JPH0229675B2 - DERUTAARAKUTONJUDOTAINOSEIZOHO - Google Patents

Description

[Detailed description of the invention]

general formula [In the formula, R ¹ is an amino group with or without a protecting group, R ² is a hydrogen atom, a protection-forming group or a salt-forming cation, and ~ may be axial or equatorial, or a mixture thereof Show that. ] By oxidizing the hexopyranose derivative represented by the general formula [In the formula, R ¹ , R ² and ~ have the same meanings as above. ] It is related with the manufacturing method of obtaining the delta-lactone derivative represented by these. In recent years, with the discovery of thienamycin (USP.3950357), which has useful biological activities,
Research is being actively conducted to obtain various carbapenems purely synthetically. In particular, in synthetic reactions,
It is desired to obtain optically active substances in high yield. Conventionally, optically active substances have been obtained by using optical resolution, etc., but these methods are complicated and have low yields.
For example, the δ-lactone derivative, which is a useful intermediate for the synthesis of thienamycin derivatives obtained by the method described in Tetrahedron Letters, Vol. 22, pp. 913-916 (1981), is However, it is racemic and must be optically resolved to obtain a useful product. Under these circumstances, hexopyranose derivatives of general formula () can be oxidized to produce general formula (), which is a useful intermediate for the synthesis of thienamycin derivatives.
It was discovered that a δ-lactone derivative represented by the formula (2) can be produced, and furthermore, an optically active hexopyranose derivative represented by the general formula () obtained by using a natural sugar, such as D-glucose, in this oxidation reaction. It was discovered that an optically active δ-lactone derivative represented by the general formula () can be obtained by using the following, and the present invention was completed. The present invention will be explained in detail below. The protecting group for R ¹ includes all groups that can normally be used as amino protecting groups, such as acetyl, trichloroethoxycarbonyl,
Tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfenyl, (mono-, di-, tri-)chloroacetyl, tri- Fluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl,
4-(phenylazo)benzyloxycarbonyl,
4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridine-1-oxide-2-
yl-methoxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl,
Examples include acyl groups that are easily eliminated such as 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl, and further include trityl, 2-Nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1- Methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene,
1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-[N-2-methoxyphenyl)carbamoyl]-2-propylidene,
1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5- Examples include groups that are easily eliminated such as oxocyclohexylidene, and protecting groups for amino groups such as di- or trialkylsilyl. In addition, the protection-forming group for ^R2 includes all groups that can normally be used as carboxyl protecting groups, such as methyl, ethyl, n-propyl,
iso-propyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonyl Benzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2
-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl, succinimidomethyl, 1-cyclopropylethyl, Methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinoline-1-oxide-2-ylmethyl, pyridine-1-oxide-
Groups such as 2-yl-methyl and bis(p-methoxyphenyl)methyl are described in JP-A-46-7073 and Dutch Publication No. 7105259. Examples include silyl groups such as dimethylchlorosilyl. Furthermore, as the salt-forming cation, those that form non-toxic salts are particularly preferred. Examples of the non-toxic salts include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; ammonium salts;
and salts with nitrogen-containing organic bases such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N-dibenzylethylenediamine. Next, embodiments of the present invention will be described in detail. The method of the present invention is carried out by reacting the compound represented by the general formula () with an oxidizing agent. The compound represented by the general formula () as a raw material can be obtained by the following production method. The manufacturing route can be diagrammed as follows. [In the formula, R ¹ , R ² and ~ have the same meanings as above,
~ may be cis or trans or a mixture thereof, R ³ is an alkyl group, R ⁴
is an alkyl group, an aralkyl group, an alkoxy group,
R 5 represents an aryloxy group or an aryl group, R ⁵ represents an alkyl group, a cycloalkyl group or a saturated heterocyclic group, and R ⁶ represents an alkyl group. ] Examples of the alkyl group in R ³ , R ⁴ , R ⁵ and R ⁶ include C ₁ to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. The aralkyl group in R ⁴ is a benzyl group, the alkoxy group is a methoxy and ethoxy group, and the aryloxy group is a phenoxy _, naphthyloxy group, etc. However, examples of aryl groups include phenyl and naphthyl groups, and examples of cycloalkyl groups in ^R5 include cyclohexyl groups.
Examples of the saturated heterocyclic group include a tetrahydropyranyl group. Furthermore, each step of (a) to (f) will be briefly explained. Process (a) Carbohydrate Res., Volume 4, Page 422 (1967
Compounds represented by the general formula () obtained by methods such as those described in Journal of Organic Chemistry (J.Org, Chem.), Volume 34, Page 1045 (1969) are , Raney nickel, etc. as a catalyst to perform dehalogenation and reduction of azide, as well as,
Deacylation can be simultaneously performed using a base such as triethylamine as a catalyst to obtain an amino alcohol. This reaction requires a solvent that is inert to the reaction,
For example, it can be carried out in methanol, ethanol, ethyl acetate or acetic acid. The above-mentioned amino alcohol can be subjected to conventional acylation without purification to introduce a protecting group into the amino group to obtain a compound of general formula (). Step (b) The compound of general formula () can be led to the compound represented by general formula () by a normal mild oxidation reaction. Oxidizing agents include pyridinium chlorochromate (PCC), Johns reagent,
Examples include manganese dioxide, ruthenium oxide, dimethylsulfoxide-trifluoroacetic anhydride, dimethylsulfoxide-dicyclohexylcarbodiimide, and dimethylsulfoxide-acetic anhydride. (Reference: Journal of Organic Chemistry (J.Org.Chem), Volume 41, No. 20
No., pp. 3329-3331 (1961)) Steps (c), (d) The compound of general formula () is converted into a compound of general formula () by Horner-Wittig reaction, This can lead to a compound of general formula (). First, for the carbonyl group of the compound represented by the general formula (),

