoxy, halogen, particularly preferably wherein R is¹Those which are phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl, 4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl, 2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, or 4-tert-butyl-phenyl. Preferably wherein R is¹Are phenyl substituted by methyl and/or fluorine, in particular 2-methyl-phenyl or 2-fluoro-phenyl.

In addition, preferred is the case where R is²Compounds as defined above which are hydrogen or lower alkyl, particularly preferably wherein R²Is hydrogen or methyl. Hydrogen and methyl alone constitute respectively preferred embodiments. Also preferred is where R²Is a lower alkyl, preferably methyl, compound.

A preferred embodiment of the present invention also relates to compounds of formula (I), wherein R³And R⁴Independently of one another, hydrogen, hydroxy, halogen, lower alkyl, fluoro lower alkyl, or lower alkoxy, wherein R³And R⁴At least one of which is not hydrogen. Preferably wherein R is³Is hydrogen or methyl. Hydrogen and methyl are individually related to preferred embodiments of the present invention. Particular preference is given to compounds as defined above in which R⁴Is methyl, ethyl, fluoro, chloro, trifluoromethyl, hydroxy, methoxy, ethoxy, or isopropoxy. Preferably, R³Is hydrogen and R⁴Is lower alkyl, especially methyl.

Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above, wherein R⁵Is lower alkoxy, more preferably methoxy or ethoxy, more preferably ethoxy. Other preferred compounds are those wherein R is⁶Those that are hydrogen.

Preferred compounds are those wherein R is¹Is phenyl substituted by methyl and/or fluorine, R²Is lower alkyl, R³Is hydrogen, R⁴Is lower alkyl, R⁵Is lower alkoxy and R⁶Are those of hydrogen. More preferred compounds are those wherein R is¹Is 2-methyl-phenyl or 2-fluoro-phenyl, R²Is methyl, R³Is hydrogen, R⁴Is methyl, R³Is ethoxy and R⁶Are those of hydrogen.

Compounds of formula (I) wherein n is 1, 2 or 3 individually relate to preferred embodiments of the invention.

The pharmaceutically acceptable salts of the compounds of formula (I) and the pharmaceutically acceptable esters of the compounds of formula (I) alone constitute preferred embodiments of the invention. Particular preference is given to compounds of the formula (I).

Preferred compounds of formula (I) are those selected from the group consisting of:

(S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -3- (4- {2- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid,

(S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid,

(S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid,

(S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid,

(S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid,

(S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid,

(S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-trifluoromethyl-phenyl } -propionic acid,

(S) -3- { 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -2-methoxy-propionic acid,

(S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid,

(S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -2-ethoxy-propionic acid,

(S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid,

(S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid,

(S) -3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid,

(S) -3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -propionic acid,

(S) -2-ethoxy-3- { 2-methyl-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

(S) -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid,

(S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-ethoxy-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- { 2-ethoxy-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid,

(S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-ethoxy-phenyl } -2-ethoxy-propionic acid,

(S) -2-ethoxy-3- { 2-ethoxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -propionic acid,

(S) -2-ethoxy-3- { 2-ethoxy-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid,

(S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-isopropoxy-phenyl } -2-ethoxy-propionic acid, and

(S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.

Particularly preferred compounds of formula (I) are those selected from the group consisting of:

(S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-ethoxy-phenyl } -2-ethoxy-propionic acid, and

(S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-isopropoxy-phenyl } -2-ethoxy-propionic acid,

Other particularly preferred compounds of formula (I) are those selected from the group consisting of:

Each of the above compounds individually constitutes a preferred embodiment of the present invention, in particular (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. Another example of a preferred individual compound is (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. Preferred are compounds as described above, which are not pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

The compounds of formula I may contain one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, optically pure diastereomers or mixtures of diastereomers. The optically active forms can be obtained, for example, by resolution of the racemate, asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). The invention includes all forms wherein R⁵The attached asymmetric carbon is in the S configuration.

It will be appreciated that the compounds of general formula (I) of the invention may be derivatised at functional groups to provide derivatives which are capable of inversion to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives capable of producing the parent compound of formula (I) in vivo are also within the scope of the invention.

A further aspect of the invention is a process for the preparation of a compound of formula (I) as defined above, which process comprises removing the protecting group in a compound of formula (II),

wherein R is¹，R²，R³，R⁴，R⁵And n is as defined above and PG is a protecting group.

Possible protecting groups PG in compounds of formula (II) are, for example, lower alkyl-, beta-trimethylsilylethyl-and beta-trichloroethyl-esters, which can be used for protecting the corresponding carboxyl group. Can be, for example, in the temperature range of 10-50 ℃ in the presence of a base such as, for example, LiOH or NaOH, in a solvent such as, for example, H₂Removing the lower alkyl-ester protecting group from a solvent such as O, ethanol, tetrahydrofuran or dioxane, or a mixture of such solvents. The β -trichloroethyl protecting group may be removed, for example, at a temperature in the range of 10-50 ℃ and in the presence of zinc in acetic acid. The beta-trimethylsilylethyl ester protecting group may be removed, for example, in tetrahydrofuran at a temperature in the range of 20-65 ℃ in the presence of tetrabutylammonium fluoride. Methods for converting compounds of formula (I) as defined above into pharmaceutically acceptable salts are well known in the art.

The invention further relates to compounds of formula (I) as defined above, prepared according to the process as defined above.

As mentioned above, the compounds of formula (I) according to the invention can be used as medicaments for the treatment and/or prevention of diseases which are modulated by PPAR α and/or PPAR γ agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases (such as e.g. crown disease, inflammatory bowel disease, colitis (colitis), pancreatitis, cholestasis/fibrosis of the liver, and diseases with an inflammatory component such as e.g. Alzheimer's disease or impaired/improvable cognitive function) and proliferative diseases (cancers such as e.g. liposarcoma, colon cancer, prostate cancer, pancreatic cancer and breast cancer). Preferably as a medicament for the treatment and/or prevention of non-insulin dependent diabetes mellitus.

The invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Furthermore, the present invention relates to compounds as defined above for use as therapeutically active substances, in particular for use as therapeutically active substances for the treatment and/or prevention of diseases which are modulated by PPAR α and/or PPAR γ agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases and proliferative diseases, preferably non-insulin dependent diabetes mellitus.

In another embodiment, the invention relates to a method for the treatment and/or prevention of diseases which are modulated by PPAR α and/or PPAR γ agonists, which method comprises administering a compound of formula (I) to a human being or animal. Preferred examples of such diseases are diabetes, in particular non-insulin dependent diabetes mellitus, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases and proliferative diseases, preferably for the treatment and/or prevention of non-insulin dependent diabetes mellitus.

The invention furthermore relates to the use of compounds as defined above for the treatment and/or prevention of diseases which are modulated by PPAR α and/or PPAR γ agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases and proliferative diseases, preferably non-insulin dependent diabetes mellitus.

Furthermore, the invention relates to the use of a compound as defined above for the preparation of a medicament for the treatment and/or prevention of diseases which are modulated by PPAR α and/or PPAR γ agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases and proliferative diseases, preferably non-insulin dependent diabetes mellitus. These medicaments comprise a compound as defined above.

The compounds of formula (I) may be prepared by the methods provided below, by the methods provided in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The starting materials are commercially available or can be prepared by methods analogous to those provided below, or by methods described in the literature references cited in the text or in the examples, or by methods well known in the art.

Homochiral compounds of formula (I) (compounds 10 and 11 in scheme 1 and compounds 6 and 7 in scheme 3) can be prepared according to the methods described in schemes 1 and 3 or by analogous methods.

Racemates of the compounds of formula (I) [ compounds 9 and 10 in scheme 2, and compounds 9 and 11 in scheme 4 ] can be synthesized, for example, according to the procedures described in scheme 2 or 4 or by analogous procedures. Optically pure enantiomers can then be prepared from the racemates of the compounds of formula (I) by methods known in the art, such as by separation of the enantiomers through diastereomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or by specific chromatographic methods using chiral adsorbents or chiral eluents.

Reaction scheme 1

Homochiral alpha-alkoxy-phenyl-propanoates of formula 10 and free acids of formula 11 can be prepared according to the methods described in scheme 1 or by analogous methods in the art.

The well-known chiral auxiliary 2[ (S) -4-benzyl-oxazolidin-2-one ] is condensed with alkoxy-acetyl chloride 1 in the presence of a strong base such as n-butyllithium in an inert solvent such as tetrahydrofuran at a temperature of about-78 ℃ to give building block 3 (step a). The latter is then treated with dibutylboron-triflate (dibutylboron-triflate) and a quaternary amine such as triethylamine in dichloromethane according to the prior art [ tetrahedron asymmetry (1999), 10, 1353-. In these aldol compounds 5 one of the four possible stereoisomers strongly predominates (stereochemistry as shown without strict evidence for the benzyl position). Compound 5 is converted to phenolic intermediate 8 by a three-step sequence comprising: i) ester formation is carefully controlled at temperatures from-20 ℃ to room temperature using only a minimal excess of the alcoholate in the corresponding alcohol as solvent or in a solvent such as tetrahydrofuran or dioxane to give ester compound 6 (step c); ii) removal of the benzylic hydroxy group in 6 with a reducing agent such as e.g. triethylsilane in the presence of a lewis acid such as boron trifluoride or a protic acid such as trifluoroacetic acid in a suitable solvent such as trifluoroacetic acid itself or dichloromethane at between 0 ℃ and 60 ℃ to yield the protected phenolic compound 7 (step d); iii) ensuring removal of the protecting group, e.g. benzyl, by standard techniques, e.g. catalytic hydrogenation using hydrogen and a catalyst such as palladium, or by using dimethyl sulphide and boron trifluoride diethyl etherate in a solvent such as dichloromethane between room temperature and the reflux temperature of the solvent, to provide phenolic compound 8 (step e); the order of the three reaction steps c, d, e can be interchanged, catalytic hydrogenation can also be used for the simultaneous removal of the benzylic hydroxyl function and the benzyl protecting group, preferably in the presence of an acid such as oxalic acid in a solvent such as alcohols using palladium on charcoal as catalyst at about room temperature and a hydrogen pressure of up to 100 bar.

Aryl-oxazole compounds 9 (prepared as described in schemes 6 and 7) are condensed with phenols 8 according to well known methods: if R is⁷Represents a hydroxyl group, for example by a Mitsunobu-reaction, using triphenylphosphine and di-tert-butyl-, diisopropyl-or diethyl-azodicarboxylate as reagents; the transformation is excellentOptionally in a solvent such as toluene, dichloromethane or tetrahydrofuran at ambient temperature. Alternatively, if R⁷Representing a halide, mesylate or tosylate moiety, aryl-oxazole compound 9 can be reacted with phenol 8 in a solvent such as N, N-dimethylformamide, acetonitrile, acetone or methyl-ethyl ketone at a temperature in the range of room temperature to 140 ℃, preferably at a temperature around 50 ℃ and in the presence of a weak base such as cesium carbonate or potassium carbonate to produce ether compound 10 (step f). Those may optionally be hydrolysed according to standard methods, for example by treatment with an alkaline hydroxide such as LiOH or NaOH in a polar solvent mixture such as tetrahydrofuran/ethanol/water, resulting in carboxylic acid 11 (step g). If carefully controlled reaction conditions are applied as detailed in the experimental part, hardly any racemization occurs in this reaction sequence. By chiral HPLC or by¹H-NMR-spectroscopy the optical purity of compounds 10 and 11 can be determined in the presence of chiral solvents such as 1- (9-anthracenyl) -2, 2, 2-trifluoro-ethanol, which has been found to be above 95% in all exemplified cases.

Reaction scheme 2

Aldehyde 1 (prepared as described in scheme 5) can be reacted with Wittig (Wittig) salt 2 such as (1, 2-diethoxy-2-oxoethyl) triphenylphosphonium chloride or (1, 2-dimethoxy-2-oxoethyl) triphenylphosphonium bromide in a solvent such as isopropanol, dichloromethane or tetrahydrofuran or mixtures thereof in the presence of a base such as potassium carbonate, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 1, 3, 3-tetramethylguanidine, preferably between 0 ℃ and the reflux temperature of the solvent, to provide acrylate 3 as the E and/or Z isomer (step a). Hydrogenation of acrylate 3 using palladium on charcoal as a catalyst, preferably at room temperature and 1atm hydrogen pressure, in solvents such as methanol, ethanol, tetrahydrofuran, acetic acid, dichloromethane and mixtures thereof, provides racemic ester 7, provided that the protecting group can be reductively cleaved (step e).

Alternatively, the enolate of the aldehyde 1 with the alkoxy-acetate 4 (preferably lithium enolate, prepared by treating 4 with a strong non-nucleophilic base such as lithium diisopropylamide at-78 ℃ in an inert solvent such as tetrahydrofuran) is reacted in a solvent such as tetrahydrofuran, preferably at a temperature of about-78 ℃, to provide the aldol product 5 as a mixture of diastereomers (step b). Removal of the benzylic hydroxy group, as described above for the conversion of compound 6 to compound 7 in scheme 1, yields the racemic ester 6 (step d); removal of the protecting group, e.g. benzyl, can then be carried out by standard techniques, as described for the conversion of compound 7 to compound 8 in scheme 1, to provide phenolic compound 7 (step g). Catalytic hydrogenation can also be used to convert the benzyl protected hydroxy compound 5 into phenolic compound 7 in one step (step f), as described for the conversion of compound 6 to compound 8 in scheme 1. Cleavage of the protecting function may also be carried out before removal of the benzylic hydroxyl group; in this case, similar reaction conditions as just described for the conversion of compound 5 can be chosen to remove the benzylic hydroxy group.

