KR100308876B1 - Preparation Method for Oxazoline Compounds - Google Patents

Abstract

The present invention relates to a method for preparing an oxazoline compound having easy chemical conversion to beta-amino-alpha-hydroxy acid or gamma-amino-beta-hydroxy acid, which are strong pharmacologically active compounds. First, a compound of the following structural formula (4) is prepared with an α-amino acid such as alanine, valine, leucine, cysteine, cyclohexylglycine, cyclohexylalanine, phenylglycine, p-hydroxyphenylglycine, phenylalanine or p-hydroxyphenylalanine Then, an oxazoline compound (3) is prepared by using an intramolecular cyclization reaction using a palladium compound as a catalyst. Then, an oxazoline compound (1) which is easily chemically converted into beta-amino-alpha-hydroxy acid by oxidation of the vinyl group of the oxazoline compound (3) using RuCl ₃ and NaIO ₄ is synthesized. Or a hydroxyl group at the end of the vinyl group of the oxazoline compound (3) with 9-Borabicyclo [3.3.1] nonane, and the terminal hydroxyl group was subjected to oxidation reaction using RuCl ₃ and NaIO ₄ to gamma-amino-beta. It is possible to prepare an oxazoline compound (2) which is easily chemically converted to -hydroxy acid.

Description

Preparation method for oxazoline compounds {Preparation Method for Oxazoline Compounds}

The present invention relates to beta-amino-alpha-hydroxy acid (β-amino-α-hydroxy acid; β-a-α-h) or gamma-amino-beta-hydroxy, which is a pharmacologically active compound. Easy chemical conversion to acid (γ-amino-β-hydroxy acid; γ-a-β-h) The present invention relates to a method for preparing an oxazoline compound.

β-a-α-h and γ-a-β-h are of great interest due to their various pharmacological activities. Among these compounds, the most representative compounds in chemistry include (2R, 3S) -N-benzoyl-3-phenylisoserine (I), a side chain of Taxol, which is used as an anticancer agent. And (2S, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid (II), ACE (Angiotensin Converting Enzyme), a non-leucine portion of bestatin which has antifungal action. ) Statin (III), an inhibitor, and an analog thereof, 4-amino-3-hydroxy-5-phenylpentanoic acid (IV).

Many methods for preparing β-a-α-h and γ-a-β-h have been published. For the preparation of (2R, 3S) -N-benzoyl-3-phenylisoserine, which is a side of Taxol, Tetrahedron Letters. , 1994, 35, 2845-2848, 1994, 35, 9289-9292 and J. Org. Chem., 1994, 59, 1238-1240, J. Am. Chem. Soc., 1995, 117, 7824-7825 The preparation of (2R, 3S) -N-benzoyl-3-phenylisoserine has been reported, and David, Tetrahedron Letters, 1994, 26, 4483-4484, et al. (2R, 3S) -N-benzoyl-3- The preparation of phenylisoserine and oxazoline compounds with easy chemical conversion has been reported.

The preparation of (2S, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid (II), the virucin portion of bestatin, is described in Tetrahedron Letters, 1995, 36, 909-912, 1994, 35, 6123 -6126, 1993, 34, 7557-7560.

The preparation of statin (III) and 4-amino-3-hydroxy-5-phenylpentanoic acid (IV) is described in J. Org. Chem., 1997, 62, 2292-2297, J.Org. Chem., 1995, 60, 6248-6249, US Pat. No. 4,803,292, Tetrahedron Letters. 1990, 31, 7359-7362.

The present invention is Alanine, Valine, Leucine, Leucine, Cysteine, Cyclohexylglycine (Cyclohexylglycine), Cyclohexylalanine (Cyclohexylalanine), Phenylglycine, p-hydroxyphenylglycine Intramolecular cyclization reaction using α-amino acid such as (p-hydroxyphenylglycine), Phenylalanine or p-hydroxyphenylalanine as a starting material, followed by several steps of reaction, and palladium compound as catalyst To develop a method for preparing an oxazoline compound that is easy to chemical conversion into β-a-α-h or γ-a-β-h having a large pharmacological activity.

The present invention uses the following structural formulas using α-amino acids such as alanine, valine, leucine, cysteine, cyclohexylglycine, cyclohexylalanine, phenylglycine, p-hydroxyphenylglycine, phenylalanine or p-hydroxyphenylalanine as starting materials. After preparing the compound of (4), an oxazoline compound of formula (3) was prepared by intramolecular cyclization reaction using palladium, and the vinyl group of the oxazoline compound was oxidized using RuCl ₃ and NaIO ₄ . To prepare an oxazoline compound which is easily chemically converted to beta-amino-alpha-hydroxy acid represented by the following structural formula (1), or to the vinyl group of the oxazoline compound (3) is 9-Borabicyclo [3.3.1]. amino-introducing the hydroxy group at the terminal and a nonane-terminal hydroxy group a RuCl ₃ and NaIO ₄ to the oxidation reaction can be represented as a compound of formula (2) by chopping with gamma -Hydroxy acid and to a method for chemically preparing the oxazoline compound is easy to switch to.

The composition of the present invention is a method for preparing a compound capable of reacting α-amino acid mentioned above with palladium and a method for preparing an oxazoline compound by an intramolecular cyclization reaction using a palladium compound as a catalyst. .

(Manufacturing Method I)

In the above scheme

LAH is Lithium aluminum hydride (Li (AlH ₄ )),

THF is Tetrahydrofuran,

DMSO is dimethylsulfoxide,

DMAP is DiMethylaminopyridine,

DIBAL is diisobuthylaluminium hydride,

Bz is a benzoyl group,

X is acetate, benzoate, carbonate or Halide which is Cl, Br or I.

Manufacturing Method I is as follows.

The above-mentioned α-amino acid is used for 2.0 to 3.0 equivalents and stirred at 60 to 100 DEG C for 6 to 10 hours to obtain an amino alcohol, which is then subjected to 6 to 6 using 1.0 to 1.5 equivalents of di-tert-butyl dicarbonate. Stirring at 40-60 ° C. for 10 hours gives N-tert-butyloxycarbonyl amino alcohol.

Reaction of N-tert-butyloxycarbonyl amino alcohol with 1.0-2.0 equivalents of oxalyl chloride, 1.1-2.1 equivalents of dimethylsulfoxide and 4.0-8.0 equivalents of diisopropylethylamine for 1 hour Each of the aldehydes was reacted with 1.0-1.5 equivalents of lithium chloride, 1.0-1.5 equivalents of trimethylphosphonoacetate, and 1.0-1.5 equivalents of diisopropylethylamine in anhydrous acetonitrile solvent for 1-24 hours. Prepare β-unsaturated esters.

α-β-unsaturated ester is reacted at 1.0-1.5 equivalents of boron trifluoride-diethyl etherate with -3.0-4.0 equivalents of diisobutylaluminum at -60 to -78 ° C for 30 minutes to 2 hours to prepare allyl alcohol. .

To the synthesized allyl alcohol, 2-4 N HCl dissolved in ethyl acetate was added and reacted at room temperature for 1 to 3 hours, followed by reaction with 0.95 to 1.05 equivalents of benzoyl chloride to prepare N-benzoyl allyl alcohol. To each breaker marked with X.

As the leaving group, acetate, benzoate, carbonate, or halide are used, each of which is 1.0-1.2 equivalents of acetic anhydride, benzoyl chloride, methyl chloroformate, The halide is prepared using 1.0-2.0 equivalents of methane sulfonyl halide, 0.1-0.5 equivalents of dimethylaminopyridine, 1.0-2.0 equivalents of triethylamine.

(Manufacturing Method II)

In the above scheme

R is Methyl, isopropyl, isobutyl, sec-butyl, thiomethyl, cyclohexyl, cyclohexylmethyl, phenyl, p-hydroxyphenyl, phenylmethyl, p-hyroxyphenylmethyl,

9-BBN is 9-Borabicyclo [3.3.1] nonane,

THF is tetrahydrofuran,

Pd (Ph ₃ ) ₄ is tetrakis triphenylphosphine palladium,

X is acetate, benzoate, carbonate or halide which is Cl, Br or I.

Production Method II is as follows.

As a base used for the preparation of the substance of the formula (3) from the substance of the above formula (4), 1.0 to 2.0 equivalents of sodium hydride or 2.0 to 3.0 equivalents of potassium carbonate can be used. The solvent is stirred methylene chloride for 24 to 48 hours at 30 to 40 ℃ when using sodium hydride as a base, and acetonitrile at 2 to 12 hours at 80 to 120 ℃ for potassium carbonate.

The preparation of the substance of the formula (1) from the substance of the above formula (3) is carried out at room temperature using 0.02 to 0.2 equivalents of ruthenium chloride, 4.5 to 8.5 equivalents of sodium bicarbonate, and 4.5 to 6.5 equivalents of sodium periodate at room temperature. Stir for hours. The solvent used for stirring is a mixed solvent of acetonitrile / carbon tetrachloride / water, the composition ratio of which is 1: 1: 1 to 2: 2: 3, and the amount used is 1 to 20 ml per mmol.