A compound represented by the general formula () can be obtained by reacting a lithium salt of phosphine oxide represented by the formula. This reaction can be carried out in the presence of a solvent inert to the reaction, such as tetrahydrofuran, dimethyl sulfoxide, benzene or diethyl ether. general formula

The lithium salt of phosphine oxide of the formula is prepared by adding a base, such as lithium diisopropyramide or n
- Obtained by reacting butyllithium, etc. This reaction can be carried out at -78°C to room temperature. Next, the compound represented by the general formula () can be reacted with a base to perform a dephosphinic acid reaction to obtain the compound represented by the general formula ().
This reaction can be carried out in the presence of a solvent inert to the reaction, such as dimethylformamide and tetrahydrofuran, and examples of the base include potassium hydride, sodium hydride, and lithium hydride. Horner-Wittig reaction: Reference: Journal of the Chemical Society (J.Chem.
Soc.), Perkin I: pp. 3099-3106 (1979) Step (e) A chromic acid-based oxidizing agent, such as pyridinium chlorochromate (PCC), Collins reagent, A compound of general formula () can be obtained by reacting Johns reagent or pyridinium chromate. This reaction can be carried out using a solvent that is inert to the reaction, e.g.
This can be carried out in the presence of methylene chloride, dimethylformamide, acetone, or the like. Reference: Tetrahedron Letters,
No. 39, pp. 3483-3484 (1977) Step (f) A compound of the general formula () is obtained by subjecting the compound represented by the general formula () to conventional hydrolysis using an acid catalyst. Obtainable. This reaction can be carried out in the presence of a solvent inert to the reaction, such as tetrahydrofuran, acetone, water, or a mixed solvent thereof, and the acid catalyst is
Examples include hydrochloric acid, sulfuric acid, acetic acid and phosphoric acid. When the raw material thus obtained, that is, the hexopyranol derivative represented by the general formula (), is reacted with an oxidizing agent, the target compound, that is, the δ-lactone derivative represented by the general formula () can be obtained. Examples of the solvent used in this reaction include those that do not adversely affect the reaction, such as acetone, tetrahydrofuran, dioxane, and water, and two or more of these solvents may be used as a mixture. The oxidizing agent used in this reaction is
Examples include chromic acid-based oxidizing agents such as John's reagent, pyridinium chlorochromate (PCC) and Collins' reagent, and ruthenium oxide and dimethyl sulfoxide-trifluoroacetic anhydride.
It is used in an amount of 1 to 20 equivalents relative to the compound represented by the general formula (). Reaction temperature is -30℃~50℃