As an alternative method, compound 5 can be treated with a catalytic amount of an acid, such as p-toluenesulfonic acid, in a solvent such as benzene or toluene, preferably under conditions that allow removal of the water formed (e.g., using a dean-stark trap or in the presence of a molecular sieve), at a temperature between room temperature and the reflux temperature of the solvent, to yield acrylate 3 (step c).

The conversion of the phenolic intermediate 7 to the ester 9 and/or the acid 10 can be performed completely analogously as described for the homochiral phenolic intermediate in scheme 1 (steps h and i).

Reaction scheme 3

Homochirality can also be prepared by a linear synthetic sequence as depicted in scheme 3The α -alkoxy-phenyl-propanoate of formula 6 and the free acid of formula 7. Thus, starting with the condensation of aryl-oxazole synthon (synthon)1 (prepared as depicted in schemes 6 and 7) with phenol 2 (prepared as depicted in scheme 5), using the reaction types already described in scheme 1 in a different order, ether compound 3 with an aldehyde moiety is provided (step a). If R is³And/or R⁴Containing functional groups, e.g. R, which may be incompatible with the following reaction steps³And/or R⁴Possibly a phenolic OH-function, then a protecting group such as a tert-butyl-dimethyl-silyl moiety should be attached to this function. This protecting group can then be removed at an appropriate stage later in the reaction sequence.

These ether compounds 3 are then reacted with chiral synthons (compounds 3 in scheme 1) to form aldol-adducts 4 (step b). Removal of the benzylic hydroxy function in compound 4 leads to compound 5 (step c), which can be converted to the corresponding ester 6 (step d) or acid 7 (step e), respectively, as described for analogous reactions in schemes 1 and 2.

Optionally, ester compound 6 can be hydrolyzed to acid 7 (step f). By chiral HPLC or by¹H-NMR-spectroscopy the optical purity of compounds 6 and 7 can be determined in the presence of chiral solvents such as 1- (9-anthracenyl) -2, 2, 2-trifluoro-ethanol, which has been found to be above 95% in all exemplified cases.

Scheme 4, part I

Scheme 4, part II

Completely analogous to homochirality as described in connection with scheme 1Phenol intermediate 8 and aryl-oxazole compound 9 aryl-oxazole compound 2 (prepared as described in schemes 6 and 7) is condensed with phenol 1 or aldehyde 6 (prepared as described in scheme 5); thus, an ether compound 3 or an aldehyde 5 is obtained (step a). The former is then bromomethylated, for example by treatment with trioxane and HBr, preferably 62% aqueous HBr, in an inert solvent, preferably dichloromethane, preferably at 0 ℃, yielding a highly reactive, often very unstable electrophile 4 (step b). Electrophiles 4 are suitable for alkylating alkoxy-acetates 7 (R)⁶Lower alkyl), preferably lithium enolate, prepared by treatment of 4 with a strong non-nucleophilic base such as lithium diisopropylamide in an inert solvent such as tetrahydrofuran at-78 ℃ to give ester 9 (step d). To increase the reactivity of the enolate nucleophile, the reaction is preferably carried out in the presence of a co-solvent such as Hexamethylphosphoramide (HMPA) or 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU).

Alternatively, as described for a similar reaction of compound 1 and compound 4 in scheme 2, aldehyde compound 5 is reacted with an enolate of alkoxy-acetate 7 to yield aldol product 8 as a mixture of diastereomers (step e), said aldehyde compound 5 also being obtainable from ether intermediate 3 (step c) by Vilsmeier formylation or by formylation using dichloromethyl ether in the presence of titanium tetrachloride, preferably in dichloromethane at a temperature between-78 ℃ and the solvent reflux temperature. Removal of the benzylic hydroxy group in compound 8 results in the racemic ester 9 (step f), as described for analogous reactions in schemes 1, 2 and 3, respectively.

Alternatively, as described for the conversion of compound 1 to compound 3 in scheme 2, aldehyde 5 can be reacted with a Wittig salt yielding acrylate 10 as E and/or Z isomer (step g). As described for analogous reactions in scheme 2, hydrogenation of acrylate 10 leads to compound 9 (step h). Completely analogous to that described for homochiral compound 10 in scheme 1, hydrolysis of racemic ester compound 9 can be performed, leading to carboxylic acid 11 (step i).

Aldehyde 4 (scheme 1), aldehyde 1 (scheme 2), aldehyde 2 (scheme 3), and aldehyde 6 (scheme 4) are known or can be synthesized by methods known in the art. An example of a possible synthesis of these key intermediates is given in scheme 5.

Reaction scheme 5

Known phenols 1 can be converted into aldehydes 3 by known formylation reactions such as, for example, Vilsmeier formylation, by treatment with hexamethylenetetramine under acidic conditions, for example in the presence of sulfuric acid, or preferably with trifluoroacetic acid as solvent between 0 ℃ and the reflux temperature of trifluoroacetic acid, or by formylation with dichloromethyl ether in the presence of titanium tetrachloride, preferably in dichloromethane between-78 ℃ and the reflux temperature of the solvent (step a); alternatively, a two-step approach may be used: the halogen atom is introduced para, for example by using N-bromo-or N-iodo-succinimide, for example in a mixture of concentrated sulfuric acid and tetrahydrofuran, preferably at ambient temperature, followed by metal halogen exchange by treatment with an alkyl-lithium reagent, such as N-butyllithium, preferably at a temperature of about-78 ℃, and quenching with a formyl transfer reagent, such as N, N-dimethylformamide or N-formyl-piperidine (steps b and c). Alternatively, a carbonylation reaction may be used to introduce formyl groups in step c, for example by using sodium formate, bis (triphenylphosphine) palladium (II) dichloride and CO gas in a solvent such as N, N-dimethylformamide at a temperature of preferably about 100 ℃.

Reaction scheme 6

Aldehyde 1 is commercially available or known. In hydroxy acids, typically in accordance with the previous literature (Diels, O.; Riley, K.; Chem Ber (1915), 48, 897)They condense with diketo-monooxime 2 in a polar solvent such as AcOH in the presence of HCl to give oxazole-N-oxide 3 (step a). Followed by refluxing with POCl in dichloromethane₃Treatment to afford the corresponding primary chloride 4(Goto, y.; Yamazaki, m.; Hamana, m.; Chem Pharm Bull (1971), 19, 2050, step b. primary chloride 4 used as such, is converted to the corresponding primary alcohol in a very exact manner [ e.g. using acetic acid in the presence of sodium iodide, potassium carbonate at elevated temperature followed by saponification of the acetate formed (e.g. using lithium hydroxide at room temperature in ethanol/water))]. Alternatively, the primary chloride 4 is further passed through S using NaCN_N2-reaction work-up, via nitrile 5 (step c), exhaustive hydrolysis (step d) and reduction (step e), for example using borane in tetrahydrofuran, gives structural unit 7. The hydroxy-ethyl compound 7 or hydroxymethyl compound prepared from primary chloride 4 corresponds to or can be converted into compound 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4), for example by treatment with methanesulfonyl chloride in dichloromethane in the presence of a base such as triethylamine, preferably in a temperature range between-20 ℃ and room temperature, or by reaction with carbon tetrachloride or carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in a temperature range between room temperature and the reflux temperature of the solvent; this gives compound 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4), respectively, as a methanesulfonyl ester, chloride or bromide.

R²4-chloromethyl-2-aryl or 2-heteroaryl-oxazole 4, which is equal to hydrogen, is preferably prepared from the corresponding aryl or heteroaryl carboxamides and 1, 3-dichloroacetone as described, for example, in bioorg.Med.chem.Lett. (2000), 10(17), 2041-.

Reaction scheme 7

N-acyl-glycinates 1 are commercially available, known or accessible via N-acylPreparation of the basic standard procedure. Monoallylated ester 2 can be readily obtained by double deprotonation with a strong acid, a non-nucleophilic base such as LiHMDS in an aprotic solvent such as THF, typically at-78 ℃, followed by treatment with allyl bromide to selectively yield the C-alkylated product 2 (step a). Standard hydrolysis yields the intermediate acid 3 (step b), which is then converted to compound 4 (step c) according to well established literature (j.med. chem. (1996), 39, 3897). The ring closure to oxazole using trifluoroacetic acid and trifluoroacetic anhydride or Burgess-reagent (methyl-N-triethylammoniumsulfonyl-carbamate) gives the key intermediate 5 (step d), which is finally processed to the target alcohol 6 by hydroboration, e.g. using 9-BBN in THF and subsequently H₂O₂And NaOH oxidation process (step e). Alcohol 6 corresponds to or can be converted into compound 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4), for example by treatment with methanesulfonyl chloride in dichloromethane in the presence of a base such as triethylamine, preferably in a temperature range between-20 ℃ and room temperature, or by reaction with carbon tetrachloride or carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in a temperature range between room temperature and the reflux temperature of the solvent; this gives compound 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4), respectively, as a methanesulfonyl ester, chloride or bromide.

The following tests were carried out in order to determine the activity of the compounds of formula (I).

Background information on the experiments performed can be found in the following documents: nichols JS et al, "Development of scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain" ("Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain"), (1998) - "annual biochemical analysis (anal. biochem.) 257: 112-119.

Full-length cDNA clones of human PPAR α and mouse PPAR γ were obtained from human adipocytes and mouse hepatic cRNA, respectively, by RT-PCR, cloned into plasmid vectors and verified by DNA sequencing. Bacterial and mammalian expression vectors were constructed to produce glutathione-s-transferase (GST) and Gal4DNA binding domain proteins fused to the Ligand Binding Domains (LBD) of PPAR γ (aa 174-476) and PPAR α (aa 167-469). To accomplish this step, portions of the cloned sequences encoding LBDs are amplified from the full-length clones by PCR and then subcloned into plasmid vectors. The final clones were verified by DNA sequence analysis.

The induction, expression and purification of the GST-LBD fusion protein was carried out by standard methods in E.coli strain BL21(pLysS) cells (reference: Current protocols in Molecular Biology, Wiley Press, edited by Ausubel et al).

Radioligand binding assays

PPAR α receptor binding was tested in TKE10(10mM Tris-HCl, pH 8, 50mM KCl, 2mM EDTA, 0.1mg/ml fatty acid free BSA and 10mM DTT). For each of the 96 wells, 2.4ug of an equivalent amount of GST-PPAR α -LBD fusion protein and a radioligand, e.g., 40000dpm 2(S) - (2-benzoyl-phenylamino) -3- {4- [1, 1-ditritio-2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -propionic acid, were incubated in 100ul volume for 2 hours at RT. Bound ligand was removed from unbound ligand by solid phase separation using MultiScreen plates (Millipore) filled with 80ul SG25 according to the manufacturer's recommendations.

PPAR γ receptor binding was tested in TKE50(50mM Tris-HCl, pH 8, 50mM KCl, 2mM EDTA, 0.1mg/ml fatty acid free BSA and 10mM DTT). For each of the 96 well reactions, 140ng aliquots of GST-PPAR γ -LBD fusion protein were bound to 10ug SPA beads (pharmacia Amersham) in a final volume of 50ul by shaking. The resulting slurry was incubated at RT for 1 hour and centrifuged at 1300g for 2 minutes. The supernatant containing unbound protein was removed and the semidry pellet containing the receptor-coated beads was redissolved in 50ul TKE. For radioligand binding, 10000dpm 2(S) - (2-benzoyl-phenylamino) -3- {4- [1, 1-ditritio-2- (5-methyl) -are added in a volume of 50ul2-phenyl-oxazol-4-yl-ethoxy]-phenyl } -propionic acid, the reaction system was incubated for 1 hour at RT and scintillation proximity counting was performed. All binding assays were performed on 96-well plates and the amount of bound ligand was determined on a Packard TopCount using OptiPlates (Packard). At 10 is^-4Non-specific binding is determined in the presence of M unbound compound. 10 were made in triplicate^-10M-10^-4Dose response curves over the range of M concentrations.

Luciferase transcriptional reporter assay

Baby hamster kidney cells (BHK21ATCC CCL10) were grown at 37 ℃ and 95% O2: 5% CO₂DMEM medium containing 10% FBS in air. At 10⁵Density of cells/well cells were seeded on 6-well plates and then batch transfected with either the pFA-PPAR γ -LBD or pFA-PPAR α -LBD expression plasmid + a reporter plasmid and an expression plasmid encoding a secretable form of alkaline phosphatase (SEAP) as a normalization control. Transfection was accomplished using Fugene 6 reagent (Roche Molecular Biochemicals) according to the suggested protocol. Cells were harvested by trypsinization 6 hours after transfection and 10 hrs⁴The density of individual cells/well was seeded on 96-well plates. After 24 hours to allow the cells to adhere, the medium was removed and replaced with 100ul of medium without phenol red and containing the test substance or control ligand (final concentration 0.1% DMSO). After incubation of the cells with the material for 24 hours, 50ul of the supernatant was recovered and analyzed for SEAP activity (Roche Molecular Biochemicals). The remaining supernatant was discarded, 50ul PBS per well followed by one volume of luciferase Constant-Light reagent (Roche Molecular Biochemicals) to lyse the cells and initiate the luciferase reaction. Luminescence of SEAP and luciferase was measured using a Packard TopCount. Luciferase activity was calibrated against the SEAP control and transcriptional activation in the presence of the test substance was expressed as fold-activation in cells incubated in the absence of the substance. EC50 values were calculated using the XLfit program (ID Business Solutions ltd. uk).