Synthesis of the structural formula (2) from the substance of the structural formula (3) is divided into hydroboration and oxidation reaction. First, hydroboration is carried out using 2 to 6 equivalents of 9-BBN at room temperature for 12 to 36 hours, and then primary alcohol is obtained by using ethyl alcohol, 6N-NaOH or H ₂ O ₂ , followed by oxidation. The compound of formula (2) is prepared.

The oxidation reaction is stirred at room temperature for 12 to 24 hours using 0.02 to 0.16 equivalents of ruthenium chloride, 4.5 to 8.5 equivalents of sodium bicarbonate, and 4.5 to 6.5 equivalents of sodium periodate. The amount of the solvent used at the time of stirring is 1-20 ml per mmol, the solvent is acetonitrile / carbon tetrachloride / water, and the ratio of 1: 1: 1-2: 2: 3 is used.

The palladium compound used as a catalyst in the present invention is represented by tetrakistriphenylphosphine palladium, but tributylphosphine, tri-o-tolylphosphine, and tri-p as ligands. Tri-o-tolylphosphine or tris (dibenzylidene) dipalladium is also possible.

Also, palladium (II) acetate (Pd (OAc) ₂ ) or palladium (II) chloride (Palladium (II) chloride, PdCl ₂ ) and triphenylphos phine (Ph ₃ P) Reactivity is also good, but tetrakistriphenylphosphine, palladium, is the best.

Hereinafter, the present invention will be described by the following examples. However, the technical scope of the present invention is not limited by these examples.

Example 1.

4.55 g (120 mmol) of lithium tetrahydroaluminate (Li (AlH ₄ )) is suspended in 210 ml of tetrahydrofuran and 9.07 g (60 mmol) of (S)-(+)-phenylglycine is slowly added. After addition of (S)-(+)-phenylglycine, the mixture was heated to reflux at 90 ° C. for 6 hours, cooled to room temperature, and then added with 7.3 ml of 10% aqueous sodium hydroxide (NaOH) solution and 9.1 ml of H ₂ O, followed by 5 minutes. Was stirred.

After stirring, 14.40 g (66 mmol) of di-tert-butyl dicarbonate dissolved in 80 ml of methylene chloride and 200 mg (1.64 mmol) of dimethylaminopyridine were added and heated to reflux at 90 ° C. for 6 hours. The mixture was cooled to room temperature, filtered through a sodium sulfate layer (Na ₂ SO ₄ pad), and washed four times with methylene chloride.

After washing, the organic layer was concentrated under reduced pressure and recrystallized with methylene chloride-cyclohexane to give 10.49 g (74%) of N-tert-butyloxy-carbonylphenylglycinol.

¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 3.82 (br s, 2H), 4.77 (br s, 1H), 5.31 (br s, 1H), 7.26-7.38 (m, 5H);

¹³ C NMR (CDCl ₃ ) δ 22.1, 57.6, 67.6, 80.7, 127.3, 128.4, 129.5, 140.1, 156.8

Example 2.

<Synthesis of N-tert-butyloxycarbonylphenylalaninol>

4.55 g (120 mmol) of Li (AlH ₄ ) are suspended in 210 ml of THF, and 9.91 g (60 mmol) of (S)-(-)-phenylalanine is carefully added, followed by heating to reflux at 90 ° C. for 6 hours, and cooling to room temperature. 7.3 ml of% NaOH aqueous solution and 9.1 ml of H ₂ O were added sequentially, followed by stirring for 5 minutes.

After stirring, 14.40 g (66 mmol) of di-tert-butyl dicarbonate dissolved in 80 ml of methylene chloride and 200 mg (1.64 mmol) of dimethylaminopyridine were added thereto, heated and refluxed at 70 ° C. for 6 hours, and then cooled to room temperature. Filter through layer (Na ₂ SO ₄ pad) and wash four times with methylene chloride.

After washing, the organic layer was concentrated under reduced pressure and recrystallized with methylene chloride-cyclohexane to obtain 11.31 g (75%) of N-tert-butyloxy-carbonylphenylalaniol.

¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H), 2.85 (d, J = 7.2 Hz, 2H), 3.56 (dd, J = 10.8 Hz, J = 5.4 Hz, 1H), 3.67 (dd, J = 10.8 Hz, J = 3.6 Hz, 1H), 3.88 (m, 1H), 4.86 (br s, 1H), 7.22-7.34 (m, 5H);

¹³ C NMR (CDCl ₃ ) δ 28.3, 37.5, 53.7, 64.2, 79.7, 126.5, 128.5, 129.3, 137.8, 156.1

Example 3.

<Synthesis of N-tert-butyloxycarbonylleucinol>

4.55 g (120 mmol) of Li (AlH ₄ ) was suspended in 210 ml of THF, and 7.87 g (60 mmol) of (S)-(+)-leucine was carefully added and heated to reflux at 90 ° C. for 6 hours, followed by cooling to room temperature. Then, 7.3 ml of 10% aqueous NaOH solution and 9.1 ml of H ₂ O were added thereto, followed by stirring for 5 minutes.

After stirring, 14.40 g (66 mmol) of di-tert-butyl dicarbonate dissolved in 80 ml of methylene chloride and 200 mg (1.64 mmol) of dimethylaminopyridine were added thereto, and the mixture was heated and refluxed at 70 ° C. for 6 hours, followed by Na ₂ SO ₄ Filter through pad and wash 4 times with methylene chloride.

After washing, the organic layer was concentrated under reduced pressure, and then column chromatography (hexane: ethyl acetate = 3: 1) gave 8.74 g (67%) of N-tert-butyloxy-carbonyl leucinol.

¹ H NMR (CDCl ₃ ) δ 0.93 (dd, 6H), 1.31 (m, 2H), 1.45 (s, 9H), 1.664 (m, 1H), 2.56 (br s, 1H), 3.50 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.66 (d, J = 10.5 Hz, 1H), 3.72 (m, 1H), 4.58 (br s, 1H);

¹³ C NMR (CDCl ₃ ) δ 22.9, 23.7, 25.5, 29.1, 41.3, 51.7, 67.2, 80.3, 157.2

Example 4.

<Synthesis of 2-N- (tert-butyloxycarbonyl) -amino-3-cyclohexyl-1-propanol>

2 g (10.3 mmol) of (S) -2-amino-3-cyclohexyl-1-propanol, 2.26 g (10.3 mmol) of sodium bicarbonate (NaHCO ₃ ), 2.6 g (31 mmol) of di-tert-butyl dicarbonate It was suspended in 50 ml of methanol and stirred at room temperature for 8 hours.

After the reaction was completed, the mixture was filtered, and the solvent methanol was concentrated under reduced pressure, diluted with 30 ml of diethyl ether, and then filtered again. After filtration, the organic layer was concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 1: 1) to give 2.42 g (91%) of 2-N- (tert-butyloxycarbonyl) -amino-3-cyclohexyl. -1-propanol was obtained.

¹ H NMR (CDCl ₃ ) δ 0.84-0.96 (m, 2H), 1.12-1.28 (m, 8H), 1.64 (s, 9H), 1.75 (m, 2H), 1.78 (d, 1H), 3.49 (dd) , J = 10.5 Hz, J = 6.5 Hz, 1H), 3.66 (d, J = 10.5 Hz, 1H), 3.74 (m, 1H), 4.57 (br s, 1H);

¹³ C NMR (CDCl ₃ ) δ 26.8, 27.0, 27.2, 29.0, 33.6, 34.4, 34.9, 39.8, 51.0, 67.4, 80.3, 157.3

Example 5.

<Synthesis of methyl 4- (N-tert-butyloxycarbonyl) -amino-4-phenyl-2-butenoate>

To 20 ml of methylene chloride, 1.05 ml (12.0 mmol) of oxalyl chloride was added, cooled to −78 ° C., and 0.91 ml (12.8 mmol) of dimethyl sulfoxide was added thereto. After stirring at −78 ° C. for 5 minutes, the reaction temperature was raised to −60 ° C., and then 1.88 g of N-tert-butyloxycarbonyl-phenylglycinol suspended in 25 ml of methylene chloride-dimethylsulfoxide (24: 1) was added. mmol) was added.

The reaction temperature was raised to -35 ° C, stirred for 10 minutes, 8.36ml (48.0 mmol) of diisopropylethylamine was added dropwise for 5 minutes, stirred for 10 minutes, and the reaction temperature was raised to room temperature. H ₂ O 40ml was added to the organic layer. The resulting mixture was washed with 20 ml of 1N-HCl and 20 ml of brine, dried over anhydrous magnesium sulfate anhydrous (MgSO ₄ ), filtered and concentrated under reduced pressure, and then used in the next reaction without purification.

