JP2628909B2 - Diazo derivative - Google Patents

Description

The present invention relates to a pharmaceutical, for example, an intermediate useful for the synthesis of a renin-inhibiting peptin derivative.

Prior Art Peptide derivatives, such as (Wherein, t-Bu represents a t-butyl group, and BOC represents a t-butoxycarbonyl group).
62-252757, etc.).

For the synthesis of these peptide derivatives, the essential homostatin derivative (A) has been conventionally synthesized by the following two methods [for example, Journal of Organic Chemicals,
Chemistry, 52, 4828, 1986 (J. Org. Chem., 5
1 , 4828 (1986), JP-A-62-53952, etc.].

In the above formula, BOC has the same meaning as described above, and R represents alkyl or the like.

Problems to be Solved by the Invention However, these methods are not necessarily advantageous because the reaction step is long, the yield is low, the operation is complicated, and the desired product may not be obtained stereoselectively. Therefore, a method for producing a compound having a desirable steric coordination in a short process with a high yield has been desired.

The inventors of the present application have studied the synthesis method of the homostatin derivative (A) for many years, and have found that the diazo derivative (I) described later is a useful intermediate in an excellent production method of the compound (A). We have completed the present invention.

〔Constitution〕

The useful intermediate of the present invention has the general formula Is a diazo derivative having

In the above formula, R ¹ is a C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a substituted phenyl group (the substituted phenyl group is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group). a group or a halogen atom.) indicates, R ² represents a protecting group of an amino group, R ³ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, R ⁴ is C ₁
Represents a —C ₄ alkyl group, and R ⁵ represents a hydrogen atom or a C ₁ -C ₄ alkyl group.

In the formula (I), C ₁ to C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy group such as R ¹
-C ₄ alkyl moiety, for example, methyl, ethyl, propyl, isopropyl, may be butyl.

The C ₃ -C ₇ cycloalkyl group for R ¹ can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopentyl, cyclohexyl.

The halogen atom contained in R ¹ is, for example, fluorine, chlorine,
It may be a bromine or iodine atom, preferably a fluorine or chlorine atom.

The protection of the amino group of R ² is not particularly limited as long as it is used in the field of peptide chemistry. For example, aralkyloxycarbonyl groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl, benzyl, p
-Nitrobenzyl, aralkyl groups such as p-methoxybenzyl, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, butoxycarbonyl, C ₁ -C ₄ alkoxycarbonyl group such as t-butoxycarbonyl, 9-fluorenylmethylcarbonyl group, formyl,
Like acetyl, propionyl, butyryl, valeryl
C ₁ -C ₅ aliphatic acyl group or be a phthaloyl group, preferably, aralkyloxycarbonyl group which may be an aralkyl group or t- butoxycarbonyl group, particularly preferred,
a t-butoxycarbonyl group.

In the general formula (I), preferably, 1) a compound in which R ¹ is a C ₁ -C ₄ alkyl group, a C ₅ -C ₆ cycloalkyl group or a phenyl group, 2) R ² is a t-butoxycarbonyl group, A C ₁ -C ₅ aliphatic acyl group, an aralkyloxycarbonyl group, a compound which is an aralkyl group (particularly a t-butoxycarbonyl group), 3) a compound wherein R ⁴ is a methyl group, 4) a compound wherein R ⁵ is a hydrogen atom 5) R ¹ is an isopropyl, cyclohexyl or phenyl group, R ² is a t-butoxycarbonyl group, R ³ is a hydrogen atom or a methyl group, R ⁴ is a methyl group, and R ^{5 is}
Is a hydrogen atom.

 Next, preferred compounds are specifically exemplified.

The compound having the general formula (I) of the present invention can be easily produced according to the following method.

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above.

The compound (III) is publicly known or is easily produced according to a publicly known method (for example, the aforementioned J. Org. Chem., 51 , 482).
8 (1986)).

The first step is a step of producing the compound (I), which is achieved by converting a carboxylic acid having the general formula (II) into a reactive derivative, and then reacting the reactive derivative with a diazo compound having the general formula (III).