Free acids of the Compounds of the invention(R⁶Is hydrogen) shows IC for PPAR α and PPAR γ₅₀The value is 0.1nM to 50. mu.M, preferably 1nM to 10. mu.M. These compounds further show EC for PPAR α and PPAR γ₅₀The value is 0.1nM to 50. mu.M, preferably 1nM to 10. mu.M. Wherein R is⁶Compounds other than hydrogen are converted in vivo to compounds in which R⁶Is a compound of hydrogen. The following table shows the measured values for some selected compounds of the invention and compounds already known in the art (e.g.Rosiglitazone, Drugs 1999, Vol 57(6), 921-) 930).

	PPARαIC	PPARγIC	PPARαEC	PPARγEC
	PPARαIC	PPARγIC	PPARαEC	PPARγEC	Example 2	30nmol/l	58nmol/l	163nmol/l	115nmol/l
Example 3	87nmol/l	506nmol/l	57nmol/l	87nmol/l	Example 2	30nmol/l	58nmol/l	163nmol/l	115nmol/l
Example 3	87nmol/l	506nmol/l	57nmol/l	87nmol/l	Example 5	155nmol/l	146nmol/l	38nmol/l	124nmol/l
Example 9	196nmol/l	129nmol/l	21nmol/l	33nmol/l	Example 5	155nmol/l	146nmol/l	38nmol/l	124nmol/l
Example 9	196nmol/l	129nmol/l	21nmol/l	33nmol/l	Example 17	73nmol/l	31nmol/l	186nmol/l	174nmol/l
Example 23	52nmol/l	48nmol/l	306nmol/l	138nmol/l	Example 17	73nmol/l	31nmol/l	186nmol/l	174nmol/l
Example 23	52nmol/l	48nmol/l	306nmol/l	138nmol/l	Example 25	177nmol/l	129nmol/l	26nmol/l	75nmol/l
Example 29	2380nmol/l	1730nmol/l	213nmol/l	678nmol/l	Example 25	177nmol/l	129nmol/l	26nmol/l	75nmol/l
Example 29	2380nmol/l	1730nmol/l	213nmol/l	678nmol/l	Example 37	74nmol/l	318nmol/l	14nmol/l	12nmol/l
Example 43	131nmol/l	33nmol/l	150nmol/l	57nmol/l	Example 37	74nmol/l	318nmol/l	14nmol/l	12nmol/l
Example 43	131nmol/l	33nmol/l	150nmol/l	57nmol/l	Rosiglitazone	Non-reactive	1090nmol/l	Non-reactive	405nmol/l

The compounds of formula (I) and pharmaceutically acceptable salts and esters thereof may be used as medicaments, for example, in the form of pharmaceutical preparations for enteral, parenteral or topical administration. For example, the compounds of formula (I) and pharmaceutically acceptable salts and esters thereof may be administered orally, e.g., in the form of tablets, coated tablets, lozenges, hard and soft capsules, solutions, emulsions or suspensions; by rectal administration, e.g. in the form of suppositories

(I) And pharmaceutically acceptable salts and esters thereof; the compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, are administered parenterally, for example in the form of injections or infusions; or by topical administration, for example in the form of ointments, creams or oils, of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.

The preparation of pharmaceutical preparations can be carried out in a manner known to those skilled in the art by bringing the compounds of formula (I) and their pharmaceutically acceptable salts or esters into a galenical administration form together with suitable nontoxic inert therapeutically compatible solid or liquid carrier materials and, if desired, customary pharmaceutical auxiliaries.

Suitable support materials are not only inorganic support materials but also organic support materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Carrier materials for soft capsules are, for example, vegetable oils, waxes, fats and semi-solid liquid polyols (depending on the nature of the active ingredient, however, no carrier is required in the case of soft capsules). Suitable carrier substances for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier substances for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier substances for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, thickeners, flavoring agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) may vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will of course be adapted to the individual requirements in each particular case. For adult patients, a daily dosage of about 0.1mg to about 1000mg, especially about 0.1mg to about 100mg, is contemplated. The daily dose is suitably administered in several dosage units, depending on the dose.

The pharmaceutical formulation conveniently contains from about 0.05 to 500mg, preferably from 0.05 to 100mg, of the compound of formula (I).

The following examples serve to illustrate the invention in more detail. However, these examples are not intended to limit the scope of the present invention in any way.

Examples

Abbreviations:

AcOEt ═ ethyl acetate; AcOH ═ acetic acid, nBu₂BOTf ═ dibutyl boron triflate; n-BuLi ═ n-butyllithium; DBAD ═ di-tert-butyl azodicarboxylate; DBU ═ 1, 8-diazabicyclo [5.4.0]Undec-7-ene; DEAD ═ diethyl azodicarboxylate; DIAD ═ diisopropyl azodicarboxylate; DMPU ═ 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone; eq. ═ equivalent; h is h; HPLC ═ high performance liquid chromatography; LDA ═ lithium diisopropylamide (lithium diisopropylamide); min is minutes; POCl₃(ii) phosphoryl chloride; THF ═ tetrahydrofuran.

Example 1

a ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

(S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (12.45g, 47mmol) (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumawang, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) was dissolved in anhydrous dichloromethane (270ml) under argon atmosphere and the solution was cooled to-78 ℃. Triethylamine (7.98ml, 57mmol) was added followed by slow addition of di-n-butyl boron triflate over about 20 minutes(1M solution in dichloromethane, 50ml, 50mmol) to keep the reaction temperature below-70 ℃. The mixture was stirred at-78 ℃ for 50 minutes, the cooling bath was replaced by an ice bath, the mixture was stirred at 0 ℃ for an additional 50 minutes, after which it was cooled again to-78 ℃. A solution of 4-benzyloxy-2-methyl-benzaldehyde (10.7g, 47mmol) in anhydrous dichloromethane (130ml) was added over about 45 minutes to keep the reaction temperature below-70 ℃. The resulting mixture was stirred at-78 ℃ for 45 minutes, warmed from-78 ℃ to 0 ℃ and stirred at 0 ℃ for an additional 1.5 hours. The reaction mixture was poured into ice water/brine and extracted twice with dichloromethane. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 22.3g (45.6mmol, 96%) of the title compound as colorless oil. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：512.3(M+Na)⁺，472.3，447.2，387.2，327.2，295.3，267.3，232.1，175.1。

b ] (2S, 3R) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

5.4M sodium methoxide solution (7.3ml, 39.5mmol) was added to ice-cooled and stirred (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionyl]-a suspension of oxazolidin-2-one (17.6g, 36mmol) in dry methanol (87 ml). The mixture was stirred at 0 ℃ for 15 minutes and quenched and neutralized by addition of dilute aqueous hydrochloric acid (1.0M). The solution was concentrated under reduced pressure and the residue was dissolved in ice water/ethyl acetate 1/1. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 8.6g (25mmol, 69%) of the title compound as a pale yellow oil. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：367.2(M+Na)⁺，362.2(M+NH₄)⁺，327.3，299.3，239.3，211.2。

c ] (2S) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-propionic acid methyl ester

Triethylsilane (23ml, 145mmol) was added to a vigorously stirred, ice-cold solution of (2S, 3R) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester (5g, 14.5mmol) in trifluoroacetic acid (84ml) under an argon atmosphere. The mixture was stirred at 0 ℃ for 30 minutes and at room temperature for another 2 hours. The solution was poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed twice with water and neutralized with saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 2.15g (6.5mmol, 45%) of the title compound as colorless oil.

MS：351.2(M+Na)⁺，346.3(M+NH₄)⁺，283.2，276.2，223.2，195.5。

d ] (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester

A solution of (2S) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-propionic acid methyl ester (3.6g, 11mmol) in methanol (300ml) was hydrogenated over 10% palladium on charcoal (1g) at room temperature for 2 h. The catalyst was filtered off and the solvent was evaporated under reduced pressure to yield 2g (8.4mmol, 77%) of the title compound as a yellow liquid which was used in the next step without further purification.

MS：261.2(M+Na)⁺，256.1(M+NH₄)⁺，239.3(M+H)⁺，193.2，151.1。

e ] 4-chloromethyl-5-methyl-2-o-tolyl-oxazole

2-methyl-benzaldehyde (19.3ml, 166mmol) was dissolved in acetic acid (175ml) and treated with diacetyl monoxime (16.8g, 166 mmol). An anhydrous HCl flow was bubbled through the solution (slightly exothermic) at 0 ℃ for 2 hours, and at room temperature for an additional 2 hours. Will be reversedThe mixture was poured onto ice water and extracted twice with dichloromethane. The combined extracts were washed with water, saturated aqueous sodium bicarbonate (until pH 8 was adjusted) and brine. The organic layer was dried over sodium sulfate and the solution was concentrated under reduced pressure to a volume of about 100 ml. Chloroform (200ml) was added and the volume of the solution was made about 100ml under reduced pressure. Chloroform (100ml) was added and the solution of crude 4, 5-dimethyl-2-o-tolyl-oxazole 3-oxide was cooled to 0 ℃. A solution of phosphorus oxychloride (16.7ml, 183mmol) in chloroform (175ml) was added over 10 minutes. The reaction mixture was heated at reflux for 12 hours, cooled to 0 ℃ and concentrated NH was added carefully₃The aqueous solution was made alkaline (pH 10). The suspension was poured onto ice water and the two layers were extracted with dichloromethane. The combined extracts were washed with ice water/brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 29g (131mmol, 79%) of the title compound as a yellow oil which solidified upon standing.

MS：221.1(M)⁺，186.1，118.0，89.0，43.1。

f ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

A mixture of (S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (80mg, 0.34mmol), 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (82mg, 0.37mmol), cesium carbonate (120mg, 0.37mmol) and a trace of potassium iodide was suspended in acetone (8 ml). The suspension was heated at reflux for 5 h, the solvent was evaporated under reduced pressure and the residue was dissolved in 2N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 100mg (0.24mmol, 70%) of the title compound as a yellow oil.

MS：446.2(M+Na)⁺，424.3(M+H)⁺，345.1，269.2，229.2，215.4，186.3。

g ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

To a solution of (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester (100mg, 0.24mmol) in THF/methanol 2/1(1.5ml) was added 1N aqueous LiOH (1.4ml, 1.4 mmol). The reaction mixture was stirred at ambient temperature for 1.5 hours, neutralized with 1N aqueous HCl under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to afford the title compound (88mg, 0.21mmol, 91%) as an off-white solid which crystallized from dichloromethane/hexane to afford anhydrous crystals. According to chiral HPLC (Chiralcel-ODH) of the corresponding methyl ester, the enantiomeric excess reached 98.6%.

MS：408.5(M-H)^-，362.3，305.4，280.9，255.1，216.6。

Example 1a

a ]3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester (mixture of stereoisomers)

To a 2M solution of lithium diisopropylamide (305mmol) in THF/n-heptane (152.4ml) at-78 deg.C was added a solution of ethoxy-ethyl acetate (45.2ml, 331mmol) in tetrahydrofuran (240ml) under an argon atmosphere over 1.5 hours. The mixture was stirred for 30 minutes. A solution of 4-benzyloxy-2-methyl-benzaldehyde (30g, 132.6mmol) in tetrahydrofuran (420ml) was added dropwise over a period of 50 minutes. The reaction mixture was stirred at-78 ℃ for 2 hours, poured onto ice water/aqueous ammonium chloride 1/1 and extracted twice with ethyl acetate. The combined extracts were washed three times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, n-heptane/AcOEt) to give 48.8g (136.2mmol) of the title compound as a mixture of stereoisomers as a yellow oil.

MS：376.4(M+NH₄)⁺，341.4，186.5。

b ] (Z) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-acrylic acid ethyl ester

To a solution of 3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester (mixture of stereoisomers; 48.8g, 136.2mmol) in N, N-dimethylformamide (500ml) was added sulfuric acid (19.6ml, 96%). The reaction mixture was heated to 100 ℃ for 2.5 h, cooled to ambient temperature, poured onto ice water/saturated aqueous NaHCO3 solution 1/1 and extracted twice with ethyl acetate. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 46.1g (135.4mmol) of crude (Z) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-acrylic acid ethyl ester, which was used in the next step without further purification.

MS：358.3(M+NH₄)⁺，341.4(M+H)⁺，292.4，222.4，187.4。

c ] (Z) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -acrylic acid ethyl ester

To a solution of (Z) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-acrylic acid ethyl ester (46.1g, 135.4mmol) in dichloromethane (500ml) was added BF 3. OEt₂(186ml, 677mmol, 46%) and dimethylsulfide (149ml, 2.03 mol). The reaction mixture was stirred at ambient temperature for 14 hours, poured onto ice water and extracted twice with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, n-heptane/AcOEt) to give 23.1g (92.3mmol, 68% in all three steps) of the title compound as yellow crystals.

MS：248.9(M+H)^-，219.9。

d ] (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester

In analogy to the procedure described in example 1f ], (Z) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -acrylic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1f ]) in the presence of cesium carbonate and potassium iodide to yield (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester as colorless crystals.

MS：458.4(M+Na)⁺，436.4(M+H)⁺，291.5，187.5。

e ] (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid

To a solution of (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester (6.8g, 15.6mmol) in THF/methanol 2/1(102ml) was added 3M aqueous NaOH (26ml, 78 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, concentrated under reduced pressure, diluted with ice water and acidified with 1M aqueous HCl. Double extraction with ethyl acetate followed by washing the combined extracts with ice water/brine 1/1 (three times) and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the crude product was crystallized from dichloromethane/n-heptane to give the title compound (6.3g, 15.5mmol, 99%) as colorless crystals.

