Definitions

• the present invention relates to a stereoselective synthetic method of oxazoline derivative. More particularly, it relates to a synthetic method of oxazoline derivative having the structure of formula I .
• R represents phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl or cyclohexylmethy 1.
• ⁇ -amino- a -hydroxy acid has been regarded as a HIV protease inhibitor or a component of physiologically active compound.
• taxol having the structure of formula A has been known as an efficacious anti-cancer medicine. To express the anti-cancer effect of taxol, it has been known that 3-(N-benzoylamino)-2-hydroxy-3-phenylpropionic acid has to be placed at C-13 site of the taxol.
• the crude taxan has been isolated from the plant. However, it is hard to extract it from plant, because only a small amount of taxan exists in the plant. Meanwhile, the semi-synthetic process from baccatin El represented by formula B has been carried out, because baccatin m can be obtained in a desirable amount from the plant. Therefore, the stereoselective synthetic method of ⁇ -amino- a -hydroxy acid which is essential chain of taxol has been regarded as very important method.
• taxol can be obtained by semi-synthetic method from baccatin HI.
• the problem is how to obtain the highly purified synthetic taxol, because the purity of it affects the efficacy of taxol. Therefore, the development of synthetic method for oxazoline has important meaning due to the effect to the purity of taxol, as well as the role of intermediate of HIV protease inhibitor.
• the object of the present invention is to provide a stereoselective synthetic method of oxazoline derivative equivalent to ⁇ -amino- a -hydroxy acid using the naturally existing amino acid as starting material.
• the another object of the present invention is to provide a stereoselective synthetic method of oxazoline derivative to prepare taxol of formula A from baccatin Ul of formula B, and to afford the intermediate of HIV protease inhibitor.
• the further object of the present invention is to provide a stereoselective synthetic method of oxazoline derivative comprising the following steps of ; i ) cyclizing the compound of formula ⁇ in the presence of 0.02—0.1 mole % of palladium (Pd) catalyst at 20 ⁇ 50°C by separating the leaving group X to obtain the compound of formula HI ; and ii ) oxidizing the compound of formula m by adding the oxidizing agent in the mixed solvent (acetonitrile/ carbontetrachloride/ water) in the presence of ruthenium catalyst to obtain the compound of formula I .
• the palladium (Pd) catalyst is selected from the group consisting of tetrakistriphenylphosphine palladium ; mixture of Pd(OAc) 2 , PdCl 2 and PI 3P ; and mixture of dibenzylidene acetone palladium, dichlorodiphenyl palladium and hydrazine.
• the oxidizing agent is selected from the group consisting of sodium periodate(Na ⁇ O ⁇ ) ; potassium periodate(KI0 4 ) ; and potassium permanganate (KMn0 ).
• the compound of formula II using the starting material of the present invention can be prepared from a -amino acid.
• the reaction scheme shows the preparation method of compound of formula EL which is prepared following steps of ; i ) reducing a -amino acid (IV) to a -amino alcohol (V) using the reductant ; ii ) oxidizing a -amino alcohol (V) to a -amino aldehyde (VI) ; iii) reacting from a -amino aldehyde (VI) to 4-N-benzoylamino-4-phenyl-2- butenal (Vfl) using formylmethylenetriphenylphosphorane ; iv) reducing 4-N-benzoylamino-4-phenyl-2-butenal (VII) to 4-N-benzoyl-amino-
• R is alkyl or aryl, for example, phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl or cyclohexylmethyl ;
• X is acetyl, benzoyl or carbonate as leaving group ;
• Bz is benzoyl ;
• M. C. is methylene chloride ; Ph is phenyl ; pyr is pyridine ; THF is tetrahydrofuran ; and DMSO is dimethylsulfoxide.
• the preferred palladium (Pd) catalyst is tetrakistriphenylphosphine palladium or the mixture of Pd(OAc) 2 , PdCl and Ph 3 P. Even though the mixture of dibenzylidene acetone palladium, dichlorodiphenyl palladium and hydrazine can be used, the tetrakistriphenylphosphine palladium is much desired.
• the amount of palladium (Pd) catalyst is 0.02—0.1 mole %, desirably, 0.04 -0.06 mole %.
• the reaction can be carried out in the temperature range of 20 — 50 °C, preferably, 22 — 28 "C .
• DMF dimethylformamide
• THF tetrahydrofuran
• chloroform can be selected as preferred solvent in case of using the dibenzylidene acetone palladium catalyst.
• DMF can be selected as preferred solvent in case of using the mixture of Pd(OAc) 2 and PI ⁇ 3P.
• the reaction time requires 6 — 10 hours, preferably, 7—9 hours.
• Acetyl is the preferred leaving group represented by X among the acetyl, benzoyl and carbonate.
• the molar ratio of NaBH 4 and sulfuric acid should be about 2 : 1. Further, the sulfuric acid used should be diluted by ether.
• the reaction temperature may be in the range of 0 — 20 °C when sulfuric acid is added.
• the time for adding sulfuric acid may be for 3 — 5 hours, whereas the reflux time using 5N-sodium hydroxide may be for 3 —5 hours.
