JPH0424355B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () "In the formula, one of R ¹ and R ² represents a hydrogen atom and the other represents an alkoxy group; R ³ and R ⁴ , one represents a formula

[Formula] (wherein, R ⁶ represents an aryl group; and R ⁷ represents an alkyl group, respectively), and the other represents a hydroxyl group. ; Also, R ³ and R ⁴ are combined to form the formula =
Forms a group or an oxo group represented by CH~ ^OR8 (in the formula, ^R8 represents an alkyl group; and ~ indicates that it may be a cis or trans form, or a mixture thereof.) You can leave it there. R ⁵ is an amino group having a protecting group;
Each indicates that it may be axial or equatorial, or a mixture thereof. ” It relates to a D-hexopyranose derivative represented by the following. In recent years, with the discovery of thienamycin (US Pat. No. 3,950,357), which has useful biological activity, research has been actively conducted to obtain various carbapenems purely synthetically. In particular, in synthetic reactions, it is desired to obtain optically active substances in high yields. Conventionally, optically active substances have been obtained by using optical resolution, but this method is complicated and has a low yield. For example, (4R,
5S,6R)-4-amino-carboxy-6-methyl-δ-lactone has a fixed configuration, but
It is racemic and must be optically resolved to obtain a useful product. Under such circumstances, the present inventors
As a result of various studies, it was discovered that the compound represented by the general formula () is a useful intermediate in the synthesis of thienamycin derivatives. The present invention was completed based on the discovery that it can be obtained without optical resolution by using sugar. The present invention will be explained in detail below. As the alkoxy group in R ¹ and R ² ,
Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-
C ₁ such as butoxy or tert-butoxy
~ _C10 branched or straight chain alkoxy groups. Aryl groups in R ⁶ include phenyl or naphthyl; alkyl groups in R ⁷ and R ⁸ include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
such as sec-butyl or tert-butyl
Mention may be made of _C1 - _C10 branched or straight-chain alkyl groups. In addition, the protecting group for the amino group in R ⁵ is:
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-nitrophenylsulfinyl, (mono-, di-, tri-)
Chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4- methoxyphenylazo)
Benzyloxycarbonyl, (pyridin-1-oxide-2-yl)methoxycarbonyl, 2-
free radicals such as furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl or 8-quinolyloxycarbonyl, etc. Easily releasable acyl group; 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-tetoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene or 3,3-dimethyl-5 - an easily leaving group such as oxocyclohexylidene;
Or a silyl group such as di- or tri-alkylsilyl. Next, a method for producing the compound of the present invention will be explained. The compound of the present invention can be produced, for example, according to the production route shown below. "In the formula, R ⁵ , R ⁶ , R ⁷ , R ⁸ , ~ and ~ each have the same meaning as defined above; and
R ⁹ represents an alkyl group. ” Examples of the alkyl group for R ⁹ include the same alkyl groups as explained for R ⁷ and R ⁸ . Next, according to the above manufacturing route, (a) to (d)
Each step will be explained. Process (a) Carbohydrate Res., Volume 4, Page 422 (1967
) and the method described in Journal of Organic Chemistry (J.Org.Chem.), Volume 34, Page 1045 (1969). , dehalogenation and reduction of the azide by reduction using a catalyst such as Raney nickel, and deacylation catalyzed by a base such as triethylamine to form an amino alcohol. It can be a body. This reaction can be carried out using a reaction-inert solvent, e.g.
It can be carried out in methanol, ethanol, ethyl acetate or acetic acid. For example, by subjecting the above amino alcohol to normal acylation without purification,
By introducing a protecting group into the amino group, a compound represented by the general formula () can be obtained. Step (b) The compound represented by the general formula () can be induced to the compound represented by the general formula () by subjecting it to a normal mild oxidation reaction. Oxidizing agents include pyridinium chlorochromate (PCC), Jones reagent, manganese dioxide, ruthenium oxide, dimethysulfoxide-trifluoroacetic anhydride, dimethylsulfoxide-dicyclohexylcarbodiimide or dimethylsulfoxide-acetic anhydride, etc. [Reference: Journal of Organic Chemistry (J.Org.Chem.), Volume 41, No. 20, No. 3329
~3331 pages (1976)]. Step (c) The compound represented by the general formula () is
A compound represented by the general formula () can be obtained by subjecting it to the Horner-Witting reaction. For the carbonyl group of the compound represented by the general formula (), the general formula

[Formula] (In the formula, R ⁶ and R ⁷ each have the same meaning as described above.) By reacting the lithium salt of phosphine oxide represented by the general formula (), compound can be obtained. This reaction can be carried out using a reaction-inert solvent, e.g.