The reaction time is from 1 minute to 2 days, preferably from 30 minutes to 2 hours under ice cooling to room temperature. Further, if necessary, after the reaction, excess oxidizing agent can be removed by reduction with alcohol, for example, isopropyl alcohol. In addition, in the compounds represented by the general formulas () and (), the protection of the amino group and the carboxyl group, their removal, and the formation of a salt of the carboxyl group are carried out according to conventional methods, and the corresponding target compound is can be converted to . Also,
If an active group exists in R ¹ or R ² , it can be optionally protected with a conventional protecting group during the reaction, and the protective group can be removed by a conventional method after the reaction. can. The compound represented by the general formula () obtained as described above can be isolated by a conventional method. Furthermore, the present invention covers all optical isomers and all crystal forms and hydrates of the compounds represented by the general formulas () and (). Furthermore, δ represented by the general formula () of the present invention
-Lactone derivatives are new other than those described in the following literature, and azetidinone derivatives can be obtained by performing the following reactions, that is, removal reaction of the protecting group of the amino group, hydrolysis of the ester, alcoholysis, and ring-closing reaction. Can be done. A thienamycin derivative can be obtained by converting this into a β-ketoester form, performing a ring-closing reaction via an azide form, and introducing a mercapto group. Reference: Tetrahedron Letters, Volume 21, No. 2783~
Page 2786 (1980), Volume 22, Pages 913-916 (1981) Next, the present invention will be explained with reference to Reference Examples and Examples. Reference example 1 Carbohydrate Res., Volume 4, Page 422 (1967
Methyl-3- obtained by the method described in
Azido-4,6-O-benzylidene-2,3-dideoxy-α-D-arabinohexopyranoside
Add 550 ml of carbon tetrachloride to 10.0 g (34.3 mmol),
In addition, 7.3 g (41.2 mmol) of N-bromosuccinimide and 10.0 g (50.7 mmol) of barium carbonate.
Add and heat under reflux for 40 minutes. After cooling, insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. After dissolving the obtained residue in 200 ml of chloroform, it was washed sequentially with a 5% aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine.
Dry with anhydrous magnesium sulfate. The solvent was distilled off and the resulting oil was subjected to column chromatography.
Purification by (silica gel, C-200; eluent, hexane/ethyl acetate) yields 11.1 g of white crystals. Furthermore, when recrystallized from isopropyl alcohol, methyl-3-acido-4-O-benzoyl-6-
9.2 g (yield 76.4%) of bromo-2,3,6-trideoxy-α-D-arabinohexopyranoside are obtained. IR (KBr) cm ^-1 ; νN ₃ 2105, νC=O1722 Optical rotation; [α] ²⁰ _D +41.9° (C1.00, CHCl ₃ ) Elemental analysis; C ₁₄ H ₁₆ N ₃ O ₄ Br Calculated value ( %): C; 45.42 H; 4.36 N; 11.35 Actual value (%): C; 45.50 H; 4.33 N; 11.37 NMR ( _CDCl3 ) δ 1.50-2.45 (2H, m, _C2 -H), 3.41 (3H , s, -OCH ₃ ), 3.30-3.60 (2H, m, C ₆ -H), 3.69-4.35 (2H, m, C ₃ -H, C ₅ -H), 4.87 (1H, m, C ₁ - H), 5.06 (1H, m, C ₄ −
H), 7.10~8.20 (5H, m,