Lithium chloride (LiCl) 397 mg (9.4 mmol) was suspended in 100 ml of anhydrous acetonitrile, 1.5 ml (9.4 mmol) of trimethylphos phonoacetate, 1.36 ml (7.8 mmol) of diisopropylethylamine After sequentially adding the aldehyde (Aldehyde) prepared in advance and stirred for 24 hours.

After stirring, 100 ml of H ₂ O was added, extracted twice with 50 ml of ethyl acetate, washed twice with 50 ml of 1N-HCl, twice with 50 ml of brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Recrystallization from ethyl ether-petroleum ether gave 1.89 g (83%) of methyl 4- (N-tert-butyloxycarbonyl) amino-4-phenyl-2-butennoate. .

¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 3.75 (s, 3H), 4.97 (br s, 1H), 5.44 (br s, 1H), 5.99 (dd, J = 15.5Hz, J = 1.5 Hz, 1H), 7.07 (dd, J = 15.5 Hz, J = 5.0 Hz, 1H), 7.25-7.37 (m, 5H);

¹³ C NMR (CDCl ₃ ) δ 29.0, 52.4, 56.2, 80.9, 121.8, 127.9, 128.9, 129.7, 139.9, 148.1, 155.5, 167.3

Example 6.

<Synthesis of methyl 4- (N-tert-butyloxycarbonyl) amino-5-phenyl-2-pentenoate>

To 20 ml of methylene chloride, 1.05 ml (12.0 mmol) of oxalyl chloride was added, cooled to −78 ° C., and 0.91 ml (12.8 mmol) of dimethyl sulfoxide was added thereto. After stirring at −78 ° C. for 5 minutes, the reaction temperature was raised to −60 ° C., and 1.96 g (7.8 mmol) of N-tert-butyloxycarbonyl-phenylalanine was suspended in 25 ml of methylene chloride-dimethylsulfoxide (24: 1). ) Was added.

After raising the reaction temperature to -35 ℃ and stirred for 10 minutes, 8.36ml (48.0mmol) of diisoflophylethylamine was added dropwise for 5 minutes, stirred for 10 minutes, the reaction temperature was raised to room temperature and H ₂ O 40ml was added and the organic layer was separated. After washing with 20 ml of 1N-HCl and 20 ml of brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure, and used in the next reaction without purification.

397 mg (9.4 mmol) of lithium chloride was suspended in 100 ml of anhydrous acetonitrile, 1.5 ml (9.4 mmol) of trimethylphosphonoacetate and 1.36 ml (7.8 mmol) of diisopropylethylamine were added in this order, followed by addition of the aldehyde prepared above. After stirring for 24 hours, 100 ml of H ₂ O was added, extracted twice with 50 ml of ethyl acetate, extracted twice with 50 ml of 1N-HCl, washed twice with 50 ml of brine, dried over MgSO, filtered, and concentrated under reduced pressure. After recrystallization from diethyl ether-petroleum ether, 2.07 g (87%) of methyl 4- (N-tert-butyloxycarbonyl) amino-5-phenyl-2-penteno Obtained eight.

¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 2.89 (d, J = 6.3 Hz, 2H), 3.72 (s, 3H), 4.56 (m, 2H), 5.86 (dd, J = 15.6 Hz, J = 1.5 Hz, 1H), 6.91 (dd, J = 15.6 Hz, J = 5.1 Hz, 1H), 7.16-7.33 (m, 5H);

¹³ C NMR (CDCl ₃ ) δ 28.3, 40.8, 51.6, 53.7, 80.0, 120.7, 126.9, 128.6, 129.4, 136.3, 147.9, 154.9, 166.6

Example 7.

<Synthesis of Methyl 4- (N-tert-butyloxycarbonyl) -amino-6-methyl-2-heptenoate>

1.05 ml (12.0 mmol) of oxalyl chloride was added to 20 ml of methylene chloride, cooled to −78 ° C., and 0.91 ml (12.8 mmol) of dimethyl sulfoxide was added thereto. After stirring at −78 ° C. for 5 minutes and raising the reaction temperature to −60 ° C., 1.70 g (7.8 mmol) of N-tert-butyloxycarbonyl-rucinol suspended in 25 ml of methylene chloride-dimethyl sulfoxide (24: 1) was added. It was.

The reaction temperature was raised to -35 ° C, stirred for 10 minutes, and diisopropylethylamine 8.36ml (48.0mmol) was added dropwise for 5 minutes. After stirring for 10 minutes, the reaction temperature was raised to room temperature, H ₂ O 40ml was added, and the organic layer was separated. Washed with 20 ml of 1N-HCl and 20 ml of brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure, and used in the next reaction without purification.

397 mg (9.4 mmol) of lithium chloride was suspended in 100 ml of anhydrous acetonitrile, 1.5 ml (9.4 mmol) of trimethylphosphonoacetate, 1.36 ml (7.8 mmol) of diisopropylethylamine were added in this order, and the aldehyde prepared above was added thereto. After stirring for 24 hours, 100 ml of H ₂ O was added, extracted twice with 50 ml of ethyl acetate, twice with 50 ml of 1N-HCl, washed twice with 50 ml of brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Column chromatography (hexane: ethyl acetate = 8: 1) gave 1.52 g (72%) of methyl 4- (N-tert-butyloxycarbonyl) -amino-6-methyl-2-heptennoate.

¹ H NMR (CDCl ₃ ) δ 0.94 (dd, 6H), 1.38 (m, 2H), 1.45 (s, 9H), 1.69 (m, 1H), 3.73 (s, 3H), 4.33 (m, 1H), 4.45 (br s, 1H), 5.92 (dd, J = 15.5 Hz, J = 1.5 Hz, 1H), 6.84 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 22.2, 22.7, 24.7,28.3, 43.8, 49.8, 51.6, 80.3, 120.0, 149.2, 155.1, 166.8

Example 8.

<Synthesis of methyl-4- (N-tert-butyloxycarbonyl) -amino-5-cyclohexyl-2-pentenoate>

To 25 ml of methylene chloride, 1.07 ml (12.2 mmol) of allyl chloride was added, cooled to −78 ° C., and then 4.17 ml (23.5 mmol) of dimethyl sulfoxide was added thereto. After stirring at −78 ° C. for 5 minutes, the reaction temperature was raised to −60 ° C., and then suspended in 25 ml of methylene chloride-dimethylsulfoxide (24: 1), N-tert-butyloxycarbonyl-2-amino-3-cyclohexyl 2.42 g (9.4 mmol) of -1-propanol was dissolved in 10 ml of methylene chloride and added dropwise.

The reaction temperature was raised to -35 ° C, stirred for 10 minutes, and 6.56ml (47.0mmol) of triethylamine was added dropwise for 5 minutes. After stirring for 10 minutes, the reaction temperature was raised to room temperature, 16 ml of H ₂ O was added, and the organic layer was separated. Washed with 20 ml of HCl and 20 ml of brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure and used for the next reaction without purification.

478 mg (11.2 mmol) of lithium chloride, 1.83 ml (11.2 mmol) of trimethylphosphonoacetate are suspended in 50 ml of anhydrous acetonitrile and 1.41 ml (9.4 mmol) of 1,8-diazabicyclo [5,4,0] undec-7-ene. After sequentially adding, the aldehyde prepared above was dissolved in 20 ml of acetonitrile and added dropwise.

After stirring for 24 hours, 20 ml of H ₂ O was added and extracted twice with 50 ml of ethyl acetate, washed twice with 20 ml of 1N-HCl and 50 ml of brine, and then dried over MgSO ₄ , filtered, concentrated under reduced pressure and column chromatography (hexane Ethyl acetate = 8: 1) gave 2.04 g (70%) of methyl 4- (N-tert-butyloxycarbonyl) -amino-5-cyclohexyl-2-pentennoate.

¹ H NMR (CDCl ₃ ) δ 0.90-0.96 (m, 2H), 1.15-1.28 (m, 8H), 1.64 (s, 9H), 1.71 (m, 2H), 1.78 (d, 1H), 3.74 (s , 3H), 4.37 (br s, 1H), 4.43 (br s, 1H), 5.92 (dd, J = 15.5 Hz, J = 1.5 Hz, 1H), 6.84 (dd, J = 15.5 Hz, J = 5.0 Hz , 1H);

¹³ C NMR (CDCl ₃ ) δ 26.0, 26.1, 26.4, 28.3, 32.4, 32.9, 33.4, 42.4, 51.5, 51.8 77.4, 119.9, 149.3, 152.1, 166.8

Example 9.