MS：406.3(M-H)^-，334.2，255.2。

f ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

Analogously to example 6a c]The process comprises reacting (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl]Hydrogenation of acrylic acid at 40 ℃ under 60 bar of hydrogen in dichloromethane/methanol/30% aqueous NaOH for 16 h, using [ Ru (OAc)₂((+)-TMBTP)]The catalyst, after processing, produced a black solid with an enantiomeric purity of 93% according to HPLC and a chemical purity of > 99%. The crude product was purified by column chromatography (silica gel, n-heptane/AcOEt/AcOH, twice) to afford brown crystals which were recrystallized from ethyl acetate to afford the title compound as off-white crystals. According to chiral HPLC (Chiralcel-ODH column, 25 cm. times.4.6 mm, 97% heptane/3% isopropanol, 0.15% trifluoroacetic acid, flowing at 0.8ml/min, 25 ℃, 274 nm. Retention time: 19.3min for R-acid, 21.6min for S-acid, 28.2min for alpha, beta-unsaturated Z-acid), and the enantiomeric excess reaches 99.8 percent.

MS：408.3(M-H)^-，362.2。

Example 2

a ]2- (4-isopropoxy-phenyl) -4, 5-dimethyl-oxazole 3-oxide; hydrochloride salt

To a suspension of diacetylmonoxime (1g, 9.9mmol) and 4-isopropoxy-benzaldehyde (1.6g, 9.9mmol) in acetic acid (10ml), anhydrous hydrogen chloride was bubbled under ice-cooling for 30 minutes, and at ambient temperature for another 45 minutes. The reaction mixture was cooled to 0 ℃, diethyl ether (25ml) was added over 5 minutes, and the formed precipitate was filtered off and washed with ice-cold diethyl ether to give the title compound (2.5g, 8.8mmol, 89%) as colorless crystals.

MS：247.2(M-HCl)⁺，205.1，188.1，121.2，93.2，43.3。

b ] 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole

To 2- (4-isopropoxy-phenyl) -4, 5-dimethyl-oxazole 3-oxide over 5 minutes; a solution of the hydrochloride salt (2.5g, 8.8mmol) in chloroform (12ml) was added to a solution of phosphorus oxychloride (1ml, 11mmol) in chloroform (12 ml). The reaction mixture was heated at reflux for 45 minutes, cooled to 0 ℃ and concentrated NH was added carefully₃The aqueous solution was made alkaline (pH 10). The suspension was poured onto ice water and extracted twice with dichloromethane. The combined extracts were washed with ice water/brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a brown oil which was purified by column chromatography (silica gel, dichloromethane) to give 1.6g (6mmol, 60%) of the title compound as colorless oil.

MS：266.3(M+H)⁺，224.2，188.3。

c ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (example 1d ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：490.2(M+Na)⁺，468.2(M+H)⁺，269.2，230.2，188.3。

d ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless solid.

MS：452.3(M-H)^-，343.0，283.3，246.8，218.7。

Example 3

a ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (example 1d)) was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] propionic acid methyl ester as colorless liquid.

MS：432.3(M+Na)⁺，410.3(M+H)⁺，293.2，269.2，187.2，172.2。

b ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenylpropionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless solid, which was crystallized from hexane/dichloromethane to give colorless crystals. The enantiomeric excess reached 99.0% according to chiral HPLC of the corresponding methyl ester (Chiralcel-OJ).

MS：394.2(M-H)^-，348.2，293.2，223.1。

Example 3a

a ] (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester

In analogy to the procedure described in example 1f ], (Z) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -acrylic acid ethyl ester (example 1a c ]) was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole (example 3a ]) in the presence of cesium carbonate and potassium iodide to yield (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester as colorless solid.

MS：444.3(M+Na)⁺，422.5(M+H)⁺，267.5，213.5。

b ] (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid

In analogy to the procedure described in example 1a f ], (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid ethyl ester was treated with NaOH to obtain (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -acrylic acid as colorless solid.

MS：394.3(M+H)⁺，279.3，249.3。

c ] (S) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] propionic acid

Analogously to example 6a c]The process comprises reacting (Z) -2-ethoxy-3- [ 2-methyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl]Hydrogenation of acrylic acid in a 35ml autoclave at 60 bar hydrogen pressure in dichloromethane/methanol/30% aqueous NaOH 1/1/0.03 at 40 ℃ for 16 h, using [ Ru (OAc ]₂((+)-TMBTP)]The catalyst, after processing, produced a black solid with an enantiomeric purity of 93% according to HPLC and a chemical purity of > 99%. The crude product was purified by column chromatography (silica gel, n-heptane/AcOEt/AcOH, twice) to afford brown crystals which were recrystallized from ethyl acetate to afford the title compound as colorless crystals. The enantiomeric excess was 99.2% according to chiral HPLC (Chiralcel-OJH column, 25 cm. times.4.6 mm, 80% heptane/20% ethanol, 1.5% trifluoroacetic acid in 0.8ml/min flow, 25 ℃, 275 nm. retention time, R-acid 26.4min, S-acid 29.1min, alpha, beta-unsaturated Z-acid 32.6 min).

MS：394.2(M-H)^-，348.2。

Example 4

a ] (S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (example 1d)]) And 4-chloromethyl-2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazole (prepared from 3, 5-dimethoxy-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to yield (S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-methyl-phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：492.2(M+Na)⁺，470.1(M+H)⁺，273.2，232.1，205.2，164.2。

b ] (S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- {4- [2- (3, 5-dimethoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid as colorless solid.

MS：454.3(M-H)^-，408.2，364.1，305.0，255.0，223.1。

Example 5

a ]2- (4-fluoro-3-methyl-phenyl) -4, 5-dimethyl-oxazole 3-oxide

To a suspension of diacetylmonoxime (11g, 108.6mmol) and 4-fluoro-3-methyl-benzaldehyde (15g, 108.6mmol) in acetic acid (100ml) was bubbled anhydrous hydrogen chloride under ice-cooling for 30 minutes, and at ambient temperature for another 45 minutes. The reaction mixture was poured onto ice water and extracted twice with ethyl acetate. The combined extracts were washed with ice water, saturated aqueous sodium bicarbonate (until adjusted to pH 8) and brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (12.3g, 55.6mmol, 51%) as yellow crystals.

MS：222.1(M+H)⁺，205.1，176.1，137.1，109.1。

b ] 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole

In analogy to the procedure described in example 2b ], 2- (4-fluoro-3-methyl-phenyl) -4, 5-dimethyl-oxazole 3-oxide was treated with phosphorus oxychloride in chloroform to give 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole as colorless solid.

MS：239.0(M)⁺，204.1，136.1，43.2。

c ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (example 1d ]) was reacted with 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：464.2(M+Na)⁺，442.2(M+H)⁺，349.1，317.0，280.2，245.2，204.1。

d ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless solid.

MS：426.1(M-H)^-，348.4，263.2，174.8。

Example 6

a ] (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester (example 1d)]) With 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：450.2(M+Na)⁺，428.3(M+H)⁺，368.0，231.2，190.3。

b ] (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless solid which was crystallized from hexane/dichloromethane to give colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-ODH), the enantiomeric excess was up to 99.4%.

MS：412.3(M-H)^-，366.5，278.4，254.9，223.1。

Example 6a

a ] (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -acrylic acid ethyl ester

In analogy to the procedure described in example 1f ], (Z) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -acrylic acid ethyl ester (example 1a c ]) was reacted with 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (example 6a ]) in the presence of cesium carbonate and potassium iodide to yield (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -acrylic acid ethyl ester as colorless crystals.

MS：462.4(M+Na)⁺，440.4(M+H)⁺，206.4。

b ] (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -acrylic acid

In analogy to the procedure described in example 1a f ], (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -acrylic acid ethyl ester was treated with NaOH to obtain (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -acrylic acid as colorless solid.

MS：412.4(M+H)⁺。

c ] (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In a glove box (O)₂Content ≤ 2ppm) with 11.5g of (Z) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl } -acrylic acid (28.0mmol), 35ml dichloromethane, 35ml methanol, 2.5ml 30% aqueous NaOH (14.0mmol) and 22.6mg (0.028mmol) [ Ru (OAc)₂((+)-TMBTP)]The autoclave was filled with 185ml stainless steel. TMBTP is 4, 4 '-bis (diphenylphosphino) -2, 2', 5, 5 '-tetramethyl-3, 3' -dithiophene, the synthesis of which as (R) or (S) enantiomer is described in WO 96/01831 application by italfarmco Sud and in t.benincori et al, j.org.chem.2000, 65, 2043. The complex [ Ru (OAc) ] has been synthesized analogously to the conventional method reported in N.Feiken et al, Organometallic 1997, 16, 537)₂((+)-TMBTP)]，³¹P-NMR(CDCl₃): 61.4 ppm. The autoclave was sealed and charged with hydrogen under 60 bar of hydrogen with stirring at 40 ℃. After 16 hours, the autoclave was opened and the yellowish-brown solution was rotary evaporated to dryness (50 ℃ C./5 bar). The residue was dissolved in 60ml of ethyl acetate, 60ml of water and 3ml of aqueous hydrochloric acid (25%). The organic layer was separated and evaporated to dryness (50 ℃/5 bar) to afford 12g of crude solid product, 92% enantiomeric purity and > 99% chemical purity according to HPLC. The crude product was dissolved in dichloromethane, (S) -phenethylamine (4.12ml, 31.1mmol) was added and the solvent was removed under reduced pressure. The brown residue was crystallized from ethyl acetate to give colorless crystals, which were suspended in ice water/ethyl acetate 1/1. The suspension was adjusted to pH 1 with 1M aqueous hydrochloric acid, the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was removed in vacuo to give colorless crystals which were recrystallized from ethyl acetate to give 8.45g (20.4mmol, 73%) of the title compound as colorless crystals. According to chiral HPLC (Chiralcel-ODH column, 25 cm. times.4.6 mm, 97% heptane/3% isopropanol, containing 0.15% trifluoroacetic acid, flowing at 0.7ml/min, 25 ℃, 274 nm. retention time: R-acid 30.2min, S-acid 32.8min,. alpha.,. beta. -Unsaturated Z-acid 39.1min), enantiomeric excess up to 100%.

MS：412.0(M-H)^-。

Example 7

a ] (S) -4-benzyl-3- [ (2S) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-propionyl ] -oxazolidin-2-one

In analogy to the procedure described in example 1c ], (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one (example 1a ]) was treated with triethylsilane in trifluoroacetic acid to yield the title compound as colorless liquid.

MS：496.2(M+Na)⁺，491.3(M+NH₄)⁺，474.2(M+H)⁺，428.3，352.3，251.2，175.2。

b ] (S) -4-benzyl-3- [ (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionyl ] -oxazolidin-2-one

In analogy to the procedure described in example 1d ], (S) -4-benzyl-3- [ (2S) -3- (4-benzyloxy-2-methyl-phenyl) -2-ethoxy-propionyl ] -oxazolidin-2-one was hydrogenated over 10% palladium on charcoal to provide the title compound as yellow liquid.

MS：382.1(M-H)^-，324.9，305.1，282.9，261.8，255.2，221.4，175.6。

c ] (S) -4-benzyl-3- [ (2S) -3- (4- {2- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -2-ethoxy-propionyl ] -oxazolidin-2-one

To an ice-cold solution of (S) -4-benzyl-3- [ (2S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionyl ] -oxazolidin-2-one (100mg, 260 μmol), 2- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-yl ] -ethanol (93mg, 390mol (prepared from methyl 3-oxopentanoate and 4-chloro-benzamide analogously to the sequence described for the synthesis of 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethanol in m.salalone, PCT WO 01/79202a 1) and triphenylphosphine (103mg, 390 μmol) in tetrahydrofuran (2.5ml) was added diethyl azodicarboxylate (61 μ l, 390. mu. mol). The cooling bath was removed and stirring continued for 12 hours. Evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 70mg (120. mu. mol, 45%) of the title compound as colorless oil.

MS：626.3(M+Na)⁺，603.2(M)⁺，557.2，479.3，381.2，351.1，273.3，187.2。

d ] (S) -3- (4- {2- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -2-ethoxy-propionic acid

(S) -4-benzyl-3- [ (2S) -3- (4- {2- [2- (4-chloro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -2-ethoxy-propionyl ] -oxazolidin-2-one (70mg, 120. mu. mol) was dissolved in ice-cooled THF (0.7ml) and treated with 1N NaOH (0.3ml, 300. mu. mol) at 0 ℃ for 2 h. The reaction mixture was poured onto ice water, extracted twice with diethyl ether and the combined organic layers were washed with ice water. The combined aqueous layers were acidified with 1N HCl and extracted twice with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvent gave 47mg (110. mu. mol, 91%) of the title compound as a yellow liquid.

MS：442.1(M-H)^-，396.1，362.0，223.6，176.4。

Example 8

a ] 1-ethyl-3- (phenylmethoxy) -benzene

To a suspension of potassium carbonate (17g, 123mmol) in N, N-dimethylformamide (40ml) at 2 ℃ under an argon atmosphere was added a solution of 3-ethyl-phenol (14.8ml, 123mmol) in N, N-dimethylformamide (40 ml). After stirring for 50 min at 2 ℃ benzyl bromide (14.6ml, 123mmol) was added over 15 min at 2 ℃. The suspension was stirred at 2 ℃ for a further 30 minutes and at ambient temperature for 12 hours. After addition of ice water (250ml), the solution was extracted twice with diethyl ether. The combined extracts were washed 2 times with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane) to give 24.3g (114mmol, 93%) of the title compound as a yellow liquid.