[Formula]) Reference Example 2 Methyl-3- obtained by the method of Reference Example 1
acid-4-O-benzoyl-6-bromo 2,
10.0 g (27.0 mmol) of 3,6-trideoxy-α-D-arabinohexopyranoside with methanol
800 ml, 20 g of Raney Nickel W-4 and 3.8 ml (27.2 mmol) of triethylamine were added, and medium pressure catalytic reduction was carried out at 3.8 Kg/cm ² for 8 hours under a hydrogen atmosphere. The reaction solution is filtered and the residue is washed with 350 ml of methanol. The filtrate and washing solution are combined and the solvent is distilled off under reduced pressure to obtain crude methyl-3-amino-2,
3,6-trideoxy-α-D-arabinohexopyranoside is obtained. Without purifying the resulting residue, 100 ml of methylene chloride and 4.3 ml (30.8 mmol) of triethylamine are added, and while stirring, 4.2 ml (29.4 mmol) of benzyloxycarbonyl chloride is further added under ice cooling. After stirring at room temperature for 4 hours, the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, C-200; eluent: benzene/ethyl acetate), followed by recrystallization from benzene, with a melting point of 132~ Needle-shaped methyl-3-benzyloxycarbonylamino-2, exhibiting a temperature of 135°C.
4.1 g (yield 52.3%) of 3,6-trideoxy-α-D-arabino-hexopyranoside are obtained. IR (KBr) cm ^-1 ; νOH3410, νNH3305, νC=O1680 Optical rotation: [α] ²² _D +117.4° (C1.37, CHCl ₃ ) Elemental analysis; C ₁₅ H ₂₁ NO ₅ calculated value (%) C : 61.00 H; 7.17 N; 4.74 Actual value (%) C; 61.14 H; 7.30 N; 4.63 Mass spectrometry; (m/z) 295 (M ⁺ ) NMR (CDCl ₃ ) δ 1.27 (3H, d, J = 6 Hz , C ₆ −H), 1.63 (1H, ddd, J _C2-Ha,C2-He = 13Hz,
J _C2-Ha,C3-H = 13Hz, J _C2-Ha,C1-H = 3Hz, C ₂ -Ha), 2.01 (1H, dd, J _C2-He,C2-Ha = 13Hz, J _{C2-He, C3-H}
=4Hz, _C2 -He), 3.30 (3H, s, _-OCH3 ), 2.70~4.22 (4H, m, _C3 -H, _C4- H, _C5-
H, -OH), 4.64 (1H, bd, J _C1-H,C2-Ha = 3Hz, C ₁ -H), 5.04 (2H, s,

【formula】), 5.32 (1H, bd, J=7Hz, NH), 7.28 (5H, s,

[Formula]) Reference example 3 Dimethyl sulfoxide 3.84ml (54.2 mmol)
is diluted with 95 ml of methylene chloride and then cooled to -75°C. 5.74ml of trifluoroacetic anhydride at the same temperature
(40.6 mmol) diluted with 13 ml of methylene chloride was added dropwise over 10 minutes, followed by stirring for 15 minutes. Methyl-3- obtained by the method of Reference Example 2
8.0 g (27.1 mmol) of benzyloxycarbonylamino-2,3.6-trideoxy-α-D-arabinohexopyranoside was dissolved in 95 ml of methylene chloride and poured into the previously prepared solution at -65°C or lower. , dripping takes 20 minutes. The reaction solution was heated to -65℃
After stirring for 1.5 hours, triethylamine
11.3 ml (81.0 mmol) was added dropwise over 10 minutes at the same temperature or lower, and then the temperature was raised to 0°C. After the reaction, the reaction solution is washed with 100 ml of water, and the washing solution is re-extracted with 100 ml of methylene chloride. The methylene chloride layers are combined, washed five times with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel, C-200, eluent:
Purify with benzene/ethyl acetate) to obtain white crystals. Furthermore, when recrystallized from diisopropyl ether/hexane, a prismatic crystal of methyl-3-benzyloxycarbonylamino-2,3,6-trideoxy-α-D-arabinohexopyranoside-4 exhibits a melting point of 82-83°C. −7.4 g of ulose (yield
93.3%). IR (KBr) cm ^-1 ; νNH3310, νC=O1730, 1680 Optical rotation: [α] ²⁰ _D +91.2° (C1.00, CHCl ₃ ) Elemental analysis; C ₁₅ H ₁₉ NO ₅ Calculated value (%) C ; 61.42 H; 6.53 N; 4.78 Actual value (%) C; 61.35 H; 6.52 N; 4.60 Mass spectrometry; (m/z) 293 (M ⁺ ) NMR (CDCl ₃ ) δ 1.20 (3H, d, J = 6 Hz , C ₆ −H), 1.86 (1H, ddd, J _C2-Ha,C2-He = 15Hz,
J _C2-Ha,C1-H = 4Hz, J _C2-Ha,C3-H = 14Hz, C ₂ −
Ha), 2.64 (1H, ddd, J _C2-Ha,C2-He = 15Hz,
J _C2-He,C1-H =7Hz, J _C2-He,C3-H =4Hz, C ₂ −
He), 3.34 (3H, s, -OCH ₃ ), 4.28 (1H, q, J=7Hz, C ₅ -H), 4.43~5.23 (2H, m, C ₁ -H, C ₃ -H), 5.01 (2H,s,