Examples of the reactive derivative of the compound (II) include acid halides such as acid chloride and acid bromide; acid anhydrides; mixed acids with carboxylic acids such as acetic acid, propionic acid, pivalic acid, benzoic acid and trichloroacetic acid. Anhydrides; mixed acid anhydrides with carbonic acid monoesters such as monomethyl carbonate and monoisobutyl carbonate; active esters such as p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxyphthalimide ester and N-hydroxybenztriazole ester Or an active amide with imidazole, triazole, tetrazole, or 2-oxazolone, but is preferably a mixed acid anhydride with a carbonic acid monoester.

These reactive derivatives can be prepared by converting the compound (II) in a conventional manner, for example, in an inert solvent described below, in the presence or absence of a base (eg, an organic amine such as triethylamine, pyridine or N-methylmorpholine). Halogenating agents (eg, thionyl chloride, thionyl bromide, acetyl chloride, acetyl bromide, pivalic acid chloride, benzoic acid chloride, trichloroacetyl chloride, methyl chlorocarbonate, isobutyl chlorocarbonate, p-nitrobenzoyl chloride, pentachlorobenzoyl chloride, etc.)
Or a carboxylic acid corresponding to compound (II),
It is produced by reacting a carbonate monoester or an amine compound in the presence of a dehydrating agent (for example, dicyclohexylcarbodiimide (DCC) or the like).

The reaction between the reactive derivative of compound (II) and compound (III) is performed in an inert solvent in the presence or absence of a base.

The base used is, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, an alkali metal carbonate such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate,
Examples thereof include organic amines such as triethylamine, dimethylaniline, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, pyridine, collidine, and lutidine, and are preferably organic amines.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but is preferably, for example, ether, tetrahydrofuran, ethers such as dioxane, dichloromethane, halogenated hydrocarbons such as chloroform, hexane, Cyclohexane, benzene, toluene,
Examples thereof include hydrocarbons such as xylene, ketones such as acetone and methyl ethyl ketone, and esters such as ethyl acetate. Particularly preferred are ethers.

The reaction temperature is −20 ° C. to 50 ° C., preferably 0 ° C.
To room temperature. The time required for the reaction varies depending on the starting material, the reaction temperature and the like, but is usually 10 minutes to 20 hours, preferably 5 hours to 15 hours.

After completion of the reaction, the target compound (I) of this step can be collected from the reaction mixture by a conventional method. For example,
It can be obtained by distilling off the solvent, adding water, and extracting with a water-immiscible organic solvent. If necessary,
Purification can also be carried out by a conventional method, for example, a recrystallization method or column chromatography.

(Effect)

The compound (I) according to the present invention is useful as an intermediate for the synthesis of a homostatin derivative (IV) which is an essential component of a peptide having renin inhibitory activity. Can lead to the homostatin derivative (VI).

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above, and R ⁶ is a hydroxyl group, a C ₁ -C ₄ alkoxy group, an amino group or a C ₁ -C ₄ Represents an alkylamino group, R ⁷ is methyl,
Ethyl, butyl, 2-methylbutyl, hexyl, octyl, nonyl, the C ₁ -C ₁₀ alkyl groups such as decyl shown.

The second step is a step of producing a compound having the general formula (IV) in an inert solvent (water, alcohol, amine, etc.)
It is achieved by subjecting compound (I) to a so-called Arndt-Eistert reaction in the presence of a catalyst.

The catalyst to be used is not particularly limited as long as it is used in the reaction, but preferably, for example, silver oxide or silver organic carboxylate such as silver acetate or silver benzoate can be used.

Alcohol used is methanol, ethanol, propanol, can be mentioned C ₁ -C ₄ alcohols such as butanol, amines used are ammonia or methylamine, ethylamine, propylamine,
It can be mentioned C ₁ -C ₄ alkyl amines such as Buchiruaminon, preferably, methanol, ethanol. By carrying out this reaction in the presence of water, alcohol and amine, corresponding carboxylic acids, esters and amides are obtained, respectively. Further, water, alcohol or amine can be used in excess as a solvent.

The inert solvent used is not particularly limited as long as it does not participate in the reaction.For example, ethers, ethers such as tetrahydrofuran, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, water described above, Examples thereof include alcohols, amines and mixtures of these solvents, preferably alcohols or ethers, and particularly preferably methanol, ethanol and tetrahydrofuran.