<Synthesis of 4- (N-tert-butyloxycarbonyl) amino-4-phenyl-2-butene-1-ol>

To 29.1 g (100 mmol) of methyl 4- (N-tert-butyloxycarbonyl) amino-4-phenyl-2-butenenoate, 200 ml of methylene chloride was added and cooled to -78 ° C, followed by 13.5 ml of boron trifluoride-diethyl etherate. 100 mmol) was added dropwise. After stirring for 30 minutes, 200 ml (300 mmol) of diisobuthylaluminium hydride dissolved in 1.5 mol of toluene were added dropwise. After stirring for 1 hour, 5M acetic acid dissolved in 230 ml of methylene chloride was added dropwise, and the reaction solution was heated to room temperature and 500 ml of 3M tartaric acid solution was added thereto. The organic layer was separated, the water layer was washed with 200 ml of methylene chloride, and the combined organic layers were washed with 500 ml of saturated sodium bicarbonate aqueous solution and 500 ml with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure.

Recrystallization from diethyl ether-pyrrolium ether gave 23.4 g (89%) of 4- (N-tert-butyloxycarbonyl) -amino-4-phenyl-2-buten-1-ol.

¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 4.19 (dd, J = 5.0 Hz, J = 1.0 Hz, 2H), 4.90 (br s, 1H), 5.30 (br s, 1H), 5.81 ( dt, J = 15.5 Hz, J = 5.0 Hz, 1H), 5.88 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 7.23-7.36 (m, 5H);

¹³ C NMR (CDCl ₃ ) δ 29.1, 56.5, 63.6, 80.5, 127.6, 128.3, 129.4, 131.1, 132.0, 142.0, 155.7

Example 10.

<Synthesis of 4- (N-tert-butyloxycarbonyl) amino-5-phenyl-2-pentene-1-ol>

30.5 g (100 mmol) of methyl 4- (N-tert-butyloxycarbonyl) amino-5-phenyl-2-pentennoate was added to 200 ml of methylene chloride, cooled to -78 ° C, and then 13.5 ml of boron trifluoride-diethyl etherate. 100 mmol) was added dropwise. After stirring for 30 minutes, 200 ml (300 mmol) of diisobutylammonium hydrate dissolved in 1.5 mol of toluene were added dropwise. After stirring for 1 hour, 5M acetic acid (acetic acid) dissolved in 230 ml of methylene chloride was added dropwise, and the reaction solution was raised to room temperature and 500 ml of 3M tartaric acid solution was added thereto. The organic layer was separated, the water layer was washed with 200 ml of methylene chloride, and the combined organic layers were washed with 500 ml of saturated sodium bicarbonate aqueous solution and 500 ml with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. It was then recrystallized from diethyl ether-phytrilium ether to give 25.5 g (92%) of 4- (N-tert-butyloxycarbonyl) -amino-5-phenyl-2-penten-1-ol.

¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H), 2.83 (d, J = 6.9 Hz, 2H), 4.09 (br s, 2H), 4.41 (br s, 1H), 4.54 (br s, 1H) , 5.69 (m, 2 H), 7.16-7.32 (m, 5 H);

¹³ C NMR (CDCl ₃ ) δ 28.3, 41.6, 56.0, 62.7, 79.5, 126.4, 128.3, 129.5, 129.7, 131.4, 137.3, 155.2

Example 11.

<Synthesis of 4- (N-tert-butyloxycarbonyl) amino-6-methyl-2-heptene-1-ol>

27.1 g (100 mmol) of methyl4- (N-tert-butyloxycarbonyl) amino-6-methyl-2-heptennoate was added to 200 ml of methylene chloride, cooled to -78 ° C, and then 13.5 ml of boron trifluoride-diethyl etherate. (100 mmol) was added dropwise. After stirring for 30 minutes, 200 ml (300 mmol) of diisobutylammonium hydrate dissolved in 1.5 mol of toluene were added dropwise. After stirring for 1 hour, 5M acetic acid dissolved in 230 ml of methylene chloride was added dropwise, and the reaction solution was heated to room temperature and 500 ml of 3M tartaric acid aqueous solution was added thereto. The organic layer was separated, the aqueous layer was washed with 200 ml of methylene chloride, and the combined organic layers were washed with 500 ml of saturated aqueous sodium bicarbonate solution and 500 ml with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Column chromatography was performed (hexane: ethyl acetate = 2: 1) to obtain 20.4 g (84%) of 4- (N-tert-butyloxycarbonyl) amino-6-methyl-2-hepten-1-ol.

¹ H NMR (CDCl ₃ ) 0.89 (dd, 6H), 1.30 (m, 2H), 1.41 (s, 9H), 1.61 (m, 1H), 4.11 (t, 3H), 4.38 (br s, 1H), 5.55-5.60 (m, 1 H), 5.71-5.77 (m, 1 H);

¹³ C NMR (CDCl ₃ ) 22.4, 22.7, 24.7, 28.4, 44.7, 50.1, 63.1, 79.7, 129.0, 133.0, 155.3

Example 12.

<Synthesis of 4- (N-tert-butyloxycarbonyl) amino-5-cyclohexyl-2-pentene-1-ol>

2.04 g (6.5 mmol) of methyl-4- (N-tert-butyloxycarbonyl) amino-5-cyclohexyl-2-pentenenoate was added to 200 ml of methylene chloride, cooled to -78 ° C and boron trifluoride-diethyl etherate 0.88 ml (7.1 mmol) was added dropwise. After stirring for 30 minutes, 13.0 ml (19.5 mmol) of diisobutylammonium hydrate dissolved in 1.5 mol of toluene were added dropwise. After stirring for 1 hour, 5M acetic acid dissolved in 14 ml of methylene chloride was added dropwise, and the reaction solution was allowed to reach room temperature, and 55 ml of 3M tartaric acid aqueous solution was added thereto. The organic layer was separated, the aqueous layer was washed with 60 ml of methylene chloride, and the combined organic layers were washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Column chromatography (hexane: ethyl acetate = 2: 1) afforded 1.59 g (86%) of 4- (N-tert-butyloxycarbonyl) amino-5-cyclohexyl-2-penten-1-ol.

¹ H NMR (CDCl ₃ ) δ 0.87 (m, 2H), 1.14-1.31 (m, 8H), 1.41 (s, 9H), 1.63 (m, 2H), 1.71 (d, 1H), 4.11 (br s, 2H), 4.14 (br s, 1 H), 4.18 (br s, 1 H), 5.59-5.61 (m, 1 H), 5.70-5.76 (m, 1 H);

¹³ C NMR (CDCl ₃ ) δ 26.1, 26.2, 26.4, 28.4, 33.0, 33.4, 34.1, 43.3, 49.2, 63.1, 77.4, 128.8, 133.1, 152.0

Example 13.

<Synthesis of 4- (N-benzoyl) amino-4-pheyl-1-acetoxy-2-butene>

2.6 g (10 mmol) of 4- (N-tert-butyloxycarbonyl) amino-4-phenyl-2-butene-1-ol was added to 10 ml of 3N-HCl dissolved in ethyl acetate, followed by stirring for 30 minutes. 20 ml of H ₂ O was added, followed by extraction with 30 ml of ethyl acetate. The water layer was basified with potassium carbonate, extracted twice with 20 ml of methylene chloride, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. 1.17 g (72%) of 4-phenyl-2-butene-1-ol were obtained. 20 ml of methylene chloride was added thereto, and after cooling to 0 ° C., 0.83 ml (7.17 mmol) of benzoyl chloride and 1.0 ml (7.17 mmol) of triethylamine were added thereto. After stirring for 1 hour, 0.68 ml (7.17 mmol) of acetic anhydride and 0.58 ml (7.17 mmol) of pyridine were added, followed by stirring for 24 hours. 20 ml of H ₂ O was added to the reaction mixture, and the organic layer was separated, washed with 20 ml of 1N-HCl, 20 ml of saturated sodium bicarbonate aqueous solution and 20 ml of brine, filtered, and concentrated under reduced pressure.

Concentration and recrystallization from methylene chloride-hexane gave 2.17 g (98%) of 4- (N-benzoyl) amino-4-phenyl-1-acetoxy-2-butene.

¹ H NMR (CDCl ₃ ) δ 2.08 (s, 3H), 4.63 (dt, J = 4.5 Hz, J = 1.5 Hz, 2H), 5.82 (dt, J = 15.5 Hz, J = 6.0 Hz, 1H), 5.89 (dd, J = 8.0 Hz, J = 5.5 Hz, 1H), 6.06 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 7.31-7.54 (m , 8H), 7.79-7. 81 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 21.6, 55.2, 64.8, 126.8, 127.7, 127.9, 128.6, 129.3, 129.6, 132.4, 134.1, 134.9, 141.0, 167.1, 171.4

Example 14.