MS：212.2(M+H)⁺，183.1，91.2，65.1。

b ] 1-bromo-2-ethyl-4- (phenylmethoxy) -benzene

To a solution of 1-ethyl-3- (phenylmethoxy) -benzene (15g, 71mmol) in THF (200ml) was added N-bromosuccinimide (16.3g, 92mmol) and concentrated sulfuric acid (2.4 ml). The solution was stirred at ambient temperature for 5 hours. Sodium bicarbonate (3.6g) and 10% NaHSO were added under ice cooling₃Aqueous solution (400 ml). The resulting mixture was stirred for 10 minutes and then poured into ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with ice water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane) to give 17.1g (58.7mmol, 83%) of the title compound as a colorless liquid.

MS：292.0(M)⁺，290.0(M)⁺，212.2，91.1，65.2。

c ] 4-benzyloxy-2-ethyl-benzaldehyde

A stirred cooled (-85 ℃ C.) solution of 1-bromo-2-ethyl-4- (phenylmethoxy) -benzene (18.5g, 63.5mmol) in dry THF (22ml) was added 1.6M n-BuLi in hexane (44.4ml, 69.9mmol) over 10 minutes. The mixture was stirred at-85 ℃ under an argon atmosphere for 1 hour. N, N-dimethylformamide (25.5ml, 330.4mmol) was added and the temperature was slowly raised to room temperature. Saturated NH was added under ice cooling₄Aqueous Cl solution (70 ml). The mixture was extracted twice with dichloromethane and the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 11.9g (49.5mmol, 78%) of the title compound as a yellow oil.

MS：240.1(M+H)⁺，91.1，77.1，65.2。

d ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]Said process, (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one, see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) is reacted with 4-benzyloxy-2-ethyl-benzaldehyde in the presence of triethylamine and di-n-butylboron trifluoride to yield (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl]Oxazolidin-2-one as a yellow foam. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：526.3(M+Na)⁺，521.3(M+NH₄)⁺，486.2，381.2，309.2，281.2，253.3，178.1。

e ] (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]Said process, wherein (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl) is treated with sodium methoxide in methanol]-oxazolidin-2-one to yield (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：381.2(M+Na)⁺，376.3(M+NH₄)⁺，341.3，295.3，253.2，225.3。

f ] (2S) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1c ], (2S, 3R) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：365.2(M+Na)⁺，360.2(M+NH₄)⁺，297.3，283.2，237.2，209.3，181.2。

g ] (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester

In analogy to the procedure described in example 1d ], (2S) -3- (4-benzyloxy-2-ethyl-phenyl) -2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to yield (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester as colorless liquid.

MS：275.2(M+Na)⁺，270.3(M+NH₄)⁺，253.3(M+H)⁺，207.2，175.2，165.3，147.2。

h ] (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless liquid.

MS：446.3(M+Na)⁺，424.3(M+H)⁺，378.3，213.3，172.3。

i ] (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless foam.

MS：408.2(M-H)^-，362.0，318.2，236.7，190.0。

Example 9

a ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester (example 8g ]) and 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole (example 5b ]) were reacted in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester as colorless liquid.

MS：478.3(M+Na)⁺，456.3(M+H)⁺，371.3，271.3，245.3，204.2。

b ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless solid.

MS：440.3(M-H)^-，393.9，350.1，255.2，237.4，203.6。

Example 10

a ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester

Analogously to example 1f]The process described is carried out by reacting (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester (example 8 g)]) With 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (in analogy to example 5 a)]And 2b]Said process being prepared from 2-fluoro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment) in cesium carbonate and iodide(S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy-l in the presence of potassium]-phenyl } -propionic acid methyl ester as colorless liquid.

MS：464.2(M+Na)⁺，459.3(M+NH₄)⁺，442.2(M+H)⁺，396.2，231.2，190.3。

b ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- { 2-ethyl-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless liquid.

MS：450.2(M+Na)⁺，428.3(M+H)⁺，382.2，231.2，190.3。

Example 11

a ] (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester (example 8g ]) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1e ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless liquid.

MS：460.2(M+Na)⁺，438.3(M+H)⁺，407.2，227.2，186.3。

b ] (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-ethyl-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless liquid.

MS：446.2(M+Na)⁺，424.3(M+H)⁺，372.4，230.2，186.3。

Example 12

a ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-ethyl-4-hydroxy-phenyl) -propionic acid methyl ester (example 8g ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole (example 2b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester as colorless liquid.

MS：504.4(M+Na)⁺，482.4(M+H)⁺，271.2，230.2，188.3。

b ] (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- { 2-ethyl-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless liquid.

MS：490.2(M+Na)⁺，468.2(M+H)⁺，416.1，371.4，323.3，271.3，230.2，188.3。

Example 13

a ] 1-bromo-2-fluoro-4- (phenylmethoxy) -benzene

In analogy to the procedure described in example 8b ], 1-fluoro-3- (phenylmethoxy) -benzene (see: A.A. Durrani, J.H.P.Tyman, J.chem.Soc., Perkin Trans.11979, 8, 2079-.

b ] 4-benzyloxy-2-fluoro-benzaldehyde

In analogy to the procedure described in example 8c ], 1-bromo-2-fluoro-4- (phenylmethoxy) -benzene was treated with N-BuLi and N, N-dimethylformamide in anhydrous tetrahydrofuran to give 4-benzyloxy-2-fluoro-benzaldehyde as off-white crystals.

MS：230.1(M)⁺，91.0，65.2。

c ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]Said process, (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) is reacted with 4-benzyloxy-2-fluoro-benzaldehyde in the presence of triethylamine and di-n-butylboron to yield (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionyl-3-trifluoride]Oxazolidin-2-one as a colorless foam. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：516.2(M+Na)⁺，476.2，435.3，419.3，387.1，330.2，279.1，227.2，203.1。

d ] (2S, 3R) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]The process comprises treating (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy) with sodium methoxide in methanol2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionyl radical]-oxazolidin-2-one to yield (2S, 3R) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：371.3(M+Na)⁺，331.3，303.2，279.2，242.2。

e ] (2S) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1c ], (2S, 3R) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：355.2(M+Na)⁺，350.3(M+NH₄)⁺，333.3(M+H)⁺，287.2，273.3，245.3。

f ] (2S) -2-ethoxy-3- (2-fluoro-4-hydroxy-phenyl) -propionic acid methyl ester

In analogy to the procedure described in example 1d ], (2S) -3- (4-benzyloxy-2-fluoro-phenyl) -2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to yield (2S) -2-ethoxy-3- (2-fluoro-4-hydroxy-phenyl) -propionic acid methyl ester as colorless liquid.

MS：265.2(M+Na)⁺，260.2(M+NH₄)⁺，243.3(M+H)⁺，197.1，183.2，155.3。

g ] (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-fluoro-4-hydroxy-phenyl) -propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless liquid.

MS：436.2(M+Na)⁺，414.2(M+H)⁺，354.4，213.3，172.3。

h ] (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless solid.

MS：422.2(M+Na)⁺，400.4(M+H)⁺，304.0，269.2，241.3，213.3，187.3，172.3。

Example 14

a ] (S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (2-fluoro-4-hydroxy-phenyl) -propionic acid methyl ester (example 13 f)]) With 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-phenyl } -propionic acid methyl ester as colorless liquid.

MS：454.3(M+Na)⁺，449.3(M+NH₄)⁺，432.4(M+H)⁺，371.4，304.2，269.0，231.3。

b ] (S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- { 2-fluoro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless liquid.

MS：416.2(M-H)^-，370.1，326.2，255.3，227.2。

Example 15

a ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]The process described is carried out by reacting (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one, see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramaswamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) with 4-benzyloxy-2-chloro-benzaldehyde (for the preparation of 4-benzyloxy-2-chloro-benzaldehyde see: T.Kimachi, M.Kawase, S.Matsuki, K.tanaka, F.Yondeda, J.chem.c., Sokin Trans.90, F.Yoneda, J.chem.253, N.butyl-benzyl-2-ethyl-phenyl-ethyl-2-ethyl-butyl-benzyl-3-ethyl-2-ethyl-butyl-2-ethyl-benzyl-2-ethyl-2-ethyl 3-hydroxy-propionyl group]Oxazolidin-2-one as a colorless liquid. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：532.3(M+Na)⁺，527.2(M+NH₄)⁺，446.1，381.2，315.1，287.2，243.2，178.2。

b ] (2S, 3R) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]Said process, wherein (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-3-hydroxy-propionyl) is treated with sodium methoxide in methanol]-oxazolidin-2-one to yield (2S, 3R) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：387.1(M+Na)⁺，382.2(M+NH₄)⁺，328.2，319.2，279.2，203.2。

c ] (2S) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1c ], (2S, 3R) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：371.4(M+Na)⁺，366.2(M+NH₄)⁺，303.2，269.2，222.2，187.2。

d ] (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester

Dimethyl sulfide (5.8ml, 79mmol) and boron trifluoride diethyl etherate (46% purity, 4.3ml, 16mmol) were added to an ice-cold solution of (2S) -3- (4-benzyloxy-2-chloro-phenyl) -2-ethoxy-propionic acid methyl ester (1.1g, 3.2mmol) in dichloromethane (34ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 5 hours, poured into ice water/brine 1/1 and extracted twice with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 0.6g (2.3mmol, 74%) of the title compound as colorless oil.

MS：281.0(M+Na)⁺，276.1(M+NH₄)⁺，251.3，213.3，187.2。

e ] (S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：452.3(M+Na)⁺，430.3(M+H)⁺，251.3，213.3，172.2。

f ] (S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- [ 2-chloro-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid as colorless solid.

MS：438.0(M+Na)⁺，416.1(M+H)⁺，371.4，304.1，263.1，213.3，172.3。

Example 16

a ] (S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester (example 15d ]) was reacted with 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole (example 5b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：484.2(M+Na)⁺，462.2(M+H)⁺，345.1，245.3，204.2，166.4。

b ] (S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- { 2-chloro-4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid as colorless solid.

MS：470.0(M+Na)⁺，448.2(M+H)⁺，371.4，275.2，245.3，204.2，187.3。

Example 17

a ] (S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester (example 15d ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole (example 2b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：510.3(M+Na)⁺，488.3(M+H)⁺，271.3，230.2，188.3。

b ] (S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- { 2-chloro-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid as colorless foam.

MS：496.1(M+Na)⁺，474.2(M+H)⁺，424.3，271.2，230.2，188.3，172.2。

Example 18

a ] (S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester (example 15 d)]) With 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (substituted by 2-fluoro-phenyl)Preparation of benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to form (S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：470.1(M+Na)⁺，448.2(M+H)⁺，269.1，231.2，190.3，163.3。

b ] (S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- { 2-chloro-4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid as colorless solid.

MS：456.1(M+Na)⁺，434.2(M+H)⁺，428.3，382.1，279.1，231.2，190.3。

Example 19

a ] (S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester (example 15d ]) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1e ]) in the presence of cesium carbonate and potassium iodide to yield (S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：444.2(M+H)⁺，319.3，279.2，227.3，186.3，181.2，166.3。

b ] (S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- [ 2-chloro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid as colorless liquid.

MS：430.3(M+H)⁺,390.2, 349.3, 292.4, 279.2, 186.3, 176.2, 161.3. Example 20

a ] (S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -3- (2-chloro-4-hydroxy-phenyl) -2-ethoxy-propionic acid methyl ester (example 15 d)]) With 4-chloromethyl-2- (2-methoxy-phenyl) -5-methyl-oxazole (prepared from 2-methoxy-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to form (S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy]-phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：482.2(M+Na)⁺，360.2(M+H)⁺，391.2，330.3，284.1，254.2，202.2。

b ] (S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- { 2-chloro-4- [2- (2-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -2-ethoxy-propionic acid as colorless foam.

MS：468.1(M+Na)⁺，446.2(M+H)⁺，371.4，329.2，269.2，202.1。

Example 21

a ] 1-bromo-2-trifluoromethyl-4- (phenylmethoxy) -benzene

A solution of 1-trifluoromethyl-3- (phenylmethoxy) -benzene (5.7g, 22.6mmol) in glacial acetic acid (25ml) containing sodium acetate (2.7g, 32.5mmol) was cooled to 0 ℃ and bromine (1.6ml, 31.7mmol) was added slowly with stirring. A calcium chloride guard tube was fitted and the mixture was stirred at room temperature for 24 hours in the dark. The obtained slurry was diluted with dichloromethane, washed with 10% aqueous sodium thiosulfate solution, aqueous potassium carbonate solution and water. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure to give a yellow oil, which was purified by column chromatography (silica gel, cyclohexane) to give 6g of colorless oil. According to¹H-NMR, the oil consisted of an 1/1 mixture of starting material and title compound. The mixture was used in the next step without further purification.

b ] 4-benzyloxy-2-trifluoromethyl-benzaldehyde

In analogy to the procedure described in example 8c ], 1-bromo-2-trifluoromethyl-4- (phenylmethoxy) -benzene was treated with N-BuLi and N, N-dimethylformamide in anhydrous tetrahydrofuran to give 4-benzyloxy-2-trifluoromethyl-benzaldehyde as colorless liquid.