【formula】), 5.83 (1H, bd, J=7Hz, NH), 7.20 (5H, s,

[Upper isomer]

IR (KBr) cm ^-1 ; νNH, OH3300 (broad) νC=O1705, νP=O1125, 1110 Optical rotation: [α] ²⁰ _D +60.6° (C1.04, CHCl ₃ ) Mass spectrometry; (m/z ) 539 (M ⁺ ) NMR (CDCl ₃ ) δ 1.15 (3H, d, J=7Hz, C ₆ −H) 1.67 to 2.10 (2H, m, C ₂ −H), 3.23 (3H, s,

[Formula]), 3.26 (3H, s, −OCH ₃ ), 3.78 to 4.72 (4H, m, C ₁ −H, C ₃ −H, C ₅ −
H

【formula】), 5.06(2H,s,

【formula】), 5.22 (1H, bs, −OH) 5.40 (1H, bd, J=10Hz, NH), 7.00~8.20 (15H, m,

[Lower isomer]

IR (KBr) cm ^-1 ; νNH, OH3300 (broad), νC=O1708, νP=O1127, 1111 Optical rotation: [α] ²⁰ _D +72.2° (C1.00, CHCl ₃ ) Mass spectrometry; (m/ z) 539 (M ⁺ ) NMR (CDCl ₃ ) δ 1.19 (3H, d, C ₆ −H), 1.70 to 2.10 (2H, m, C ₂ −H), 3.15 (3H, s,

[Formula]), 3.20 (3H, s, −OCH ₃ ), 3.70 to 5.20 (6H, m, C ₁ −H, C ₃ −H, C ₅ −
H, -OH,