This reaction is suitably carried out in the presence of a base in some cases. As the base to be used, those similar to those used for producing the above-mentioned reactive derivative of the compound (II) can be mentioned, and an organic amine is preferable.

The reaction temperature is usually from −10 ° C. to room temperature, and the time required for the reaction varies depending on the reaction temperature and the like, but is usually from 10 minutes to 10 hours.

The third step is a step of producing a compound having the general formula (V), which is achieved by reacting the compound (IV) with an acid in an inert solvent.

Acids used are, for example, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, organic carboxylic acids such as acetic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfone. acid,
A sulfonic acid such as camphorsulfonic acid can be used, but sulfonic acid is preferred.

The inert solvent used is not particularly limited as long as it does not participate in the reaction.Examples include ethers, ethers such as tetrahydrofuran, methanol, alcohols such as ethanol, ketones such as acetone, and acetonitrile. Examples thereof include nitriles, amides such as dimethylformamide and dimethylacetamide, and mixed solvents thereof, and are preferably alcohols.

The reaction temperature is from 0 ° C to 100 ° C, and the time required for the reaction varies depending on the reaction temperature and the like, but is usually from 10 minutes to
10 hours, preferably 1 to 5 hours.

Further, the compound (Va) in which R ⁵ is a hydrogen atom can be obtained by reacting the compound (Va) in an inert solvent (for example, tetrahydrofuran),
After treatment with a base (eg, lithium, diisopropylamide) to prepare an anion, C ₁ such as methyl iodide, ethyl iodide, ethyl bromide, propyl iodide, butyl iodide, etc.
Is reacted with -C ₄ alkyl halides, formaldehyde, acetaldehyde, acetone, propionaldehyde is reacted with C ₁ -C ₄ aldehyde or ketone such as butyl aldehyde, that is reducing the hydroxyl group to reduce the double bond after the dehydration Can lead to the compound (Vb) in which R ⁵ is a C ₁ -C ₄ alkyl group.

The fourth step is a step for producing a homostatin derivative (VI), and in an inert solvent, an amine having the compound (V) and the general formula (VII) NH ₂ R ⁷ (VII) (wherein R ⁷ is as defined above) Is the same as the above.)

The amines used are methylamine, ethylamine,
Propylamine, butylamine, 2-methylbutylamine, hexylamine, octylamine, nonylamine,
Mention may be made of mono-C ₁ -C ₁₀ alkylamines such as decylamine, but preferably with C ₁ -C ₆ alkylamines such as methylamine, ethylamine, propylamine, 2-methylbutylamine, butylamine, hexylamine. is there. In addition, a large excess of amine can be used also as a solvent.

The inert solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include alcohols such as methanol and ethanol, ethers, ethers such as tetrahydrofuran, and halogenated hydrocarbons such as dichloromethane and chloroform. , Hexane, cyclohexane,
Hydrocarbons such as benzene and toluene can be mentioned, but alcohols are preferred.

The reaction temperature varies depending on the type of amine used, but is usually -20 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
° C. The time required for the reaction varies depending on the starting material, the reaction temperature and the like, but is usually from 10 minutes to 20 hours, preferably from 2 hours to 15 hours.

After completion of the reaction in each step, the product is easily collected from the reaction mixture by a conventional method. For example, the product can be obtained by distilling off the solvent from the reaction mixture, adding water, and extracting with a water-immiscible organic solvent. Further, if necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

As described above, in the step of producing the compound (VI) from the compound (I), a reaction product can be obtained under a mild condition and in a high yield, so that the compound (I) can be obtained by converting the compound (IV)
Are extremely useful as intermediates for the production of Further, when compound (I) is obtained as an optical isomer, compound (VI) is produced as an optical isomer because steric coordination is maintained in each reaction.

Hereinafter, the present invention will be further described with reference to Examples and Reference Examples.