<Synthesis of 4- (N-benzoyl) amino-5-phenyl-1-acetoxy-2-pentene>

To 2.77 g (10 mmol) of 4- (N-tert-butyloxycarbonyl) amino-5-phenyl-2-penten-l-ol, 10 ml of 3N-HCl (in ethyl acetate solution) was added and stirred for 30 minutes. 20 ml of H ₂ O was added, followed by extraction with 30 ml of ethyl acetate. The aqueous layer was basified with potassium carbonate, extracted twice with 20 ml of methylene chloride, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. 4-amino-5-phenyl-2- 1.35 g (76%) of pentene-1-ol were obtained. 20 ml of methylene chloride was added thereto, cooled to 0 ° C, and 0.88 ml (7.62 mmol) of benzoyl chloride and 1.06 ml (7.62 mmol) of triethylamine were added thereto. After stirring for 1 hour, 0.72 ml (7.62 mmol) of acetic anhydride and 0.62 ml (7.62 mmol) of pyridine were added, followed by stirring for 24 hours. 20 ml of H ₂ O was added to the reaction solution, and the organic layer was separated, washed with 20 ml of 1N-HCl, 20 ml of saturated sodium bicarbonate aqueous solution and 20 ml of brine, filtered, and concentrated under reduced pressure. Concentration and recrystallization with methylene chloride-hexane gave 2.43 g (99%) of 4- (N-benzoyl) -amino-5-phenyl-1-acetoxy-2-pentene.

¹ H NMR (CDCl ₃ ) δ 2.05 (s, 3H), 3.01 (dd, J = 6.5 Hz, J = 1.5 Hz, 2H) 4.54 (d, J = 6.0 Hz, 2H), 5.02 (m, 1H), 5.71 (dd, J = 15.5 Hz, J = 1.5 Hz, 1H), 5.84 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 7.22-7.49 ( m, 8H), 7.68-7.69 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 20.9, 41.0, 51.3, 64.1, 117.9, 125.1, 126.8, 128.5, 128.6, 129.5, 131.5, 133.8, 134.4, 136.8, 166.7, 170.6

Example 15.

<Synthesis of 4- (N-benzoyl) amino-6-methyl-1-acetoxy-2-heptene>

To 2.4 g (10 mmol) of 4- (N-tert-butyloxycarbonyl) amino-6-methyl-2-hepten-1-ol, 10 ml of 3N-HCl (in ethyl acetate solution) was added and stirred for 30 minutes. 20 ml of H ₂ O was added, followed by extraction with 30 ml of ethyl acetate. The water layer was basified with potassium carbonate, extracted twice with 20 ml of methylene chloride, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain 4-amino-6-methyl. 1.07 g (75%) of 2-heptene-1-ol were obtained. 20 ml of methylene chloride was added thereto, cooled to 0 ° C., and 0.83 ml (7.17 mmol) of benzoyl chloride and 1.0 ml (7.17 mmol) of triethylamine were added thereto. After stirring for 1 hour, 0.68 ml (7.17 mmol) of acetic anhydride and 0.58 ml (7.17 mmol) of pyridine were added, followed by stirring for 24 hours. 20 ml of H ₂ O was added to the reaction mixture, and the organic layer was separated, washed with 20 ml of 1N-HCl, 20 ml of saturated aqueous sodium bicarbonate solution, and brine (20 ml), filtered and concentrated under reduced pressure. After concentration, column chromatography (hexane: ethyl acetate = 2: 1) afforded 2.11 g (98%) of 4- (N-benzoyl) -amino-6-methyl-1-acetoxy-2-heptene.

¹ H NMR (CDCl ₃ ) δ 0.97 (dd, 6H), 1.50 (m, 2H), 1.71 (m, 1H), 2.07 (s, 3H), 4.56 (d, J = 3.5 Hz, 2H), 4.78 ( m, 1H), 5.78 (m, 2H), 5.96 (d, J = 7.5 Hz, 1H), 7.43-7.53 (m, 3H), 7.77-7.79 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 20.9, 22.3, 22.8, 24.9, 44.2, 48.9, 64.3, 124.4, 126.8, 128.5, 131.5, 134.5, 135.2, 166.6, 170.6

Example 16.

<Synthesis of 4- (N-benzoyl) amino-5-cyclohexyl-1-acetoxy-2-pentene>

To 1.5 g (5.3 mmol) of 4- (N-tert-butyloxycarbonyl) amino-5-cyclohexyl-2-penten-1-ol, 10 ml of 3N-HCl (in ethyl acetate solution) was added and stirred for 30 minutes. . 20 ml of H ₂ O was added, followed by extraction with 30 ml of ethyl acetate, the aqueous layer was basified with potassium carbonate, extracted twice with 20 ml of methylene chloride, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain 4-amino-5-cyclohexyl-2. 0.75 g (78%) of pentene-1-ol was obtained. 20 ml of methylene chloride was added thereto, cooled to 0 ° C., and 0.49 ml (4.29 mmol) of benzoyl chloride and 0.60 ml (4.29 mmol) of triethylamine were added thereto. After stirring for 1 hour, 0.52 ml (6.43 mmol) of acetic anhydride and 0.81 ml (8.58 mmol) of pyridine were added, followed by stirring for 24 hours. 20 ml of H ₂ O was added to the reaction mixture, and the organic layer was separated, washed with 20 ml of 1N-HCl, 20 ml of saturated aqueous sodium bicarbonate solution and 20 ml of brine, filtered, and concentrated under reduced pressure. After concentration, column chromatography (hexane: ethyl acetate = 3: 1) to give 1.20 g (90%) of 4- (N- benzoyl) amino-5-cyclohexyl-1-acetoxy-2-pentene.

¹ H NMR (CDCl ₃ ) δ 0.87-1.02 (m, 2H), 1.10-1.26 (m, 4H), 1.33-1.41 (m, 1H), 1.51 (m, 3H), 1.72 (m, 2H), 1.83 (d, 1H), 2.06 (s, 3H), 4.57 (m, 2H), 4.80 (m, 1H), 5.75 (m, 2H), 5.98 (m, 1H), 7.42 (m, 1H), 7.51 ( m, 1 H), 7.77 (m, 1 H);

¹³ C NMR (CDCl ₃ ) δ 21.7, 26.8, 26.9, 27.1, 33.6, 34.2, 35.0, 43.5, 48.9, 65.0, 124.9, 127.5, 129.3, 132.2, 135.2, 136.1, 167.3, 171.4

Example 17.

<Synthesis of (4S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyloxazoline>

50 ml of acetonitrile was added to 927 mg (3 mmol) of 4- (N-benzoyl) amino-4-phenyl-1-acetoxy-2-butene, followed by potassium 930 mg (6 mmol) and tetrakistriphenylphosphine palladium ( 172 mg (0.15 mmol) of Pd (PPh ₃ ) ₄ ) were added sequentially. The mixture was heated to reflux at 70 ° C. for 24 hours, cooled to room temperature in air, filtered through a celite pad and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 10: 1) to give 546 mg (73%). (4S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline was obtained.

¹ H NMR (CDCl ₃ ) δ 4.88 (dd, J = 7.0, 8.0 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 5.33 (d, J = 10.5 Hz, 1H), 5.38 (d, J = 17.5 Hz, 1H), 6.09 (ddd, J = 7.0, 10.5, 17.5 Hz, 1H), 7.31-7.53 (m, 8H), 8.08 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 76.8, 89.2, 118.6, 127.4, 128.3, 128.4, 129.1, 129.2, 129.5, 132.3, 136.6, 142.4, 164.7

Example 18.

<Synthesis of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyl-5-vinyl-oxazoline>

120 mg (60% dispersion, 3 mmol) of sodium hydride was suspended in methylene chloride, and then 970 mg (3 mmol) of 4- (N-benzoyl) amino-5-phenyl-1-acetoxy-2-pentene was dissolved in 10 ml of methylene chloride. The solution was added dropwise at 0 ° C. and added 172 mg (0.15 mmol) of Pd (PPh ₃ ) ₄ . Heated to reflux at 35 ° C. for 24 hours, and after completion of the reaction, cooled to room temperature in air, filtered through a silica pad, washed with 20 ml of methylene chloride, and distilled under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 10: 1) yielded 616 mg (yield 78%, 91% de (diastereomeric excess)) (4S-trans) -4,5-dihydro-4-benzyl-2-phenyl-5-vinyl-oxazoline.

¹ H NMR (CDCl ₃ ) δ 2,79 (dd, J = 7.5, 13 Hz, 1H), 3.26 (dd, J = 5.5, 13 Hz, 1H), 4.26 (ddd, J = 5.5, 7.0, 7.5 Hz, 1H ), 4.76 (dd, J = 6.5, 7.0 Hz, 1H), 5.06 (dd, 2H), 5.72 (ddd, 1H), 7.22-7.51 (m, 8H), 7.97-8.01 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 42.2, 74.5, 84.6, 116.5, 126.5, 128.3, 128.4, 129.2, 129.5, 131.3, 136.2, 137.5, 163.0

Example 19.