【formula】

[Formula]), 5.75 (1H, bd, J=8Hz, NH), 6.90~8.20 (15H, m,

[Formula]) Reference Example 6 480 mg (4.14 mmol) of potassium hydride (purity: 35%) is washed twice with dry hexane and then dried under reduced pressure. 3 ml of dimethylformamide was added to the obtained potassium hydride to form a suspension, into which methyl-3-benzyloxycarbonylamino-4-diphenylphosphinoylmeximethyl-2,3 obtained in Reference Example 5 was added. ,6-trideoxy-
A solution of 747 mg (1.38 mmol) of the upper isomer of α-D-arabino-hexopyranoside in dimethylformamide is added dropwise under ice cooling over 20 minutes. After stirring for 1 hour under ice cooling, 20 ml of water was added to the reaction solution.
Extraction is carried out four times with 50 ml of ethyl acetate. The organic layers are combined, washed three times with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.
The resulting residue was purified by column chromatography (silica gel, C-200; eluent: benzene/ethyl acetate) and then recrystallized from hexane to form needle-shaped crystals with a melting point of 66-67°C. Methyl-
3-benzyloxycarbonylamino-4-methoxymethylene-2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside 333mg
(yield 74.9%). IR (KBr) cm ^-1 ; νNH3325, νC=O1700 Optical rotation: [α] ²⁰ _D +86.9° (C1.04CHCl ₃ ) Mass spectrometry; (m/z) 321 (M ⁺ ) Elemental analysis; C ₁₇ H ₂₃ NO ₅ Calculated value (%) C; 63.5 H; 7.21 N; 4.36 Actual value (%) C; 63.49 H; 7.26 N; 4.34 NMR (CDCl ₃ ) δ 3.39 (3H, d, J = 6 Hz, C ₆ − H), 1.70-1.85 (1H, m, _C2 -Ha), 2.12-2.45 (1H, ddd, J _C2-Ha,C2-He = 14Hz,
J _C2-He,C3-H =9Hz, J _C2-He,C1-H =4Hz, C ₂ −
He), 3.36 (3H, s, −OCH ₃ ), 3.57 (3H, s, CH ₃ O−CH=), 4.12 to 4.38 (1H, m, C ₃ −H), 4.66 (1H, dq, J _{C5 -H,C5-CH3} =7Hz, J _C5-H,=CH-
=2Hz, _C5 -H), 4.87(1H, dd, J _C1-H,C2-Ha =8Hz, J _C1-H,C2-He
=4Hz, C1 _- H), 5.09(2H,s,

[Formula]), 5.33 (1H, bd, J=8Hz, NH), 6.01 (1H, m, CH ₃ O− CH =), 7.35 (5H, s,

[Formula]) If the same operation is performed for the lower isomer obtained in Reference Example 5, methyl-3-benzyloxycarbonylamino-4-methoxymethylene-
2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside is obtained. Reference Example 7 Methyl-3-benzyloxycarbonylamino-4-methoxymethylene obtained in Reference Example 6
2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside 250 mg (0.78 mmol)
was dissolved in 2.5 ml of methylene chloride, 503 mg (2.33 mmol) of pyridinium chlorochromate was added,
Stir for 1 day at room temperature. Diethyl ether in the reaction solution
After adding 10ml and stirring for 15 minutes, filter silica gel G through a glass filter with a thickness of about 3cm.
Wash the residue with 100 ml of diethyl ether. The filtrate and washing solution were combined, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, C-200; eluent: benzene/ethyl acetate).
If purified with , 78.6 mg of white crystals (yield 30%) will be obtained. Furthermore, if this is recrystallized from diisopropyl ether, methyl-3 crystals with a melting point of 128℃ are formed into needle-like crystals.
-benzyloxycarbonylamino-4-methoxycarbonyl-2,3,4.6-tetradeoxy-
α-D-arabino-hexopyranoside is obtained. IR (KBr) cm ^-1 ; νNH3320, νC=O 1718,
1680 Optical rotation: [α] ²⁰ _D +79.6° (C1.06, CHCl ₃ ) Mass spectrometry; (m/z) 337 (M ⁺ ) Elemental analysis; C ₁₇ H ₂₃ NO ₆ calculated value (%) C; 60.52 H; 6.87 N: 4.15 Actual value (%) C; 60.61 H; 6.93 N; 4.39 NMR ( _CDCl3 ) δ 1.17 (3H, d, J = 6Hz, _C6 - H), 1.65 (1H, ddd, J _C2-Ha,C2-He = 13Hz,
J _C2-Ha,C3-H = 13Hz, J _C2-Ha,C1-H = 3Hz, C ₂ −
Ha), 1.93~2.40 (2H, m, J _C4-H,C5-H = 10Hz, C ₂ −
He, C ₄ −H), 3.32 (3H, s, .OCH ₃ ), 3.60 (3H, s, −COOCH ₃ ), 3.80 to 4.46 (2H, m, J _C4-H,C5-H = 10Hz, C ₃ −
H, C ₅ -H), 4.75 (1H, d, J = 3Hz, C ₁ -H), 4.93 (1H, bd, J = 10Hz, NH), 5.02 (2H, s,