This can be carried out in the presence of tetrahydrofuran, dimethyl sulfoxide, benzene or diethyl ether. General formula that is the starting compound for this reaction

The lithium salt ^of phosphine oxide represented ^by formula a base, such as lithium diisopropylamide or n
- It can be obtained by reacting butyllithium, etc. The reaction temperature for this reaction is usually -78°C to room temperature. Step (d) A compound represented by the general formula () can be obtained by reacting the compound represented by the general formula () with a base (dephosphinic acid reaction). This reaction can be carried out using a reaction-inert solvent, e.g.
It can be carried out in the presence of dimethylformamide or tetrahydrofuran, etc., and as a base,
Examples include potassium hydride, sodium hydride or lithium hydride [Horner-Witting reaction; see: Journal of the Chemical Society (J.
Chem.Soc.), Perkin, No. 3099~
3106 pages (1979)]. Furthermore, in the compounds represented by the general formulas (), (), () and (), the protection of the amino group and the carboxyl group and their elimination are carried out in accordance with conventional methods, and the compounds are converted into the corresponding target compounds. can do. In addition, if an active group exists in the R ⁵ group, it can be optionally protected with a conventional protecting group during the reaction, and after the reaction, the protective group can be removed by a conventional method. can. The target compounds obtained as described above, that is, the compounds represented by the general formulas (), (), and (), can be isolated by conventional methods. By the manufacturing method explained above, for example, D-
An optically active compound represented by the general formula () can be obtained from an optically active sugar such as glucose. Further, the present invention provides D represented by the general formula ()
- Covering all crystalline forms and hydrates of hexopyranose derivatives. General formula () of the present invention thus obtained
A compound represented by the general formula () can be obtained by oxidizing and hydrolyzing the D-hexopyranose derivative represented by the formula (). This manufacturing route is shown below. [Wherein, R ⁵ , R ⁸ , ~, ~ and R ⁹ each have the same meaning as described above; and R ¹⁰ represents a hydrogen atom, a protection-forming group, or a salt-forming cation, respectively. The protection-forming group for ^R10 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-methocybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p
-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3- Methyl-3-butynyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfinylmethyl, phenylthiomethyl, dimethylaminomethyl, (quinoline-1-oxide-2-yl)methyl, (pyridine-1-oxide) -2-yl)methyl or bis(p-methoxyphenyl)methyl and the like. In addition, as described in Japanese Patent Application Laid-Open No. 46-7073 and Dutch Publication No. 7105259, for example,
Examples include groups derived from silyl compounds such as dimethylchlorosilane. In addition, as the salt-forming cation of ^R10 , those that form non-toxic salts are particularly preferable.Specifically, the non-toxic salts include salts with alkali metals such as sodium or potassium; calcium or magnesium, etc. salts with alkaline earth metals; ammonium salts; or triethylamine;
Procaine, dibenzylamine, N-benzyl-
Examples include salts with nitrogen-containing organic bases such as β-phenethylamine, 1-ephenamine, or N,N-dibenzylethylenediamine. Next, each step (e) to (g) will be explained. Step (e) By reacting the compound represented by the general formula () with a chromic acid-based oxidizing agent, such as pyridinium chlorochromate (PCC), Collins reagent, Jones reagent, or pyridinium chromate. , a compound represented by the general formula () can be obtained. This reaction can be carried out using a reaction-inert solvent, e.g.