<Synthesis of (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyl-5-vinyl-oxazoline>

120 mg (60% dispersion, 3 mmol) of sodium hydride was suspended in 30 ml of methylene chloride, and then 895 mg (3 mmol) of 4- (N-benzoyl) amino-6-methyl-1-acetoxy-2-heptene was dissolved in 10 ml of methylene chloride. Slowly dropwise at 0 ° C. and Pd (PPh ₃ ) ₄ 172 mg (0.15 mmol) were added. After refluxing for 24 hours and confirming the completion of the reaction, the mixture was filtered through a silica layer, washed with 20 ml of methylene chloride, distilled under reduced pressure, and separated by column chromatography (hexane: ethyl acetate = 20: 1) to give 515 mg (yield 75%, 91). (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyl-5-vinyl-oxazoline of% de) was obtained.

¹ H NMR (CDCl ₃ ) δ 0.98 (dd, 6H), 1.41 (m, 1H), 1.65 (m, 1H), 1.89 (m, 1H), 4.01 (dd, J = 9.5 Hz, J = 7.0 Hz, 1H), 4.63 (dd, J = 7.0 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 5.39 (d, J = 16 Hz, 1H), 5.96 (ddd, J = 16.0 Hz, J = 10.5 Hz, J = 7.0 Hz), 7.39-7.49 (m, 3H), 7.95-7.98 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 22.6, 22.9, 25.0, 45.2, 70.8, 86.3, 117.1, 128.0, 128.2, 128.3, 131.2, 136.5, 162.4

Example 20.

<Synthesis of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyl-5-vinyl-oxazoline>

65 mg (60% dispersion, 2.73 mmol) of sodium hydride are suspended in 15 ml of methylene chloride, and then 900 mg (2.73 mmol) of 4- (N-benzoyl) amino-5-cyclohexyl-1-acetoxy-2-pentene is added to methylene chloride. It was dissolved in 10 ml and slowly added dropwise at room temperature, and 312 mg (0.27 mmol) of Pd (PPh ₃ ) ₄ was added thereto. After stirring for 24 hours at 40 ℃, the reaction was completed, cooled to room temperature in air, filtered through a silica layer (silica pad), washed with 20 ml of methylene chloride and distilled under reduced pressure and then column chromatography (hexane: ethyl acetate = 20: 1 ), 528 mg (yield 72%, 90% de) of (4S-trans) -4,5-dihydro-2-phenyl-4-cyclonuxylmethyl-5-vinyl-oxazoline were obtained.

¹ H NMR (CDCl ₃ ) δ 0.95-0.98 (m, 2H), 1.21-1.28 (m, 5H), 1.41-1.44 (m, 1H), 1.64-1.72 (m, 3H), 1.80 (m, 2H) , 4.04 (dd, J = 7.5 Hz, J = 7.0 Hz, 1H), 4.62 (dd, J = 7.0 Hz, 1H), 5.24 (d, J = 10.0 Hz, 1H), 5.37 (d, J = 17.0 Hz , 1H), 5.96 (ddd, J = 17.0 Hz, J = 10.0 Hz, J = 7.0 Hz), 7.38-7.48 (m, 3H), 7.95-7.97 (m, 2H); ¹³ C NMR (CDCl ₃ ) δ 26.2, 26.5, 26.6, 33.3, 33.5, 34.3, 43.7, 70.1, 86.3, 117.0, 128.23, 128.25, 128.26, 131.2, 136.4, 162.4

Example 21.

<Synthesis of (4S-trans) -4,5-dihydro-2,4-diphenyloxazoline-5-carboxyli cacid>

346 mg (1.5S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline (1.5S) while stirring 30 ml of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution at room temperature m mol) was added, followed by adding 819 mg (9.75 mmol) of sodium bicarbonate and 1.76 g (17.25 mmol) of sodium periodate (NaIO ₄ ), stirring for 5 minutes, and then stirring the catalyst ruthenium chloride (about 3 mg). ) Was added and stirred for 2 days. After completion of the reaction, the mixture was extracted with 20 ml of diethyl ether, and then the aqueous layer was acidified with 1N-HCl and extracted with methylene chloride to obtain 317 mg (75%) of (4S-trans) -4,5-dihydro-2,4-di. Phenyloxazoline-5-carboxylic acid was obtained. 20 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, concentrated under reduced pressure, and 330 mg of (4S-trans) -4,5-dihydro-2,4-diphenyloxazoline-5-carboxylic acid methyl. An ester was obtained.

¹ H NMR (CDCl ₃ ) δ 3.87 (s, 3H), 4.93 (d, J = 6.5 Hz, 1H), 5.46 (d, J = 6.5 Hz, 1H), 7.31-7.57 (m, 8H), 8.09- 8.12 (m, 2 H);

¹³ C NMR (CDCl ₃ ) δ 53.5, 75.4, 83.9, 127.2, 127.5, 128.8, 129.2, 129.4, 129.6, 132.7, 141.8, 164.7, 171.4

Example 22.

<Synthesis of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyl-oxazoline-5-carboxylic acid>

395 mg of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyl-5-vinyl-oxazoline (30 ml) of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution at room temperature with stirring 1.5 mmol) was added, followed by 819 mg (9.75 mmol) of sodium bicarbonate and 1.76 g (17.25 mmol) of sodium periodate, followed by stirring for 5 minutes, followed by the addition of ruthenium chloride (about 3 mg) for 2 days. After the reaction was completed, the mixture was extracted with 20 ml of diethyl ether, and the aqueous layer was acidified with 1N-HCl and extracted with methylene chloride to obtain 317 mg (75%) of (4S-trans) -4,5-dihydro-4-benzyl-2. -Phenyloxazoline-5-carboxylic acid was obtained. 20 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, concentrated under reduced pressure, and 330 mg of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyloxazoline-5-carboxylic acid. Methyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 2.89 (dd, J = 7.1 Hz, 13.9 Hz, 1H), 3.12 (dd, J = 6.1 Hz, J = 13.9 Hz, 1H), 3.62 (s, 3H), 4.57 (dd , J = 6.1 Hz, J = 7.1 Hz, 1H), 4.65 (d, J = 6.1 Hz, 1H), 7.13-7.43 (m, 8H), 7.88-7.90 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 41.5, 52,4, 72.7, 79.5, 126.7, 127.0, 128.3, 128.4, 128.5, 129.6, 131.6, 136.6, 163.2, 170.8

Example 23.

<Synthesis of (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyl-oxazoline-5-carboxylic acid>

30 ml of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution at room temperature with stirring (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyl-5-vinyl-oxazoline 392 mg After adding (1.5 mmol), 819 mg (9.75 mmol) of sodium bicarbonate and 1.76 g (17.25 mmol) of sodium periodate were added thereto, followed by stirring for 5 minutes, and then 3 mg of ruthenium chloride as a catalyst was added thereto, followed by stirring for 2 days. After the reaction was completed, the mixture was extracted with 20 ml of diethyl ether, and the aqueous layer was acidified with 1N-HCl, extracted with methylene chloride, and 286 mg (77%) of (4S-trans) -4,5-dihydro-4-isobutyl- 2-Phenyl-oxazoline-5-carboxylic acid was obtained. 20 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, and concentrated under reduced pressure to obtain 302 mg of (4S-trans) -4,5-dihydroxy-4-isobutyl-2-phenyloxazoline-5-carbox. Acid acid methyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 1.00 (dd, 6H), 1.51 (m, 1H), 1.69 (m, 1H), 1.98 (m, 1H), 3.80 (s, 3H), 4.35 (dd, J = 6.0 Hz, J = 9.9 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 7.39-7.52 (m, 8H), 7.96-8.00 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 22.5, 22.8, 25.0, 45.8, 52.5, 70.5, 81.1, 127.2, 128.4, 128.5, 131.6, 162.5, 171.2

Example 24.

<(4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyl-oxazoline-5-carboxylic acid>

(4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyl-5-vinyl-oxazoline with 30 ml of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution at room temperature with stirring After adding 350mg (1.3mmol), 819mg (8.45mmol) of sodium bicarbonate and 1.76g (14.95mmol) of sodium periodate were added thereto, and after stirring for 5 minutes, 3mg of ruthenium chloride as a catalyst was added thereto, followed by stirring for 2 days. After the reaction was completed, the mixture was extracted with 20 ml of diethyl ether, and then the aqueous layer was acidified with 1N-HCl and extracted with methylene chloride to obtain 278 mg (75%) of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl. 2-Phenyl-oxazoline-5-carboxylic acid was obtained. 20 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, and concentrated under reduced pressure. Then, 290 mg of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyl-oxazoline-5- Carboxylic acid methyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 0.95-1.05 (m, 2H), 1.12-1.34 (m, 6H), 1.47-1.84 (m, 5H), 3.80 (s, 3H), 4.40 (dd, J = 6.6 Hz, J = 6.9 Hz, 1H), 4.64 (d, J = 6.6 Hz, 1H), 7.39-7.52 (m, 3H), 7.96-8.00 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 26.2, 26.5, 26.6, 33.2, 33.5, 34.3, 44.4, 52.5, 69.9, 81.2, 128.4, 128.5, 131.2, 136.4, 165.2, 171.7

Example 25.