MS：298.3(M+NH₄)⁺，281.1(M)⁺，236.1，224.3，181.2。

c ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]Said process, (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) is reacted with 4-benzyloxy-2-trifluoromethyl-benzaldehyde in the presence of triethylamine and di-n-butylboron trifluoride to give (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl-2-trifluoromethyl-benzaldehyde]Oxazolidin-2-one as a colorless liquid. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates.According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：566.3(M+Na)⁺，561.4(M+NH₄)⁺，526.3，458.2，349.3，301.3。

d ] (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]Said process, the treatment of (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl) -with sodium methoxide in methanol]-oxazolidin-2-one, providing (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：421.2(M+Na)⁺，416.2(M+NH₄)⁺，381.3，353.2，313.3，222.2，192.4。

e ] (2S) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1c ], (2S, 3R) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：405.4(M+Na)⁺，400.4(M+NH₄)⁺，337.2，269.2。

f ] (2S) -2-ethoxy-3- (4-hydroxy-2-trifluoromethyl-phenyl) -propionic acid methyl ester

In analogy to the procedure described in example 1d ], (2S) -3- (4-benzyloxy-2-trifluoromethyl-phenyl) -2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to yield (2S) -2-ethoxy-3- (4-hydroxy-2-trifluoromethyl-phenyl) -propionic acid methyl ester as yellow solid.

MS：291.1(M-H)^-，255.2，206.0，174.1，141.1。

g ] (S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-trifluoromethyl-phenyl) -propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid methyl ester as colorless liquid.

MS：486.3(M+Na)⁺，464.3(M+H)⁺，411.0，371.4，304.2，279.3。

h ] (S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -2-trifluoromethyl-phenyl ] -propionic acid as colorless solid.

MS：448.2(M-H)^-，431.1，402.2，277.2，231.1。

Example 22

a ] (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-trifluoromethyl-phenyl } -propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (4-hydroxy-2-trifluoromethyl-phenyl) -propionic acid methyl ester (example 21 f)]) With 4-chloromethyl-2- (2-fluoro-phenyl) -5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl } -propionic acid methyl ester,as a colorless solid.

MS：504.3(M+Na)⁺，482.3(M+H)⁺，428.5，345.2，303.8，269.2，231.2。

b ] (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-trifluoromethyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-trifluoromethyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-trifluoromethyl-phenyl } -propionic acid as colorless liquid.

MS：466.3(M-H)^-，420.1，376.3，316.9，277.1，231.2。

Example 23

a ] 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -benzaldehyde

A solution of 2, 4-dihydroxy-benzaldehyde (2g, 14.5mmol) in 20ml THF was cooled to 0 ℃. To this solution was added triphenylphosphine (9.7g, 37mmol), 2- (2-phenyl-5-methyl-oxazol-4-yl) -ethanol (2.84g, 14mmol) and finally a solution of di-tert-butyl azodicarboxylate (8.52g, 37mmol) in 20ml THF over a period of 0.75 h. The reaction mixture was stirred at room temperature overnight, evaporated to dryness and purified by chromatography (SiO)₂(ii) a AcOEt/heptane) and the product was crystallized from AcOEt/diethyl ether/heptane to yield 2.2g (46%) of the title compound as a colorless solid.

b ]2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy ] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -benzaldehyde

To 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy]To a cooled 0 ℃ solution of benzaldehyde (540mg, 1.67mmol) in 8ml of N, N-dimethylformamide was added 398mg (5.85mol) of imidazole and 1.1ml (5.85mmol) of thexyl-dimethylchlorosilane. The reaction mixture was stirred at 0 ℃ for 50 minutes with AcOEtDilute, wash with water/ice, HCl (1M)/ice and brine, extract the aqueous layer with AcOEt. With Na₂SO₄The combined organic layers were dried and evaporated. Chromatography (SiO)₂(ii) a AcOEt/heptane) provided 346mg (45%) of the title compound as an oil.

MS：(M+H⁺)⁺466.3。

c ] (S) -4-benzyl-3- ((2S, 3R) -3- {2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy ] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -3-hydroxy-2-methoxy-propionyl) -oxazolidin-2-one

1.8g (7.21mmol) of (S) -4-benzyl-3-methoxyacetyl-oxazolidin-2-one (for the preparation of (S) -4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D.Hunziker, N.Wu, K.Kenoshita, D.E.Cane, C.Khosla, Tetrahedron Lett.1999, 40, 635-₂Cl₂In (1), treatment with 1.44ml (8.42mmol) of Hunig's base. After cooling to-78 ℃, nBu was added slowly₂BOTf(7.21ml CH₂Cl₂1M solution) allows enol boride (enoboronate) formation to proceed at-78 c for 0.25 hours and at 0 c for 1 hour. After renewed cooling to-78 ℃ 2.8g (6mmol) of 2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy-were added via the dropping funnel over 90 minutes]-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy]Benzaldehyde in 10ml CH₂Cl₂The mixture was kept at-78 ℃ for 95 minutes and at 0 ℃ for 1 hour. Poured onto crashed ice, extracted twice with AcOEt, washed with brine and water, dried over magnesium sulfate, evaporated solvent and chromatographed (silica gel, heptane/AcOEt) leaving finally 2.905g (67%) of the title compound as yellow oil. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：(M+Na⁺)⁺737.3，(M+H⁺)⁺715.3。

d ] (S) -4-benzyl-3- (3- {2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy ] -4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -2- (2S) -methoxy-propionyl) -oxazolidin-2-one

(S) -4-benzyl-3- ((2S, 3R) -3- {2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy) prepared above]-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy]-phenyl } -3-hydroxy-2-methoxy-propionyl) -oxazolidin-2-one (2.8g, 3.91mmol) was dissolved in 10ml trifluoroacetic acid, treated with 10ml triethylsilane at 0 ℃ and then kept at ambient temperature for 3 hours. The reaction mixture was then poured onto crashed ice/AcOEt/NaOH (1M), the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO)₂heptane/AcOEt) provided 1.6g (58%) of the title compound (purity 80%) as a yellow foam.

MS：596.4(M)⁺。

e ] (S) -4-benzyl-3- (3- { 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } - (2S) -2-methoxy-propionyl) -oxazolidin-2-one

To (S) -4-benzyl-3- (3- {2- [ dimethyl- (1, 1, 2-trimethyl-propyl) -silanyloxy]-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy](iii) -phenyl } -2- (2S) -methoxy-propionyl) -oxazolidin-2-one (1.6g, 2.29mmol) in 10ml methanol to which NH was added₄F (169mg, 4.58mmol), the reaction mixture was kept at room temperature for 2 hours. Then diluted with AcOEt, washed with water/ice water and brine, the aqueous layer extracted with AcOEt, over Na₂SO₄The combined organic layers were dried and evaporated. The crude product (1.22g) was found to be the title compound and (S) -3- { 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy]-phenyl } -2-methoxy-propionic acid methyl ester mixture, used in the final step without purification.

f ] (S) -3- { 2-hydroxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -2-methoxy-propionic acid

1.22g of the mixture prepared above are dissolved in 5ml of THF and treated with 5ml of 1N NaOH. The reaction mixture was kept at 0 ℃ overnight. Then, it was washed twice with diethyl ether. The aqueous layer was acidified (with HCl (1M)/ice, pH3), extracted twice with AcOEt, the organic layer was dried over magnesium sulfate and evaporated to give the crude product which was purified by crystallization from AcOEt/heptane to remove the chiral auxiliary. Thus, 0.240g (27%) of the title compound was obtained as a white solid. According to chiral HPLC (Chiralpak-AD), an enantiomeric excess of nearly 100% was observed.

MS：396.2(M-H)^-。

Example 24

a ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]Said process, (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-propan 1367) is reacted with 4-benzyloxy-2-methoxy-benzaldehyde in the presence of triethylamine and di-n-butylboron to yield (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionyl-3-trifluoride]-oxazolidin-2-one as a light yellow solid. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：528.3(M+Na)⁺，523.3(M+NH₄)⁺，488.3，442.4，311.2，239.3。

b ] (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]Said process, wherein (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionyl) is treated with sodium methoxide in methanol]-oxazolidin-2-one to yield (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：383.2(M+Na)⁺，378.2(M+NH₄)⁺，343.2，311.2，283.2，239.3，163.2。

c ] (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester

A solution of (2S, 3R) -3- (4-benzyloxy-2-methoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester (100mg, 200. mu. mol) and oxalic acid dihydrate (150mg, 1.2mmol) in isopropanol (2ml) was hydrogenated over 10% palladium on charcoal (20mg) at ambient temperature under 50 atmospheres for 6.5 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ice water/aqueous sodium bicarbonate 1/1 and extracted twice with ethyl acetate. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow liquid, which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 43mg (170mol, 85%) of the title compound as a light yellow liquid.

MS：277.1(M+Na)⁺，209.2，195.3，181.2，177.2，167.2。

d ] (S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless liquid.

MS：448.2(M+Na)⁺，426.3(M+H)⁺，380.2，319.2，213.3，172.2。

e ] (S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-methoxy-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless solid.

MS：410.6(M-H)^-，369.9，304.2，285.2，261.3，238.9，229.6，191.3。

Example 25

a ] (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester (example 24c ]) was reacted with 4-chloromethyl-2- (4-isopropyl-phenyl) -5-methyl-oxazole

(prepared from 4-isopropyl-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl } -propionic acid methyl ester as orange liquid.

MS：490.2(M+Na)⁺，468.2(M+H)⁺，344.3，311.2，255.2，214.4，198.4。

b ] (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid as colorless solid.

MS：476.2(M+Na)⁺，454.3(M+H)⁺，404.5，255.2，214.3。

Example 26

a ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester (example 24c ]) was reacted with 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole (example S5 b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl ] -propionic acid methyl ester as colorless liquid.

MS：480.4(M+Na)⁺，458.3(M+H)⁺，412.2，245.3，204.2，177.2。

b ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid as colorless solid.

MS：466.1(M+Na)⁺，444.2(M+H)⁺，392.1，365.2，297.3，245.3，204.2。

Example 27

a ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester (example 24c ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole (example 2b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid methyl ester as colorless liquid.

MS：506.5(M+Na)⁺，484.3(M+H)⁺，323.3，271.3，230.2，188.3。

b ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -propionic acid as colorless solid.

MS：492.2(M+Na)⁺，470.2(M+H)⁺，357.2，335.2，279.2，235.2，187.3。

Example 28

a ] (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -2-ethoxy-propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (4-hydroxy-2-methoxy-phenyl) -propionic acid methyl ester (example 24 c)]) With 4-chloromethyl-2- (3-chloro-phenyl) -5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：482.2(M+Na)⁺，460.2(M+H)⁺，414.1，357.2，335.3，279.2，235.2，206.1。

b ] (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methoxy-phenyl } -2-ethoxy-propionic acid as colorless liquid.

MS：468.1(M+Na)⁺，446.1(M+H)⁺，394.2，352.2，302.2，269.2，206.1，149.1。

Example 29

a ] 4-benzyloxy-2, 6-dimethyl-benzaldehyde

In analogy to the procedure described in example 8a ], 4-hydroxy-2, 6-dimethyl-benzaldehyde was reacted with benzyl bromide in the presence of potassium carbonate to give 4-benzyloxy-2, 6-dimethyl-benzaldehyde as orange liquid.

MS：241.2(M+H)⁺，181.0。

b ] (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl ] -oxazolidin-2-one

Analogously to example 1a]Said process, the (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D.Haigh, H.C.Birrell, B.C.C.Cantello, D.S.Eggeston, R.C.Haltiwanger, R.M.Hindley, A.Ramasumamy, N.C.Stevens, Tetrahedron: Asymmetry1999, 10, 1353-, yielding (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl.]Oxazolidin-2-one as a colorless liquid. According to¹H-NMR spectroscopy, one of the four isomers strongly predominates. According to d.haigh et al, Tetrahedron: asymmetry1999, 10, 1353-1367, the configuration was tentatively designated 2S, 3R.

MS：526.3(M+Na)⁺，486.3，425.3，358.2，309.1，281.2，253.1，237.2，178.2。

c ] (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester

Analogously to example 1b]Said process, wherein (S) -4-benzyl-3- [ (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionyl) is treated with sodium methoxide in methanol]-oxazolidin-2-one to yield (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to¹H-NMR spectroscopy, to obtain a single diastereomer.

MS：381.2(M+Na)⁺，376.3(M+NH₄)⁺，341.2，313.2，269.2，213.3，187.2。

d ] (2S) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1c ], (2S, 3R) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：360.3(M+NH₄)⁺，284.1，269.2，201.1，163.3。

e ] (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester

In analogy to the procedure described in example 1d ], (2S) -3- (4-benzyloxy-2, 6-dimethyl-phenyl) -2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to obtain (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester as colorless liquid.

MS：275.2(M+Na)⁺，270.3(M+NH₄)⁺，253.3(M+H)⁺，207.2，165.3。

f ] (S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：446.4(M+Na)⁺，357.0，275.0，169.1。

g ] (S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- [2, 6-dimethyl-4- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -2-ethoxy-propionic acid as colorless solid.

MS：432.2(M+Na)⁺，410.2(M+H)⁺，355.0，329.4，293.4，244.3，174.3，166.3。

Example 30

a ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester (example 29e ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole (example 2b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：504.3(M+Na)⁺，482.3(M+H)⁺，299.3，271.2，230.2，188.3，161.3。

b ] (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid as colorless foam.