Example 1 (4S, 5S) -N-tert-butoxycarbonyl-5- (3
-Diazo-2-oxopropyl) -2,2-dimethyl-4
-Cyclohexylmethyl-1,3-oxazolidine 605 mg of the compound obtained in Reference Example 1 was dissolved in 20 ml of anhydrous tetrahydrofuran, and 0.187 ml of N-methylmorpholine and 0.22 ml of isobutyl chloroformate were added at -20 ° C under a nitrogen atmosphere. Was. After stirring the reaction solution at -20 ° C for 20 minutes, the precipitated N-methylmorpholine hydrochloride was removed by stripping. The solution was added at -20 ° C to a solution of diazomethane in ether obtained from 4 g of N-nitrosomethylurea. Reaction solution at -20 ° C
, And further stirred at room temperature overnight. Excess diazomethane was removed by passing nitrogen gas through the reaction solution, and the solvent was distilled off under reduced pressure. Dissolve the residue in ethyl acetate, water, 5%
-Washed sequentially with aqueous citric acid, saturated aqueous sodium bicarbonate and brine, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain pale yellow crystals. The crystals were recrystallized from n-hexane to obtain 378 mg of the desired product as pale yellow needles. The mother liquor was separated and purified by silica gel column chromatography using cyclohexane / ethyl acetate (3/1) as a developing solvent to obtain 230 mg of the desired product.

Melting point: 80-82 ° C IR spectrum (KBr) cm ^-1 : 2107,1691,1639,1391 Elemental analysis: As C ₂₀ H ₃₃ N ₃ O ₄ Calculated: C; 63.30, H; 8.77, N; 11.07 Actual measurement Value: C; 63.20, H; 8.71, N; 11.01 NMR spectrum (CDCl ₃ ) δ (ppm): 0.8-1.80 (13H, m) 1.50 (9H, s) 1.60 (6H, s) 2.58 (2H, d; J = 7 Hz) 3.60-3.90 (1H, m) 4.10-4.47 (1H, m) 5.38 (1H, s) Example 2 (4S, 5S) -N-tert-butoxycarbonyl-5- (3
-Diazo-2-oxopropyl) -2,2-dimethyl-4
-Benzyl-1,3-oxazolidine 600 mg of the compound obtained in Reference Example 6 was dissolved in 20 ml of anhydrous tetrahydrofuran, and 0.187 ml of N-methylmorpholine and 0.22 ml of isobutyl chloroformate were added at -20 ° C.
Stirred for minutes. The precipitated hydrochloride of N-methylmorpholine was removed by filtration, and the solution was added to an ether solution of diazomethane obtained from 4.0 g of N-methylnitrosourea at -20 ° C and stirred at -20 ° C for 30 minutes. After stirring at room temperature overnight,
Excess diazomethane was removed by passing nitrogen gas through the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 5% aqueous citric acid, aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oil. Purification by silica gel column chromatography using cyclohexane / ethyl acetate (3/1) as a developing solvent gave 608 mg of the desired compound as a yellow oil. Crystallize a small amount with n-hexane,
Light yellow crystals were obtained.

Mp: 77-79 ° C. Elemental analysis: Calculated as _{C 20 H 27 N 3 O 4} : C; 64.32, H; 7.29, N; 11.25 Found: C; 64.09, H; 7.25 , N; 11.17 IR spectrum ( KBr) cm ^-1 : 2118,1705,1623 NMR spectrum (CDCI ₃ ) δ ppm: 1.25 to 1.76 (6H, m) 1.53 (9H, s) 2.17 (1H, m) 2.45 (1H, m) 2.80 (1H, m ) 3.26 (1H, m) 3.83 (1H, m) 4.33 (1H, m) 5.11 (1H, s) 7.20 to 7.33 (5H, m) Reference Example 1 (4S, 5S) -N-tert-butoxycarbonyl-5 -(Carboxymethyl) -2,2-dimethyl-4-cyclohexylmethyl-1,3-oxazolidine 3.45 g of (4S, 5S) -N-tert-butoxycarbonyl-
5- (methoxycarbonylmethyl) -2,2-dimethyl-
90 m of 4-cyclohexylmethyl-1,3-oxazolidine
The mixture was dissolved in 1 l of methanol, and 40 ml of normal sodium hydroxide was added under ice-cooling. After stirring at room temperature for 4 hours and 20 minutes, the reaction solution was ice-cooled again, and 40 ml of normal hydrochloric acid was added. The methanol was distilled off under reduced pressure, and the obtained white crystals were collected, dried, and n-
Recrystallize from hexane to give 3.18 g of the desired product as white crystals
Obtained.