【formula】), 7.30 (5H, s,

[Formula]) Reference Example 8 Methyl-3-benzyloxycarbonylamino-4-methoxycarbonyl- obtained in Reference Example 7
36 mg (0.11 mmol) of 2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside was dissolved in 0.7 ml of tetrahydrofuran, and added to it.
Add 0.7 ml of 0.6N hydrochloric acid and heat under reflux for 3 hours. Add 3 ml of water to the reaction solution and extract twice with 15 ml of ethyl acetate. The ethyl acetate layers are combined, washed successively with saturated brine, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. If the resulting residue is washed with diisopropyl ether, the melting point
3-benzyloxycarbonylamino-4-methoxycarbonyl- as white crystals showing 184-187℃
34 mg (yield 98.4%) of 2,3,4,6-tetradeoxy-α-D-arabinohexopyranose is obtained. IR (KBr) cm ^-1 ; νC=O3410 (shoulder), νNH3320, νC=O1720, 1677 Optical rotation: [α] ²⁰ _D +36.5° (C1.02, MeOH) Mass spectrometry; 323 (M ⁺ ) Implemented Example 1 (1) 3-benzyloxycarbonylamino-4-methoxycarbonyl-2,3,4,6-tetradeoxy-α-D- obtained by the method of Reference Example 8
Arabinohexopyranose 129mg (3.99×
10 ^-4 mol) in 6 ml of acetone and cooled on ice.
8N-Johns reagent 0.172ml (4.56×10 ^-4 mol)
Add. After stirring for 40 minutes under ice cooling, add 0.08 ml of isopropyl alcohol and stir for 10 minutes. Add 40 ml of ethyl acetate to the reaction solution, and wash sequentially with saturated brine, saturated aqueous sodium bicarbonate solution, water, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel, C-200; eluent: benzene/ethyl acetate) to give white crystals. 65 mg (yield
50.7%). Furthermore, if this is recrystallized from benzene/diisopropyl ether, the melting point
(4R, 5S, 6R) − of needle crystals showing 118.5 to 119℃
4-Benzyloxycarbonylamino-5-methoxycarbonyl-6-methyl-δ-lactone is obtained. IR (KBr) cm ^-1 ; νNH3365, νC=O1720 Optical rotation: [α] ²⁰ _D +2.2° (C1.20, CHCl ₃ ) Mass spectrometry; (m/z) 321 (M ⁺ ) Elemental analysis; C ₁₆ H ₁₉ NO ₆ Calculated value (%) C; 59.81 H; 5.96 N; 4.36 Actual value (%) C; 59.88 H; 6.01 N; 4.26 NMR (CDCl ₃ ) δ 1.38 (3H, d, J = 6 Hz, - CH ₃ ), 2.38~2.79 (2H, m, J _C5-H,C6-H = 10Hz, C ₃ −
Ha, C ₅ −H), 3.00 (1H, dd, J = _{C3-He, C3-Ha} = 15Hz,
J _C3-He,C4-H = 7Hz, C ₃ -He), 3.69 (3H, s, -COOCH ₃ ), 4.13~4.62 (2H, m, J _C5-H,C6-H = 10Hz, C ₄ -
H, C ₆ −H), 5.08 (2H, s,

【formula】), 5.22 (1H, bd, J=8Hz, NH), 7.33 (5H, s,

[Formula]) ¹³ C-NMR (CDCl ₃ ) δ 19.6 (Q, -CH ₃ ), 35.4 (T, C-3), 47.3
(D, C-4), 52.4 (D, C-5), 52.8 (Q, -OCH ₃ ), 66.8 (T,