MS：490.2(M+Na)⁺，468.2(M+H)⁺，416.2，305.2，271.3，230.2，188.3。

Example 31

a ] (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester (example 29e ]) was reacted with 4-chloromethyl-2- (4-isopropyl-phenyl) -5-methyl-oxazole

(prepared from 4-isopropyl-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2, 6-dimethyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：488.3(M+Na)⁺，466.3(M+H)⁺，255.2，214.4，187.3。

b ] (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid as colorless solid.

MS：474.2(M+Na)⁺，452.3(M+H)⁺，400.4，357.1，279.2，214.4。

Example 32

a ] (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid methyl ester

Analogously to example 1f]The process described is the reaction of (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester (example 29 e)]) With 4-chloromethyl-2- (3-chloro-phenyl) -5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to give (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid methyl ester as colorless liquid.

MS：480.3(M+Na)⁺，458.3(M+H)⁺，412.2，330.2，302.2，247.2，206.1。

b ] (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -2-ethoxy-propionic acid as colorless solid.

MS：466.2(M+Na)⁺，444.2(M+H)⁺，380.2，305.2，287.2，254.3，215.3，206.2，198.2。

Example 33

a ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester (example 29e ]) was reacted with 4-chloromethyl-2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazole (example 5b ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester as colorless liquid.

MS：478.3(M+Na)⁺，456.3(M+H)⁺，371.4，339.1，304.1，245.3，222.2，204.2。

b ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- {4- [2- (4-fluoro-3-methyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2, 6-dimethyl-phenyl } -propionic acid as colorless solid.

MS：464.2(M+Na)⁺，442.3(M+H)⁺，349.3，285.1，266.2，245.4，225.3，187.2。

Example 34

a ]3- (4-benzyloxy-2-methyl-phenyl) -2(Z, E) -ethoxy-acrylic acid ethyl ester

Stirring (1, 2-diethoxy-2-oxoethyl) triphenyl phosphonium chloride [ Tetrahedron 50(25), 7543-56(1994) at ambient temperature]A suspension of (35.5g, 82.9mmol) and DBU (13.6ml, 91.2mmol) in THF (60ml) was suspended for 10 min. 4-benzyloxy-2-methyl-benzaldehyde (12.5g, 55.2mmol) was added and the reaction mixture was heated under reflux for 16 h. The solvent was concentrated under reduced pressure, the residue was taken up in AcOEt and saturated NH was used₄Aqueous Cl and brine. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/AcOEt)To afford 14.5g (42.6mmol, 77%) of the title compound as a yellow liquid.

MS：340.2(M)⁺，249.2，147.1，91.1。

b ] [ rac ] -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester

A solution of 3- (4-benzyloxy-2-methyl-phenyl) -2(Z, E) -ethoxy-acrylic acid ethyl ester (1g, 2.9mmol) in ethanol (50ml) was hydrogenated over 10% palladium on charcoal (250mg) at ambient temperature for 2 h. The catalyst was filtered off and the solvent evaporated under reduced pressure to give 600mg (2.4mmol, 81%) of the title compound as a yellow liquid which was used in the next step without further purification.

MS：270.4(M+NH₄)⁺，253(M)⁺，207.2，165.3。

c ] [ rac ] -3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-ethyl 2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionate was prepared with 4-chloromethyl-2- (3, 5-dichloro-phenyl) -5-methyl-oxazole (prepared from 3, 5-dichloro-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester as colorless liquid.

MS：493.3(M+H)⁺，453.3，375.4，331.4，275.2，240.2，200.2。

d ] (S) -3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain (rac) -3- {4- [2- (3, 5-dichloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：486.1(M+Na)⁺，466.1(M+H)⁺，464.2(M+H)⁺，433.1，351.0，293.2，269.2，187.2。

Example 35

a ] [ rac ] -3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-2- (3, 5-dimethyl-phenyl) -5-methyl-oxazole (prepared from 3, 5-dimethyl-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester as colorless liquid.

MS：474.2(M+Na)⁺，452.3(M+H)⁺，431.4，375.3，331.3，275.2，241.3，200.2。

b ] (S) -3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain (rac) -3- {4- [2- (3, 5-dimethyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：422.3(M-H)^-，375.9，339.2，319.3，305.6，282.2，255.4，222.9。

Example 36

a ] [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-5-methyl-2- (2-trifluoromethyl-phenyl) -oxazole (prepared from 2-trifluoromethyl-benzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy]-phenyl } -propionic acid ethyl ester as colorless liquid.

MS：514.2(M+Na)⁺，492.2(M+H)⁺，448.2，407.2，322.2，281.1，266.3，240.2。

b ] (S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：462.2(M-H)^-，416.4，372.1，353.4，337.3，309.5，255.0，223.0。

Example 37

a ] [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-5-methyl-2- (3-trifluoromethyl-phenyl) -oxazole (prepared from 3-trifluoromethyl-benzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy]-phenyl } -propionic acid ethyl ester as colorless liquid.

MS：514.3(M+Na)⁺，509.4(M+NH₄)⁺，492.2(M+H)⁺，446.1，281.1，240.2。

b ] (S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless solid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：462.1(M-H)^-，404.8，387.0，353.2，319.0，282.9，268.7，255.2，241.0，226.9。

Example 38

a ] [ rac ] -2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-2- (4-fluoro-phenyl) -5-methyl-oxazole (prepared from 4-fluoro-benzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl } -propionic acid ethyl ester as colorless liquid.

MS：442.2(M+H)⁺，391.2，319.3，231.2，198.2，190.3，181.2，166.3。

b ] (S) -2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester was treated with LiOH to obtain (rac) -2-ethoxy-3- {4- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：412.2(M-H)^-，366.0，322.3，303.1，283.3，254.8，222.9，194.6。

Example 39

a ] [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method, [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-5-methyl-2- (4-trifluoromethyl-phenyl) -oxazole (prepared from 4-trifluoromethyl-benzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy]-phenyl } -propionic acid ethyl ester as colorless liquid.

MS：514.2(M+Na)⁺，509.4(M+NH₄)⁺，492.2(M+H)⁺，446.2，418.2，281.1，240.2，172.2。

b ] (S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester was treated with LiOH to obtain (rac) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless solid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：462.2(M-H)^-，416.2，399.1，372.3，341.7，317.1，255.4。

Example 40

a ] [ rac ] -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-2- (4-isopropyl-phenyl) -5-methyl-oxazole (prepared from 4-isopropylbenzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 5a]And 2b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl } -propionic acid ethyl ester as colorless liquid.

MS：488.3(M+Na)⁺，466.2(M+H)⁺，422.3，391.2，279.2，214.4。

b ] (S) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester was treated with LiOH to obtain (rac) -2-ethoxy-3- {4- [2- (4-isopropyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：436.2(M-H)^-，410.9，389.8，363.3，328.7，305.0，282.9，254.9，222.8。

EXAMPLE 41

a ] [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 4-chloromethyl-5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazole (prepared from 3, 4, 5-trimethoxy-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 2a]And b]Said process) in the presence of cesium carbonate and potassium iodide to produce [ rac ]]-2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy]-phenyl } -propionic acid ethyl ester as yellow liquid.

MS：536.3(M+Na)⁺，514.3(M+H)⁺，470.2，340.0，303.2，262.2，214.3，168.2。

b ] (S) -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -2-ethoxy-3- { 2-methyl-4- [ 5-methyl-2- (3, 4, 5-trimethoxy-phenyl) -oxazol-4-ylmethoxy ] -phenyl } -propionic acid as colorless solid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：485.3(M)^-。

Example 42

a ] [ rac ] -2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -propionic acid ethyl ester

Analogously to example 7c]Said method comprises reacting [ rac ]]-2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34 b)]) With 2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl]Ethanol (prepared from 4-fluoro-2-hydroxy-benzaldehyde [ j.chem.soc., perkintrans.1(1994), (13), 1823-31) by the following procedure]: i) treatment with ethyl iodide, potassium carbonate in N, N-dimethylformamide yields 2-ethoxy-4-fluoro-benzaldehyde; ii) analogously to example 2a]And b]The process converts 2-ethoxy-4-fluoro-benzaldehyde to 4-chloromethyl-2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazole; iii) by treatment with sodium cyanide in DMSO, followed by hydrolysis of the nitrile function with sodium hydroxide in ethanol/water at reflux, in tetrahydrofuran at room temperature with BH₃Reduction of the acid formed by xTHF to convert 4-chloromethyl-2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazole to 2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl]-ethanol) in the presence of triphenylphosphine and diethyl azodicarboxylate to produce [ rac ]]-2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl]-ethoxy } -2-methyl-phenyl) -propionic acid ethyl ester as light yellow liquid.

MS：522.2(M+Na)⁺，500.3(M+H)⁺，456.3，426.3，398.2，248.2，220.2，149.1。

b ] (S) -2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -propionic acid ethyl ester was treated with LiOH to obtain (rac) -2-ethoxy-3- (4- {2- [2- (2-ethoxy-4-fluoro-phenyl) -5-methyl-oxazol-4-yl ] -ethoxy } -2-methyl-phenyl) -propionic acid as colorless solid, which was separated into its enantiomers by methods known in the art, such art-known methods as separation of enantiomers via diastereomeric salts by crystallization with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine, or separation of enantiomers by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compounds.

MS：470.1(M-H)^-，424.2，387.0，326.5，281.1，255.0，204.9。

Example 43

a ] [ rac ] -2-ethoxy-3- { 2-methyl-4- {3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid ethyl ester

In analogy to the procedure described in example 7c ], [ rac ] -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34b ]) was reacted with 3- (5-methyl-2-phenyl-oxazol-4-yl) -propan-1-ol (J.L.Collins, M.Dezube, J.A.Oplinger, A.Jeffrey, T.M.Willson, International patent application No. WO0008002(A1), 2000) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [ rac ] -2-ethoxy-3- { 2-methyl-4- {3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid ethyl ester, as a yellow liquid.

MS：474.3(M+Na)⁺，452.5(M+H)⁺，382.4，241.3。

b ] (S) -2-ethoxy-3- { 2-methyl-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- { 2-methyl-4- {3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -2-ethoxy-3- { 2-methyl-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals the enantiomers are separated via diastereomeric salts or the enantiomers are separated by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：422.3(M-H)^-，376.3，299.1。

Example 44

a ] (S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (S) -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 1d ]) was reacted with 4-chloromethyl-2-phenyl-oxazole [ prepared from benzamide and 1, 3-dichloroacetone as described in bioorg.Med.chem.Lett. (2000), 10(17), 2041-4 ] in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless liquid.

MS：418.2(M+Na)⁺，396.2(M+H)⁺，350.2，336.3，308.1，251.2，186.3，158.2。

b ] (S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-methyl-4- (2-phenyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless solid.

MS：404.3(M+Na)⁺，382.2(M+H)⁺，325.2，293.2，250.2，212.3，172.3，158.2。

Example 45

a ] [ rac ] -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester

In analogy to the procedure described in example 1f ], [ rac ] -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34b ]) was reacted with 4-chloromethyl-2- (2-chloro-phenyl) -oxazole [ prepared from 2-chloro-benzamide and 1, 3-dichloroacetone in analogy to the procedure described for the synthesis of 4-chloromethyl-2-phenyl-oxazole (2000, 10 (17); 2041-4 ] in the presence of cesium carbonate and potassium iodide to yield [ rac ] -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester, it is a colorless liquid.

MS：466.1(M+Na)⁺，444.2(M+H)⁺，371.4，327.0，192.2，163.4。

b ] (S) -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -3- {4- [2- (2-chloro-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -2-ethoxy-propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, the crystalline brucine, quinine and quinidine separate the enantiomers via diastereomeric salts or by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：438.2(M+Na)⁺，416.1(M+H)⁺，340.4，280.2，220.4，192.2，173.1。

Example 46

a ] [ rac ] -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester

In analogy to the procedure described in example 1f ], [ rac ] -2-ethoxy-3- (4-hydroxy-2-methyl-phenyl) -propionic acid ethyl ester (example 34b ]) was reacted with 4-chloromethyl-2- (3-methoxy-phenyl) -oxazole [ in analogy to the procedure described in bioorg.med.chem.lett. (2000), 10(17), 2041-flaker 2044 for the synthesis of 4-chloromethyl-2-phenyl-oxazole, prepared from 3-methoxy-benzamide and 1, 3-dichloroacetone ] in the presence of cesium carbonate and potassium iodide to yield [ rac ] -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester, it is a colorless liquid.