• the reaction temperature at the time of adding benzoylchloride is preferably about O'C having the addition velocity of 1.0 — 2.0 ml/min.
• the reaction temperature is 20 — 90 "C, preferably, about 60 ° C .
• the reaction time may be for 1.5—2.5 hours.
• benzene, toluene or chloroform can be used as reaction solvent.
• tetrahydofuran/water (9:1) is much preferred solvent.
• the reaction time may be for 30 minutes.
• the reaction temperature is preferably 0 — 20 ° C.
• 4-N-benzoylamino-4-phenyl-2-butenol (V ) can be converted into the starting material of oxazoline synthesis by the reaction with acetic anhydride, benzoyl chloride or ethylchloroformate.
• the reaction time may be for 6 — 10 hours.
• the reaction temperature is preferably 0°C — room temperature.
• the required amount of acetic anhydride, benzoyl chloride or ethylchloroformate is 1.5 — 2.5 in an equivalent ratio, preferably, about 2.0 in an equivalent ratio.
• N-benzoylphenylglycinol is synthesized by following steps of : i ) suspending 1 mole (151g) of (S)-(+)-phenylglycine to 1 L of tetrahydrofuran, ii ) adding 2.5 mole (100g) of NaBH to the solution, iii) dropping 1.25 mole of ether-diluted sulfuric acid (66ml, total volume 200ml) to the solution at 0 °C, iv) after reacting the solution for 12 hours at room temperature, adding 200ml of methanol slowly, v ) after adding 1 L of 5N-NaOH, evaporating organic solvent and refluxing for 3 hours, vi) after cooling to room temperature, adding 1 L of methylenechloride to the solution, vii) adding 1 mole of benzoylchloride to the solution slowly at 0°C, vi ⁇ ) after finishing the reaction, filtering the reaction mixture, ix) washing the product with hot water three times, and x
• N-benzoylaminoaldehyde is synthesized by following steps of : i ) suspending 0.1 mole (24.1g) of N-benzoylphenylglycinol to 100 ml of methylenechloride/methylsulfoxide (5:1), ii ) after cooling to 0°C, adding 31.8g (0.2 mole) of sulfurtrioxide-pyridine to the solution, ⁇ i) after adding 55 ml (0.4 mole) of triethylamine, agitating the solution for 2 hours, iv) after finishing the reaction, adding 200 ml of ethylacetate to the reaction mixture, v ) washing the reaction mixture with 100 ml of water and 100 ml of saturated NH C1 solution, vi) drying the reaction mixture with magnesium sulfate, and vii) obtaining 21g (87%) of crude N-benzoylaminoaldehyde after filtering and drying the product.
• 4-N-benzoylamino-4-phenyl-2-butenol is synthesized by following steps of : i ) adding 50 ml of tetrahydrofuran/ water (9:1) to 13.3g (0.05 mole) of 4-N-benzoylamino-4-phenyl-2-butenal, ii ) after adding 1.9g (0.05 mole) of NaBH ⁇ agitating the solution for 30 minutes, iii) after adding 30 ml of 1N-HC1, extracting the reaction mixture with 50 ml of ether, iv) drying the reaction mixture with magnesium sulfate, and v ) obtaining 13.6g of crude 4-N-benzoylamino-4-phenyl-2-butenol after filtering the product.
• l-acetoxy-4-N-benzoylamino-4-phenyl-2-butene is synthesized by following steps of : i ) adding 20 ml of pyridine to 13.6g (0.05 mole) of 4-N-benzoylamino-4-phenyl-2-butenol, ii ) after adding 10.2g (0.1 mole) of acetic anhydride, agitating the solution for 4 hours, iii) after finishing the reaction, adding 50 ml of methylene chloride, iv) washing the reaction mixture with 50 ml of 1N-HC1 and 50 ml of saturated NaHC0 3 solution, and v ) obtaining 14.7g (95%) of l-acetoxy-4-N-benzoylamino-4-phenyl-2-butene after recrystallizing the product using the solvent of hexane/ethylacetate (2:1).
• N-benzoylphenylalaninol is synthesized by following steps of : i ) suspending 1 mole (163g) of L-phenylalaninol to 1 L of tetrahydrofuran, ii ) adding 2.5 mole (lOOg) of NaBH to the solution, iii) dropping 1.25 mole of ether-diluted sulfuric acid (66ml, total volume 200ml) to the solution at 0°C, iv) after reacting the solution for 12 hours at room temperature, adding 200ml of methanol slowly, v ) after adding 1 L of 5N-NaOH, evaporating organic solvent and refluxing for 3 hours, vi) after cooling to room temperature, adding 1 L of methylenechloride to the solution, vii) adding 1 mole of benzoylchloride to the solution slowly at 0"C, vi ⁇ ) after finishing the reaction, filtering the reaction mixture, ix) washing the product with hot water three times, and x ) obtaining
• N-benzoylaminoaldehyde is synthesized by following steps of : i ) suspending 0.1 mole (25.5g) of N-benzoylphenylalaninol to 100 ml of methylenechloride/methylsulfoxide (5:1), ii ) after cooling to 0°C, adding 31.8g (0.2 mole) of sulfurtrioxide-pyridine to the solution, iii) after adding 55 ml (0.4 mole) of triethylamine, agitating the solution for 2 hours, iv) after finishing the reaction, adding 200 ml of ethylacetate to the reaction mixture, v ) washing the reaction mixture with 100 ml of water and 100 ml of saturated NH C1 solution, vi) drying the reaction mixture with magnesium sulfate, and vii) obtaining 22g (87%) of crude N-benzoylaminoaldehyde after filtering and drying the product.