<Synthesis of (4S-trans) -4,5-dihydro-2,4-diphenyl-5- (2-hydroxyethyl) oxazoline>

10 ml of tetrahydrofuran was added to 249 mg (1.0 mmol) of (4S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyloxazoline and 9-vorabicyclo [3.3.1] nonane (9-Borabicyclo [3.3] 1] nonane, 9-BBN) (0.5M in THF) 6ml (3.0mmol) was added and stirred for 8 hours at room temperature. After the reaction was completed, ₂ ml of ethanol, 0.65 ml of 6N-NaOH, and 1.3 ml of H ₂ O ₂ were sequentially added, stirred for 30 minutes, and extracted twice with 10 ml of ethyl acetate.

The combined organic layers were washed twice with 10 ml of brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 1: 2) to 222 mg (83% yield) of 4S-trans) -4,5. -dihydro-2,4-diphenyl-5- (2-hydroxyethyl) oxazoline was obtained.

¹ H NMR (CDCl ₃ ) δ2.05 (m, 2H), 3.87 (m, 2H), 4.66 (m, J = 4.9Hz, J = 7.3Hz, 1H), 4.96 (d, J = 7.3Hz, 1H ), 7.26-7.52 (m, 8H), 8.02-8.04 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 38.0, 59.5, 75.8, 85.4, 126.7, 127.6, 127.8, 128.4, 128.5, 128.8, 131.7, 141.9, 163.9

Example 26.

<Synthesis of (4S-trans) -4,5-dihydro-4-benzyl-5- (2-hydroxyethyl) -2-phenyloxazoline>

10 ml of tetrahydrofuran was added to 63 mg (1.0 mmol) of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyl-5-vinyloxazoline and 6 ml (3.0 mmol) of 9-BBN (0.5 M in THF) was added. After the addition, the mixture was stirred at room temperature for 8 hours. After the reaction was completed, ₂ ml of ethanol, 0.65 ml of 6N-NaOH, and 1.3 ml of H ₂ O ₂ were sequentially added, stirred for 30 minutes, and extracted twice with 10 ml of ethyl acetate. The combined organic layers were washed twice with 10 ml brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 1: 2) to give 231 mg (82% yield) of (4S-trans) -4, 5-dihydro-4-benzyl-5- (2-hydroxyethyl) -2-phenyloxazoline was obtained.

¹ H NMR (CDCl ₃ ) δ1.52 (m, 1H), 1.83 (m, 1H), 2.71 (dd, J = 9.0 Hz, J = 13.5 Hz, 1H), 3.26 (dd, J = 5.0 Hz, J = 13.5 Hz, 1H), 3.63 (m, 2H), 4.18 (m, J = 5.0 Hz, 6.5 Hz, 9.0 Hz, 1H), 4.55 (m, J = 6.5 Hz), 7.23- 7.50 (m, 8H) , 7.93-7.95 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 38.7, 42.5, 60.0, 74.1, 82.6, 127.4, 128.5, 128.9, 129.0, 129.1, 130.1, 132.1, 138.3, 163.7

Example 27.

<Synthesis of (4S-trans) -4,5-dihydro-5- (2-hydroxyethyl) -4-isobutyl-2-phenyloxazoline>

To 229 mg (1.0 mmol) of (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyl-5-vinyloxazoline, 10 ml of tetrahydrofuran was added and 6 ml (3.0 mmol) of 9-BBN (0.5 M in THF) was added. After the addition, the mixture was stirred at room temperature for 8 hours. After the reaction was completed, ₂ ml of ethanol, 0.65 ml of 6N-NaOH, and 1.3 ml of H ₂ O ₂ were sequentially added, stirred for 30 minutes, and extracted twice with 10 ml of ethyl acetate. The combined organic layers were washed twice with 10 ml brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 1: 1) to give 161 mg (65% yield) of (4S-trans) -4, 5-dihydro-5- (2-hydroxyethyl) -4-isobutyl-2-phenyoxazoline was obtained.

¹ H NMR (CDCl ₃ ) δ 0.98 (d, 6H), 1.38 (m, 1H), 1.62 (m, 1H), 1.90 (m, 2H), 1.97 (m, 1H), 3,88 (m, 2H), 3.95 (m, 1H), 4.44 (m, 1H), 7.39-7.49 (m, 3H), 7.92-7.94 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 23.4, 23.6, 25.6, 38.8, 46.1, 60.4, 71.1, 83.7, 128.7, 128.9, 129.0, 131.9, 163.0

Example 28.

<Synthesis of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-5- (2-hydroxyethyl) -2-phenyloxa zoline>

10 ml of tetrahydrofuran was added to 269 mg (1.0 mmol) of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyl-5-vinyloxazoline and 6 ml (3.0 mmol) of 9-BBN (0.5 M in THF) was added. After the addition, the mixture was stirred at room temperature for 8 hours. After the reaction was completed, ₂ ml of ethanol, 0.65 ml of 6N-NaOH, and 1.3 ml of H ₂ O ₂ were sequentially added thereto, stirred for 30 minutes, and extracted twice with 10 ml of ethyl acetate. The combined organic layers were washed twice with 10 ml brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 2: 1) to 210 mg (78% yield) of (4S-trans) -4, 5-dihydro-4-cyclohexylmethyl-5- (2-hyd roxyethyl) -2-phenyloxazoline was obtained.

¹ H NMR (CDCl ₃ ) δ 0.95-1.00 (m, 2H), 1.15-1.31 (m, 3H), 1.37 (m, 1H), 1.54 (m, 1H), 1.61 (m, 1H), 1.65- 1.98 (m, 8H), 3.88 (m, 2H), 3,98 (m, 1H), 4.42 (m, 1H), 7.38-7.48 (m, 3H), 7.92-7.94 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 26.9, 27.3, 34.2, 34.3, 35.0, 38.8, 44.8, 60.4, 70.5, 83.8, 128.7, 128.9, 129.0, 131.9, 163.0.

Example 29.

<(4S-trans) -4,5-dihydro-2,4-diphenyloxazoline-5-acetic acid synthesis>

(4S-trans) -4,5-dihydro-2,4-diphenyl-5- (2-hydroxyethyl) oxazoline to 267 mg (1.0 mmol) of acetonitrile / carbon tetrachloride / water (1: 1: 1) After adding 10 ml of the mixed solution, 546 mg (6.50 mmol) of sodium bicarbonate and 1.18 g (5.50 mmol) of sodium periodate (NaIO ₄ ) were added thereto, stirred for 5 minutes, and then 33.2 mg of ruthenium chloride as a catalyst was added thereto, followed by stirring for 24 hours. After completion of the reaction, the mixture was extracted with 20 ml of diethyl ether, and the water layer was acidified with 1N-HCl, extracted with methylene chloride, and 275 mg (97%) of (4S-trans) -4,5-dihydro-2, 4-diphenyloxazoline-5-acetyl acid was obtained. 10 ml of diethyl ether was added thereto, and 1.0 ml of diazomethane was added dropwise, followed by concentration under reduced pressure, and 2860 mg of (4S-trans) -4,5-dihydro-2,4-diphenyl-oxazoline-5 acetyl acid methyl ester Got.

¹ H NMR (CDCl ₃ ) δ 2.81 (dd, J = 5.6 Hz, J = 15.8 Hz, 1H), 2.91 (dd, J = 7.6 Hz, J = 15.8 Hz, 1H), 3.73 (s, 3H), 4.91 (m, J = 5.6 Hz, 6.3 Hz, 7.6 Hz, 1H), 5.02 (d, J = 6.3 Hz, 1H), 7.26-7.54 (m, 8H), 8.03-8.05 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 39.8, 52.0, 75.3, 83.2, 126.7, 127.3, 127.9, 128.4, 128.6, 128.8, 131.7, 141.4, 163.8, 170.2

Example 30.

<Synthesis of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyloxazoline-5-acetic acid>

(4S-trans) -4,5-dihydro-4-benzyl-5- (2-hydroxyethyl) -2-phenyl-oxazoline in 281 mg (1.0 mmol) of acetonitrile / carbon tetrachloride / water (1: 1 : 1) After 10 ml of mixed solution was added, 546 mg (6.50 mmol) of sodium bicarbonate and 1.18 g (5.50 mmol) of sodium periodate (NaIO ₄ ) were added thereto, followed by stirring for 5 minutes, followed by addition of 33.2 mg of ruthenium chloride as a catalyst and stirring for 24 hours. It was. After completion of the reaction, the mixture was extracted with 20 ml of diethyl ether, and the water layer was acidified with 1N-HCl, extracted with methylene chloride, and 289 mg (98%) of (4S-trans) -4,5-dihydro-4- Benzyl-2-phenyloxazoline-5-acetyl acid was obtained. 10 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, and concentrated under reduced pressure to obtain 303 mg (98% yield) of (4S-trans) -4,5-dihydro-4-benzyl-2-phenyloxazoline- 5-acetyl acid methyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 2.32 (dd, J = 5.5 Hz, J = 16.0 Hz, 1H), 2.62 (dd, J = 8.0 Hz, J = 16.0 Hz, 1H), 2.79 (dd, J = 8.0 Hz , J = 13.5 Hz, 1H), 3.22 (dd, J = 5.5 Hz, J = 13.5 Hz, 1H), 3.63 (s, 3H), 4.21 (m, J = 5.5 Hz, 6.0 Hz, 8.0 Hz, 1H) 4.78 (m, J = 5.5 Hz, 6.0 Hz, 8.0 Hz, 1H), 7.22-7.50 (m, 8H), 7.92-7.94 (m, 2H).