Melting point: 109-111 ° C. Reference Example 2 (4S, 5S) -N-tert-butoxycarbonyl-5- (2
-Methoxycarbonylethyl) -2,2-dimethyl-4-
Cyclohexylmethyl-1,3-oxazolidine 785 mg of the compound of Example 1 was dissolved in 15 ml of anhydrous methanol, and a solution of 68 mg of silver benzoate in 2 ml of triethylamine was added at room temperature. After stirring at room temperature overnight, 5 ml of saturated saline was added to the reaction solution, and the mixture was further stirred for 5 minutes. The reaction solution was passed through celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain 830 mg of a light brown oil. The oil was purified by silica gel column chromatography using cyclohexane / ethyl acetate (10/1) as a developing solvent to obtain 722 mg of the desired product as a colorless oil.

NMR spectrum (CDCI ₃ ) δ (ppm): 0.8 to 1.95 (15H, m) 1.48 (9H, s) 1.58 (6H, s) 2.35 to 2.54 (2H, m) 3.69 (3H, s) 3.62 to 3.90 (2H , m) Reference Example 3 (5s) -5-[(1s) -1- (Nt-butoxycarbonylamino) -2-cyclohexylethyl] dihydrofuran-2 (3H) -one 722 mg of the compound of Reference Example 2 was prepared. Dissolve in 20 ml of methanol, add 50 mg of paratoluenesulfonic acid monohydrate and add
Stir for 20 minutes at room temperature. Further, 100 mg of paratoluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 55 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless oil. This was separated and purified by silica gel column chromatography using cyclohexane / ether 1 (1/1) as a developing solvent to obtain 417 mg of the desired product as a colorless oil. The oil was treated with n-hexane to give white crystals.

Melting point: 70-71 ° C NMR spectrum (CDCI ₃ ) δ (ppm): 0.86-1.85 (13H, m) 1.44 (9H, s) 2.13-2.27 (2H, m) 2.49-2.56 (2H, m) 3.87-3.95 (1H, m) 4.40 (1H, d, J = 13Hz) 4.45 to 4.55 (1H, m) Reference Example 4 (3R, 5S) -5-[(1s) -1- (Nt-butoxycarbonylamino) -2-cyclohexylethyl] -3-
Methyldihydrofuran-2 (3H) -one Dissolve 0.99 ml (7.07 mmol) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran, and add-under a nitrogen atmosphere.
At 78 ° C., 2.83 ml (7.07 mmol) of n-butyllithium (25 M, n-hexane solution) was added, and the mixture was stirred for 30 minutes.
1.0 g (3.2 mmol) of (5s) -5-[(1s) -1- (Nt-butoxycarbonylamino) -2-cyclohexylethyl] dihydrofuran-2 (3H) -one was dissolved in 10 ml of anhydrous tetrahydrofuran. The solution was added, and after stirring at -78 ° C for another 30 minutes, 0.44 ml (7.07 mmol) of methyl iodide was added dropwise. After reacting at the same temperature for 1.5 hours, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to obtain a colorless oil, n-hexane was added, and after crystallization, the solvent was distilled off to obtain 0.69 g of white crystals. Obtained.

Melting point: 80-82 ° C Elemental analysis: As C ₁₈ H ₃₁ NO ₄ Calculated: C; 66.43, H; 9.60, N; 4.30 Found: C; 66.24, H; 9.67, N; 4.38 Reference Example 5 (2R , 4S, 5S) -5- (Nt-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide (3R, 5S) -5-[(1s ) -1
-(Nt-butoxycarbonylamino) -2-cyclohexylethyl] -3-methyldihydrofuran-2 (3
H) -one (0.2 g, 0.615 mmol) was dissolved in methanol (6 ml), methylamine gas was introduced for 3 minutes, and the mixture was allowed to stand for 3 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue to obtain 0.23 g as white crystals.