[Formula]), 74.8 (D, C-6), 127.9, 128, 4, 136.0
(

[Formula]) 155.3 (S, -COO-), 169.3, 170.8 (S, C-2, -COO-CH ₂ -) (2) Using 25 mg of 5% palladium on carbon, the (4R ,5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6-
Methyl-δ-lactone 65mg (2.02×10 ^-4 mol)
in a 3 ml methanol solution under a hydrogen atmosphere for 1
Time contact reduction. After filtering off 5% paldium on carbon, the solvent was distilled off under reduced pressure to obtain 38 mg of crude (4R,5S,6R)-4-amino-5-methoxycarbonyl-6-methyl-δ-lactone (yield Get 100%). Add 1 ml of concentrated hydrochloric acid to this,
After heating under reflux for 40 minutes, it is distilled off under reduced pressure. Furthermore, benzene azeotropy was performed three times to obtain crude (4R, 5S, 6R)-4-amino-
42 mg (yield 100%) of 5-carboxyl-6-methyl-δ-lactone hydrochloride is obtained. Add 0.3ml of benzyl alcohol to this, and while stirring,
React at 70℃ for 7 hours to form benzyl=(3R,4S,
5R)-3-amino-4-carboxyl-5-hydroxy-hexanate hydrochloride was obtained, and to this reaction solution were added 0.3 ml of benzyl alcohol, 42 mg (2.02 x 10 ^{-4 mol) of dicyclohexylcarbodiimide and 0.028 ml (2.02 x 10 -4} mol) of triethylamine ^{. 4} mol) and stirred at 55°C for 5.5 hours. After cooling, the precipitated crystals were filtered off, and the filtrate was subjected to column chromatography (silica gel, C-200; eluent: benzene/ethyl acetate) to obtain (3S,4R)-3
23 mg of -[(1'R)-1'-hydroxyethyl]-4-benzyloxycarbonylmethyl-2-azetidinone are obtained as an oil. [(4R, 5S, 6R)
-4-benzyloxycarbonylamino-5-
Yield from methoxycarbonyl-6-methyl-δ-lactone: 43.2%] Optical rotation: [α] ²⁰ _D +9.9° (C2.3, CHCl ₃ ) Mass spectrometry: (m/z) 263 (M ⁺ ) NHR (CDCl ₃ ) δ 1.27 (3H, d, J = 6.3Hz,

[Formula]), 2.74 (2H, d, J = 6.8Hz, C ₅ - H), 2.86 (1H, dd, J _{C3-H, C4-H} = 2.2Hz, J _{C3-H, C} ′ _1-H
= 6.7Hz, C ₃ -H), 3.09 (1H, bs, -OH), 3.94 (1H, dt, J _C4-H,C3-H = 2.2Hz, J _C4-H,C5-H =
6.8Hz, C ₄ −H), 4.14 (1H, dq, J _C ′ _1-H,C3-H = 6.6Hz, J _C ′ _1-H,CH3 =
6.6Hz

【formula】), 5.13(2H,s,

【formula】), 6.52 (1H, bs, NH), 7.35 (5H, s,

[Formula]) ¹³ C-NMR (CDCl ₃ ) δ 21.3 (Q, CH ₃ ), 39.4 (T, - CH ₂ COO-), 47.6 (D, C-4), 64.0 (D, C-3), 65.3(D,

[Formula]), 66.9(T,

【formula】), 128.4, 129.1, 135.3 (

【formula】), 168.0, 171.2 (S, C-2, COO-)

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ is an amino group with or without a protecting group, R ² is a hydrogen atom, a protection-forming group or a salt-forming cation, and ~ may be axial or equatorial, or a mixture thereof. A general formula characterized by oxidizing a hexopyranose derivative represented by A method for producing a δ-lactone derivative represented by the following formula: "In the formula, R ¹ and R ² have the same meanings as above." 2 3-benzyloxycarbonylamino-4-
Methoxycarbonyl-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranose is oxidized and (4R,5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6
-Methyl-δ-lactone is obtained. 3. The manufacturing method according to claim 1 or 2, characterized in that the oxidation is carried out using a chromic acid-based oxidizing agent. 4. The production method according to claim 3, wherein the chromic acid-based oxidizing agent is Jones's reagent.