It can be carried out in the presence of methylene chloride, dimethyllumamide or acetone, etc. [See: Tetrahedron Letters,
Vol. 39, pp. 3483-3484 (1977)]. Step (f) By subjecting the compound represented by the general formula () to conventional hydrolysis using an acid catalyst,
A compound represented by the general formula () can be obtained. This reaction can be carried out using a reaction-inert solvent, e.g.
It can be carried out in the presence of tetrahydrofuran, acetone, water, etc., and two or more of these solvents may be used as a mixture. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, acetic acid, and phosphoric acid. Step (g) An oxidizing agent, for example, a chromic acid-based oxidizing agent such as Jones reagent, Collins reagent or pyridinium chlorochromate (PCC); ruthenium oxide; or A compound represented by the general formula () can be obtained by reacting dimethyl sulfoxide with trifluoroacetic anhydride or the like. This reaction can be carried out using a reaction-inert solvent, e.g.
It can be carried out in the presence of acetone, tetrahydrofuran, dioxane, water, etc., and two or more of these solvents may be used in combination. The amount of the oxidizing agent used is 1 to 20 equivalents relative to the compound represented by the general formula (). The reaction temperature and reaction time of this reaction are usually
The temperature is -30°C to 50°C for 1 minute to 2 days, preferably 30 minutes to 2 hours under ice cooling. Furthermore, in the compounds represented by the general formulas (), (), () and (), the protection of amino groups and carboxyl groups, their removal, and the formation of salts of carboxyl groups are carried out according to conventional methods. can be carried out and converted into the corresponding target compound. In addition, when an active group exists in each group of R ⁵ and R ¹⁰ , it can be optionally protected with a normal protecting group during the reaction, and after the reaction,
The protecting group can also be removed by conventional methods. The compounds obtained as described above, that is, the compounds represented by the general formulas (), (), and (), can be isolated by conventional methods. Further, the compound represented by the general formula () is, for example, (4R,5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6-
Azetidinone derivatives can be obtained by subjecting methyl-δ-lactone or the like to removal of the protecting group of the amino group, hydrolysis of the ester, alcoholysis, ring-closing reaction, and the like. Furthermore, thienamycin derivatives can be obtained by converting this azetidinone derivative into a β-keto ester, converting it into an azide, ring-closing reaction, and introducing a mercapto group [Reference: Tetrahedron Letters] Letters), No. 21
Volume, pp. 2783-2786 (1980), Vol. 22, No. 913
~916 pages (1981)]. Next, the present invention will be explained with reference to Reference Examples and Examples, but the present invention is not limited thereto. Note that silica gel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.) was used as a column packing material in column chromatography. Example 1 10.0 g of methyl-3-azido-4-O-benzoyl-6-bromo-2,3,6-trideoxy-α-D-arabino-hexopyranoside ( 27.0 mmol), 800 ml of methanol, Raney Nickel W
-420 g and 3.8 ml (27.2 mmol) of triethylamine are added and medium pressure catalytic reduction is carried out at 3.8 Kg/cm ² under hydrogen atmosphere for 8 hours. The reaction mixture is filtered and the residue is washed with 350 ml of methanol. The previously obtained liquid and the washing liquid are combined and the solvent is distilled off under reduced pressure to obtain crude methyl-3-amino-2,3,6-trideoxy-α-D-arabino-hexopyranoside. Without purifying the resulting residue, add 100 ml of methylene chloride and 4.3 ml of triethylamine.
(30.8 mmol) and while stirring,
Benzyloxycarbonyl chloride under ice cooling
Add 4.2 ml (29.4 mmol). After stirring at room temperature for 4 hours, the reaction mixture was washed successively with saturated aqueous sodium hydrocarbon solution, water and saturated brine,
Dry with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the resulting residue is purified by column chromatography (eluent: benzene/ethyl acetate), and then recrystallized from benzene to give a melting point of 132~
4.1 g of methyl-3-benzyloxycarbonylamino-2,3,6-trideoxy-α-D-alibino-hexopyranoside in the form of needle-like crystals exhibiting a temperature of 135°C.