Melting point: 144-145 ° C Elemental analysis: C ₁₉ H ₃₆ N ₂ O ₄ Calculated: C; 63.21, H; 10.19, N; 7.76 Found: C; 63.28, H; 10.36, N; 7.72 Reference Example 6 (4S, 5S) -N-tert-butoxycarbonyl-5- (carboxymethyl) -2,2-dimethyl-4-benzyl-1,3
-Oxazolidine (4S, 5S) -N-tert-butoxycarbonyl-5
(Methoxycarbonylmethyl) -2,2-dimethyl-4-
After dissolving 3.8 g of benzyl-1,3-oxazolidine in 40 ml of methanol, 20 ml of 1N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours and 15 minutes. Under ice cooling, 20 ml of 1N hydrochloric acid was added, and methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.45 g of the desired compound as a yellow oil.

Elemental analysis: C ₁₉ H ₂₇ NO ₅ Calculated: C; 65.31, H; 7.79, N; 4.01 Found: C; 64.92, H; 7.83, N; 3.91 IR spectrum (liquid film) cm ^-1 : 1737 , 1701 NMR spectrum (CDCI ₃ ) δ ppm: 1.20 to 1.70 (6H, m) 1.53 (9H, s) 2.23 (1H, m) 2.48 (1H, m) 2.77 (1H, m) 3.28 (1H, m) 3.86 ( 1H, m) 4.36 (1H, m) 7.24 (5H, m) Reference Example 7 (4S, 5S) -N-tert-butoxycarbonyl-5- (2
-Methoxycarbonylethyl) -2,2-dimethyl-4-
Benzyl-1,3-oxazolidine 508 mg of the compound obtained in Example 2 was dissolved in 15 ml of anhydrous methanol, a solution of 45 mg of silver benzoate in 2 ml of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After adding 5 ml of saline and stirring for 5 minutes, the reaction solution was passed through celite, and the solution was dried under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a yellow oil. Purification by silica gel column chromatography using cyclohexane / ether (2/1) as a developing solvent gave the target compound as a colorless oil (435m).
g obtained.

Elemental analysis: C ₂₁ H ₃₁ NO ₅ Calculated: C; 66.82, H; 8.28, N; 3.71 Found: C; 66.66, H; 8.25, N; 3.63 IR spectrum (liquid film) cm ^-1 : 1741 , 1699 NMR spectrum (CDCI ₃ ) δ ppm: 1.25 to 1.80 (8H, m) 1.53 (9H, s) 2.24 (2H, m) 2.79 (1H, m) 3.19 (1H, m) 3.61 (3H, s) 3.79 ( 1H, m) 3.90 (1H, m) 7.20 to 7.32 (5H, m) Reference Example 8 (5S) -5-[(1S) -1- (N-tert-butoxycarbonylamino) -2-phenylethyl] dihydro Furan-2 (3H) -one 335 mg of the compound obtained in Reference Example 7 was dissolved in 10 ml of methanol, and 116 ml of paratoluenesulfonic acid / 1 was added at room temperature.
The hydrate was added and stirred for 2 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oil. This oily product was purified by silica gel column chromatography using cyclohexane / ether (1/1) as a developing solvent to give the target compound as colorless crystals.
120 mg were obtained.

Mp: 92 to 94 ° C. Elemental analysis: C ₁₇ H ₂₃ NO ₄ Calculated: C; 66.86, H; 7.59 , N; 4.59 Found: C; 66.64, H; 7.46 , N; 4.57 IR spectrum (KBr) cm ^-1 : 1773,1689,1526 NMR spectrum (CDCI ₃ ) δ ppm: 1.39 (9H, s) 2.11 (2H, m) 2.52 (2H, m) 2.89 (2H, m) 4.01 (1H, m) 4.47 (1H , m) 4.60 (1H, d, J = 13.0Hz) 7.20 to 7.34 (5H, m)

Claims (1)

(57) [Claims] (1) General formula [Wherein, R ¹ is a C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a substituted phenyl group (the substituent is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group Or represents a halogen atom.), R ² represents a protecting group for an amino group, R ³ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, R ⁴ represents a C ₁ -C ₄ alkyl group, R ⁵ represents a hydrogen atom or a C ₁ -C ₄ alkyl group. ] The diazo derivative which has these.