¹³ C NMR (CDCl ₃ ) δ 40.6, 42.2, 52.6, 73.7, 80.4, 127.3, 128.2, 129.0, 129.3, 130.2, 132.2, 138.0, 163.7, 170.9.

Example 31.

<Synthesis of (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyloxazoline-5-acetic acid>

(4S-trans) -4,5-dihydro-4-isobutyl-5- (2-hydroxyethyl) -2-phenyl-oxazoline 247 mg (1.0 mmol) in acetonitrile / carbon tetrachloride / water (1: 1 : 1) After 10 ml of mixed solution was added, 546 mg (6.50 mmol) of sodium bicarbonate and 1.18 g (5.50 mmol) of sodium periodate (NaIO ₄ ) were added thereto, followed by stirring for 5 minutes, followed by addition of 33.2 mg of ruthenium chloride as a catalyst and stirring for 24 hours. It was. After the reaction was completed, the mixture was extracted with 20 ml of diethyl ether, and the water layer was acidified with 1N-HCl and extracted with methylene chloride to give 227 mg (87% yield) of (4S-trans) -4,5-dihydro-4. -Isobutyl-2-phenyloxazoline-5-acetic acid was obtained. 10 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, and concentrated under reduced pressure to obtain 240 mg of (4S-trans) -4,5-dihydro-4-isobutyl-2-phenyloxazoline-5-acetic acid. Methyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 0.98 (d, 6H), 1.41 (m, 1H), 1.60 (m, 1H), 1.89 (m, 1H), 2.61 (dd, J = 5.5Hz, J = 16.0Hz, 1H), 2.77 (dd, J = 7.5 Hz, 16.0 Hz, 1H), 3.75 (s, 3H), 3.98 (m, J = 5.5 Hz, J = 6.0 Hz, J = 8.0 Hz, 1H), 4.67 (m , J = 5.5 Hz, 6.0 Hz, 7.5 Hz, 1H), 7.38-7.48 (m, 3H), 7.92-7.94 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 23.5, 25.6, 28.0, 40.6, 52.7, 70.9, 81.6, 128.5, 129.0, 132.0, 162.9, 171.3

Example 32.

<Synthesis of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyloxazoline-5-acetic acid>

(4S-trans) -4,5-dihydro-4-cyclohexylmethyl-5- (2-hydroxyethyl) -2-phenyl-oxazoline 287 mg (1.0 mmol) in acetonitrile / carbon tetrachloride / water (1: 1: 1) After 10 ml of mixed solution is added, 546 mg (6.50 mmol) of sodium bicarbonate and 1.18 g (5.50 mmol) of sodium periodate (NaIO ₄ ) are added thereto, stirred for 5 minutes, and then 33.2 mg of catalyst ruthenium chloride is added for 24 hours. Stirred. After completion of the reaction, the mixture was extracted with 20 ml of diethyl ether, the water layer was acidified with 1N-HCl, extracted with methylene chloride, and 280 mg (93% yield) of (4S-trans) -4,5-dihydro-4. -Cyclohexylmethyl-2-phenyloxazoline-5-acetyl acid was obtained. 10 ml of diethyl ether was added thereto, 1.0 ml of diazomethane was added dropwise, and concentrated under reduced pressure to give 293 mg of (4S-trans) -4,5-dihydro-4-cyclohexylmethyl-2-phenyloxazoline-5-acetyl. Acid methyl esters were obtained.

¹ H NMR (CDCl ₃ ) δ 0.89-0.99 (m, 2H), 1.14-1.34 (m, 3H), 1.40 (m, 1H), 1.55-1.90 (m, 7H), 2.60 (dd, J = 5.5 Hz , J = 16.0 Hz, 1H), 2.76 (dd, J = 8.0 Hz, J = 16.0 Hz, 1H), 3.70 (s, 3H), 4.00 (dd, J = 6.0 Hz, 1H), 4.66 (dd, J = 6.0 Hz, 1H), 7.38-7.47 (m, 3H), 7.92-7.93 (m, 2H)

¹³ C NMR (CDCl ₃ ) δ 26.8, 27.2, 33.7, 34.2, 40.6, 44.7, 52.7, 70.2, 81.7, 128.5, 129.0, 132.0, 134.3, 162.9, 171.3

The method for producing an oxazoline compound according to the present invention is an α-amino acid such as alanine, valine, leucine, cysteine, cyclohexylglycine, cyclohexylalanine, phenylglycine, p-hydroxyphenylglycine, phenylalanine or p-hydroxyphenylalanine. In addition, it is possible to selectively synthesize only one stereoisomer in the preparation of (2R, 3S) -N-benzoyl-3-phenylisoserine, which is a component of Taxol side branches, and thus to efficiently produce Taxol side branches and Taxol in high purity. It can manufacture.

In addition, the oxazoline compound prepared according to the present invention can be used for the preparation of a bioactive substance because it is easy to chemically convert into β-amino-α-hydroxy acid or γ-amino-β-hydroxy acid.

Claims (6)

The compound represented by the formula (3) was prepared by using a cyclization reaction using the compound represented by the following formula (4) as a starting material and the palladium compound as a catalyst, followed by the hydrogenation and oxidation reaction. A method for producing an oxazoline compound, characterized in that to prepare a compound represented by). In the above scheme R is Methyl, isopropyl, isobutyl, sec-butyl, thiomethyl, cyclohexyl, cyclohexylmethyl, phenyl, p-hydroxyphenyl, phenylmethyl or p-hyroxyphenylmethyl, Ph is a phenyl group, X is a halide which is acetate, benzoate, carbonate or Cl, Br or I as leaving group, BZ is a benzoyl group. The method for producing an oxazoline compound according to claim 1, wherein the raw material of the compound represented by Structural Formula (4) is produced by the following method using α-amino acid. In the above scheme R is Methyl, isopropyl, isobutyl, sec-butyl, thiomethyl, cyclohexyl, cyclohexylmethyl, phenyl, p-hydroxyphenyl, phenylmethyl or p-hyroxyphenylmethyl, LAH is Lithium aluminum hydride (Li (AlH ₄ )), THF is Tetrahydrofuran, DMSO is dimethylsulfoxide, DIBAL is diisobuthylaluminium hydride, X is a halide which is acetate, benzoate, carbonate or Cl, Br or I as leaving group, Bz is a benzoyl group. The palladium compound according to claim 1, wherein the palladium compound is tetrakistriphenylphosphine palladium, the ligand is tributylphosphine, tri-o-tolylphosphine or tri-p-tolylphosphine, respectively, or palladium ( II) A method for producing an oxazoline compound, characterized in that each of acetate (Pd (OAc) ₂ ) and palladium (II) chloride (PdCl ₂ ) is mixed with triphenylphosphine (Ph ₃ P). The method according to claim 1, wherein the first oxidizing agent used for the oxidation reaction in the synthesis of the oxazoline compound represented by the formula (2) from the compound represented by the formula (3) is sodium hydroxide (NaOH) or hydrogen peroxide (H ₂ O ₂ ) , The second oxidizing agent is sodium hydrogen carbonate (NaHCO ₃ ), or sodium periodate (NaIO ₄ ) method for producing an oxazoline compound, characterized in that. The method of claim 2, wherein the α-amino acid is Alanine, Valine, Leucine, Cysteine, Cyclohexylglycine, Cyclohexyylalyine, Cyclohexylalanine, Phenylglycine , p-hydroxyphenylglycine (p-hydroxyphenylglycine), phenylalanine (Phenylalanine) or p-hydroxyphenylalanine (p-hydroxyphenylalanine) method for producing an oxazoline compound characterized in that. After preparing the oxazoline compound represented by the following structural formula (3) using a cyclization reaction using a compound represented by the following structural formula (4) prepared using a known production method as a starting material and a palladium compound as a catalyst A method for synthesizing an oxazoline compound, comprising producing a compound represented by the following structural formula (1) using an oxidation reaction. In the above scheme R is sec-butyl, thiomethyl, p-hydroxyphenyl, phenylmethyl or p-hyroxyphenylmethyl, Ph is a phenyl group, X is a halide which is Cl, Br or I as leaving group, BZ is a benzoyl group.