• 4-N-benzoylamino-5-phenyl-2-pentenol is synthesized by following steps of : i ) adding 50 ml of tetrahydrofuran/ water (9:1) to 14.0g (0.05 mole) of 4-N-benzoylamino-5-phenyl-2-pentenal, ii ) after adding 1.9g (0.05 mole) of NaBH ⁇ agitating the solution for 30 minutes, iii) after adding 30 ml of lN-HCl, extracting the reaction mixture with 50 ml of ether, iv) drying the reaction mixture with sodium sulfate, and v ) obtaining 14.06g of crude 4-N-benzoylamino-5-phenyl-2-pentenol after filtering the product.
• l-acetoxy-4-N-benzoylamino-5-phenyl-2-pentene is synthesized by following steps of : i ) adding 20 ml of pyridine to 14.6g (0.05 mole) of 4-N-benzoylamino-5-phenyl-2-pentenol, ii ) after adding 10.2g (0.1 mole) of acetic anhydride, agitating the solution for 4 hours, iii) after finishing the reaction, adding 50 ml of methylene chloride, iv) washing the reaction mixture with 50 ml of 1N-HC1 and 50 ml of saturated NaHC0 3 solution, and v ) obtaining 15.36g (95%) of l-acetoxy-4-N-benzoylamino-5-phenyl-2-pentene after recrystallizing the product using the solvent of hexane/ethylacetate (2:1).
• (4S-trans)-4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline is synthesized by following steps of : i ) suspending 15.6mg (0.65 mmole) of sodium hydride to 2 ml of DMF (dimethylfor amide), ii ) dropping 200 mg (0.65 mmole) of l-acetoxy-4-N-benzoylamino-4-phenyl-2-butene dissolved in 1 ml of DMF to the solution at 0 ° C, iii) adding 38.1mg (0.033 mmole) of tetrakistriphenylphosphine palladium, iv) after agitating the solution for 8 hours, finishing the reaction, v ) after adding 20 ml of ethylacetate, washing the product with 4 ml of distilled water five times and 20 ml of brine once, vi) after drying the reaction mixture with magnesium sulfate,
• (4S- trans) -4,5-dihydro-2-phenyl-4-benzyl-5-vinyl-oxazoline is synthesized by following steps of : i ) suspending 15mg (0.61 mmole) of sodium hydride to 2 ml of DMF, ii ) dropping 200 mg (0.61 mmole) of l-acetoxy-4-N-benzoylamino-5-phenyl-2-pentene dissolved in 1 ml of DMF to the solution at 0°C, iii) adding 36mg (0.03 mmole) of tetrakistriphenylphosphine palladium, iv) after agitating the solution for 8 hours, finishing the reaction, v ) after adding 20 ml of ethylacetate, washing the product with 4 ml of distilled water five times and 20 ml of brine once, vi) after drying the reaction mixture with magnesium sulfate, filtering the reaction mixture, and
• Table 1 shows the yield of intramolecular cyclizing reaction using palladium catalyst in R groups and leaving groups.
• (4S-trans)-4,5-dihydro-2,4-diphenyl-5-carboxylate methyl ester is synthesized by following steps of : i ) adding 124.6mg (0.5 mmole) of (4S-trans)-4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline to 10 ml of mixture of acetonitrile/carbontetrachloride/ water (1:1:1) agitated in room temperature, ii ) after adding 273mg (3.25 mmole) of sodium bicarbonate and 588mg (5.75 mmole) of sodium periodate to the solution, agitating the solution for 5 minutes, iii) adding catalytic amount (about lmg) of ruthenium chloride, agitating the solution for 2 days, iv) after finishing the reaction, extracting the reaction mixture with ether, v ) acidifying the reaction mixture with 1N-HC1, vi) obtaining 105.5mg (53%
• (4S-trans)-4,5-dihydro-2-phenyl-4-benzyl-carboxylic acid is synthesized by following steps of : i ) adding 138.6mg (0.5 mmole) of (4S-trans)-4,5-dihydro- 2-phenyl-4-benzyl-5-vinyl-oxazoline to 10 ml of mixture of acetonitrile/ carbon- tetrachloride/ water (1:1:1) agitated in room temperature, ii ) after adding 273mg (3.25 mmole) of sodium bicarbonate and 588mg (5.75 mmole) of sodium periodate to the solution, agitating the solution for 5 minutes, iii) adding catalytic amount (about lmg) of ruthenium chloride, agitating the solution for 2 days, iv) after finishing the reaction, extracting the reaction mixture with ether, v ) acidifying the reaction mixture with 1N-HC1, and vi) obtaining 9

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• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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