MS：462.2(M+Na)⁺，440.2(M+H)⁺，394.2，366.2，291.4。

b ] (S) -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid

In analogy to the procedure described in example 1g ], [ rac ] -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid ethyl ester was treated with LiOH to obtain [ rac ] -2-ethoxy-3- {4- [2- (3-methoxy-phenyl) -oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid as colorless liquid, which could be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as for example (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, the crystalline brucine, quinine and quinidine separate the enantiomers via diastereomeric salts or by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：434.3(M+Na)⁺，412.2(M+H)⁺，360.1，304.1，261.2，229.2，188.3，160.3。

Example 47

a ] [ rac ] -3- (4-benzyloxy-2-ethoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester [ mixture of diastereomers ]

LDA was prepared by adding 13.3ml of n-BuLi (1.5M, hexane) to a solution of 2.85ml (20.0mmol) diisopropylamine in 90ml anhydrous THF at-5 deg.C. After cooling to-78 ℃ it was dissolved in 10ml of anhydrous THF2.81ml (20.0mmol) of ethyl ethoxyacetate, the mixture is held at this temperature for 15 minutes to ensure complete deprotonation. Then 2.05g (8.0mmol) of 4-benzyloxy-2-ethoxy-benzaldehyde [ similar to Chemical ] dissolved in 20ml of anhydrous THF are added&4-benzyloxy-2-isopropoxy-benzaldehyde from Pharmaceutical Bulletin (1998), 46(2), 222-: 2-hydroxy-4-benzyloxy-benzaldehyde, isopropyl bromide, potassium iodide, potassium carbonate, N, N-dimethylformamide, 100 ℃ preparation from 2-hydroxy-4-benzyloxy-benzaldehyde and ethyl iodide]. After stirring for 30 minutes at dry ice temperature, the reaction mixture was quenched with ammonium chloride solution, warmed to 0 ℃, then extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO)₂Hexane/AcOEt from 9: 1 to 1: 1) gave 3.09g (99% of theory) [ rac ]]-3- (4-benzyloxy-2-ethoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester [ mixture of diastereomers]It is a light yellow oil.

MS：371.4[(M+H)⁺-H₂O]。

b ]3- (4-benzyloxy-2-ethoxy-phenyl) -2(Z, E) -ethoxy-acrylic acid ethyl ester

3.26g (8.39mmol) [ rac ] of]-3- (4-benzyloxy-2-ethoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester [ mixture of diastereomers]And 0.15g (0.84mmol) of 4-toluenesulfonic acid in 200ml of benzene are stirred for 30 minutes at reflux. Evaporative drying followed by flash chromatography (SiO)₂hexane/AcOEt ═ 95: 5 to 4: 1) gave 2.12g (68% of theory) of 3- (4-benzyloxy-2-ethoxy-phenyl) -2(Z, E) -ethoxy-acrylic acid ethyl ester as a pale yellow oil.

MS：370.1(M)⁺。

c ] [ rac ] -2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionic acid ethyl ester

0.90g Pd/C (10%) is added under argon to 4.49g (12.1mmol)3- (4-benzyloxy-2-ethoxy-phenyl) -2(Z, E) -ethoxy-acrylic acid ethyl ester dissolved in 80ml ethanol. The atmosphere was then replaced with H2 and the suspension was stirred rapidly for two hours at room temperature. On the diatomiteFiltration and evaporation of the solvent left 4.23g of a light brown oil. Flash chromatography (SiO)₂Hexane/AcOEt 95: 5 to 4: 1) gave 3.41g (99% of theory) [ rac ]]-ethyl 2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionate as a pale yellow oil.

MS：281.0(M-H)^-。

d ] (S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-ethoxy-phenyl } -2-ethoxy-propionic acid

Analogously to example 1f]Will [ rac ]]-ethyl 2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionate and 2- (4-tert-butyl-phenyl) -4-chloromethyl-5-methyl-oxazole (prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in N, N-dimethylformamide in the presence of potassium carbonate to give [ rac ]]-3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-ethoxy-phenyl } -2-ethoxy-propionic acid ethyl ester, which is analogous to example 1g]The process further saponifies to produce [ rac ]]-3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-ethoxy-phenyl } -2-ethoxy-propionic acid, as a colorless amorphous solid, which can be separated into its enantiomers by methods known in the art, such as by separating the enantiomers via diastereoisomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：480.4(M-H)^-。

Example 48

(S) -2-ethoxy-3- { 2-ethoxy-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 1f ], [ rac ] -2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionic acid ethyl ester (example 47c ]) was reacted with 4-chloromethyl-2- (4-isopropoxy-phenyl) -5-methyl-oxazole (example 2b ]) in N, N-dimethylformamide in the presence of potassium carbonate to yield [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1g ], to produce [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [2- (4-isopropoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -phenyl } -propionic acid as a colorless solid, which can be separated into their enantiomers by methods known in the art, such as by separation of the enantiomers via diastereomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or separating the enantiomers by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：482.3(M-H)^-。

Example 49

(S) -3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-ethoxy-phenyl } -2-ethoxy-propionic acid

Analogously to example 1f]Said method comprises reacting [ rac ]]-2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionic acid ethyl ester (example 47 c)]) With 4-chloromethyl-2- (3-chloro-phenyl) -5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxime, then with POCl₃Treatment analogous to example 5a]And 2b]Said process) in N, N-dimethylformamide in the presence of potassium carbonate to give [ rac ]]-3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl } -2-ethoxy-propionic acid ethyl ester, which is analogous to example 1g]The process further saponifies to produce [ rac ]]-3- {4- [2- (3-chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl } -2-ethoxy-propionic acid, as a colorless solid, which can be separated into its enantiomers by methods known in the art, such as by treatment with an optically pure amine such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine,quinine and quinidine crystals separate enantiomers via diastereomeric salts or by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：458.2(M-H)^-。

Example 50

(S) -2-ethoxy-3- { 2-ethoxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 7c ], [ rac ] -2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionic acid ethyl ester (example 47c ]) was reacted with 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethanol in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1g ], to yield [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy ] -phenyl } -propionic acid as a colorless oil, which can be separated into their enantiomers by methods known in the art, such as by separation of the enantiomers via diastereomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or separating the enantiomers by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：438.2(M-H)^-。

Example 51

(S) -2-ethoxy-3- { 2-ethoxy-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid

In analogy to the procedure described in example 7c ], [ rac ] -2-ethoxy-3- (2-ethoxy-4-hydroxy-phenyl) -propionic acid ethyl ester (example 47c ]) was reacted with 3- (5-methyl-2-phenyl-oxazol-4-yl) -propan-1-ol (J.L.Collins, M.Dezube, J.A.Oplinger, A.Jeffrey, T.M.Willson, International patent application publication No. WO0008002(A1), 2000) in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid ethyl ester, it was further saponified in analogy to the procedure described in example 1g ] to yield [ rac ] -2-ethoxy-3- { 2-ethoxy-4- [3- (5-methyl-2-phenyl-oxazol-4-yl) -propoxy ] -phenyl } -propionic acid as colorless oil, which can be separated into their enantiomers by methods known in the art, such as by separation of the enantiomers via diastereomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or separating the enantiomers by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：452.2(M-H)^-。

Example 52

a ] [ rac ] -3- (4-benzyloxy-2-isopropoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester [ mixture of diastereomers ]

In analogy to the procedure described in example 47a ], 4-benzyloxy-2-isopropoxy-benzaldehyde [ Chemical & Pharmaceutical Bulletin (1998), 46(2), 222- & 230] was reacted with the enolate of ethyl ethoxyacetate to give [ rac ] -3- (4-benzyloxy-2-isopropoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester as a mixture of diastereomers as light yellow oil.

MS：402.0(M)⁺。

b ] [ rac ] -2-ethoxy-3- (4-hydroxy-2-isopropoxy-phenyl) -propionic acid ethyl ester

0.80g Pd/C (10%) and 6.0g oxalic acid dihydrate were added under argon to 3.20g (7.95mmol) [ rac ] dissolved in 60ml isopropanol]-3- (4-benzyloxy-2-isopropoxy-phenyl) -2-ethoxy-3-hydroxy-propionic acid ethyl ester [ mixture of diastereomers]. At room temperature and 50 bar H₂Under stirring the sameThe solution was allowed to stand for 24 hours. Filtration over celite, evaporation of the solvent, followed by flash chromatography (SiO)₂Hexane/AcOEt 9: 1 to 1: 1) leaving 0.69g (29% of theory) [ rac ]]-ethyl 2-ethoxy-3- (4-hydroxy-2-isopropoxy-phenyl) -propionate as yellow oil.

MS：295.2(M-H)^-。

c ] (S) -3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-isopropoxy-phenyl } -2-ethoxy-propionic acid

Analogously to example 1f]Said method comprises reacting [ rac ]]-ethyl 2-ethoxy-3- (4-hydroxy-2-isopropoxy-phenyl) -propionate and 2- (4-tert-butyl-phenyl) -4-chloromethyl-5-methyl-oxazole (prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxime, followed by POCl₃Treatment analogous to example 5a]And 2b]Said process) in N, N-dimethylformamide in the presence of potassium carbonate to give [ rac ]]-3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-isopropoxy-phenyl } -2-ethoxy-propionic acid ethyl ester, in analogy to example 1g]The process further saponifies to produce [ rac ]]-3- {4- [2- (4-tert-butyl-phenyl) -5-methyl-oxazol-4-ylmethoxy-l]-2-isopropoxy-phenyl } -2-ethoxy-propionic acid, as a colorless viscous oil, which can be separated into its enantiomers by methods known in the art, such as by separation of the enantiomers via diastereomeric salts with optically pure amines such as, for example, (R) or (S) -1-phenyl-ethylamine, (R) or (S) -1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine crystals, or by specific chromatographic methods using chiral adsorbents or chiral eluents to provide the title compound.

MS：494.3(M-H)^-。

Example 53

a ] (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester

In analogy to the procedure described in example 1f ], (2S) -2-ethoxy-3- (2-fluoro-4-hydroxy-phenyl) -propionic acid methyl ester (example 13f ]) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1e ]) in the presence of cesium carbonate and potassium iodide to yield (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester as colorless oil.

MS：450.4(M+Na)⁺，445.4(M+NH₄)⁺，428.5(M+H)⁺，391.4，279.3，227.4，186.3。

b ] (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid

In analogy to the procedure described in example 1g ], (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid methyl ester was treated with LiOH to obtain (S) -2-ethoxy-3- [ 2-fluoro-4- (5-methyl-2-o-tolyl-oxazol-4-ylmethoxy) -phenyl ] -propionic acid as colorless liquid.

MS：412.2(M-H)^-，366.2。

Example A

Tablets containing the following ingredients may be produced in a conventional manner:

components Each sheet is

10.0-100.0mg of compound of formula (I)

Lactose 125.0mg

Corn starch 75.0mg

Talc 4.0mg

Magnesium stearate 1.0mg

Example B

Capsules containing the following components can be produced in a conventional manner:

components Each capsule

25.0mg of the Compound of formula (I)

Lactose 150.0mg

Corn starch 20.0mg

Talc 5.0mg

Example C

The injection solution may have the following composition:

3.0mg of a Compound of formula (I)

Gelatin 150.0mg

Phenol 4.7mg

Sodium carbonate to obtain a final pH of 7

Adding water for injection to 1.0ml

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or ester thereof,

wherein

R¹Is optionally substituted by 1-3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen and fluoro-C₁-C₄Phenyl substituted by alkyl substituents；

R²Is hydrogen, or C₁-C₄An alkyl group;

R³and R⁴Independently of one another, hydrogen, hydroxy, halogen, C₁-C₄Alkyl, fluoro C₁-C₄Alkyl or C₁-C₄Alkoxy radical, wherein R³And R⁴At least one of which is not hydrogen;

R⁵is C₁-C₄An alkoxy group; r⁶Is hydrogen or C₁-C₄An alkyl group;

n is a number of 1, and n is,

wherein the pharmaceutically acceptable ester is selected from the group consisting of methyl, ethyl, propyl, butyl, benzyl, and nitrate, sulfate, phosphate, citrate, formate, maleate, acetate, succinate, tartrate, mesylate, and tosylate.

2. A compound according to claim 1, wherein R is¹Is optionally substituted by 1-2 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy and halogen.

3. A compound according to claim 1 or 2, wherein R¹Is phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl, 4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl, 2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, or 4-tert-butyl-phenyl.

4. A compound according to claim 1, wherein R is²Is hydrogen or methyl.

5. A compound according to claim 1, wherein R is³Is hydrogen or methyl.

6. A compound according to claim 1, wherein R is⁴Is methyl, ethyl, fluoro, chloro, trisFluoromethyl, hydroxy, methoxy, ethoxy, or isopropoxy.

7. A compound according to claim 1, wherein R is⁵Is methoxy or ethoxy.

8. A compound according to claim 1, wherein R is⁶Is hydrogen.

9. A compound according to claim 1, wherein R is¹Is phenyl substituted by methyl and/or fluorine, R²Is C₁-C₄Alkyl radical, R³Is hydrogen, R⁴Is C₁-C₄Alkyl radical, R⁵Is C₁-C₄Alkoxy and R⁶Is hydrogen.

10. A compound according to claim 1, wherein R is¹Is 2-methyl-phenyl or 2-fluoro-phenyl, R²Is methyl, R³Is hydrogen, R⁴Is methyl, R⁵Is ethoxy and R⁶Is hydrogen.

11. A compound according to claim 1, selected from:

or a pharmaceutically acceptable salt or ester thereof,

12. A compound according to claim 1 which is (S) -2-ethoxy-3- {4- [2- (2-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy ] -2-methyl-phenyl } -propionic acid or a pharmaceutically acceptable salt or ester thereof,

13. A process for the preparation of a compound according to any one of claims 1 to 12, which process comprises removing the protecting group in a compound of formula (II),

wherein R is¹，R²，R³，R⁴，R⁵And n is as defined in any one of claims 1 to 12 and PG is a protecting group.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier and/or adjuvant.

15. The use of compounds according to any of claims 1 to 12 for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are modulated by PPAR α and/or PPAR γ agonists.

16. The use according to claim 15, wherein the disease is diabetes, elevated blood pressure, elevated lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases or proliferative diseases.

17. Use according to claim 16, wherein the disease is non-insulin dependent diabetes mellitus.