(yield 52.3%). IR (KBr) cm ^-1 ; ν _OH 3410, ν _NH 3305, ν _C=0 1680 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 value; 1.27 (3H, d, J = 6Hz, C ₆ -H), 1.63 (1H, ddd, J _C2-Ha , _C2-He = 13Hz,
J _C2-Ha , _C3-H = 13Hz, J _C2-Ha , _C1-H = 13Hz, 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, _C1 -H), 5.04 (2H, s,

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

[Formula] ) Example 2 Dimethyl sulfoxide 3.84 ml (54.2 mmol)
is diluted with 95 ml of methylene chloride and then cooled to -75°C. At the same temperature, trifluoroacetic anhydride 5.74
ml (40.6 mmol) diluted with 13 ml of methylene chloride was added dropwise over a period of 10 minutes, followed by stirring for 15 minutes. Methyl-3- obtained by the method of Example 1
Benzyloxycarbonylamino-2,3,6-
8.0 g (21.1 mmol) of trideoxy-α-D-arabino-hexopyranoside in 95 ml of methylene chloride
This solution is added dropwise into the previously prepared solution at -65°C or below over a period of 20 minutes. After stirring the reaction mixture at -65°C or lower for 1.5 hours, 11.3 ml (81.0 mmol) of triethylamine was added dropwise thereto at the same temperature or lower over 10 minutes, and then the mixture was stirred at 0°C.
Raise the temperature to After the reaction, add the reaction mixture to 100ml of water.
and re-extract the washings with 100 ml of methylene chloride. Combine the methylene chloride layers and dilute with saturated saline for 5 minutes.
After washing twice and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent: benzene/
Purification with ethyl acetate gives white crystals. Furthermore, when recrystallized from diisopropyl ether/hexane, methyl-3-benzyloxycarbonylamino-2, a prismatic crystal with a melting point of 82-83°C,
3,6-trideoxy-α-D-arabino-hexopyranoside-4-ulose 7.4g (yield 93.3%)
get. IR (KBr) cm ^-1 ; ν _NH 3310, ν _C=0 1730, 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 value; 1.20 (3H , d, J=6Hz, _C6 -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 = 7Hz, 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】 )7.20(5H,s,

[Formula] ) Example 3 Mosquila sieves (3 Å, powder, 2 at 100°C)
Carbohydrate Res., Vol. 4, p. 422 (1967)
Add 450 mg of methyl-3-acetylamino-2,3,6-trideoxy-α-D-arabino-hexopyranoside obtained by the method described in
Stir for 2.5 hours. After the reaction, the reaction mixture was diluted with a mixed solution of 25 ml of diethyl ether and 5 ml of hexane, stirred for 5 minutes, filtered through a glass filter lined with silica gel G to a thickness of about 3 cm, and the residue was diluted with 100 ml of diethyl ether. Wash with
The previously obtained solution and the washing are combined and the solvent is distilled off under reduced pressure to obtain crystalline methyl-3-acetylamino-2,3,6-trideoxy-α-D-arabino with a melting point of 105-110°C. -hexopyranoside-4
- Obtain 45 mg of ulose (10% yield). IR (KBr) cm ^-1 ; ν _NH 3290, ν _C=0 1730, 1650 Mass spectrometry; (m/z) 201 (M ⁺ ) NMR (CDCl ₃ ) δ value; 1.24 (3H, d, J=7Hz, _C6 -H), 1.17-2.30 (1H, m, _C2 -Ha), 1.99 (3H, s, _CH3CO- ), 2.50-2.97 (1H, m, _C2 -He), 3.41 (3H, s, _-OCH3 ), 4.20-4.65 (1H, m, _C5 -H) 4.70-5.27 (2H, m, _C1 -H, _C3 -H), 6.79 (1H, bd, J=7Hz, NH ) Example 4 Under an argon stream, 6.9 ml (49.0 mmol) of diisopropylamine was added to 140 ml of tetrahydrofuran, and the mixture was cooled to -70°C. 32.2 ml (49.0 mmol) of n-butyllithium (1.52N hexane solution) was added dropwise to this over 10 minutes while keeping the temperature below -60°C, and the mixture was stirred at -75°C for 20 minutes. Add methoxymethyldiphenylphosphine oxide 12.0 to this solution.
g (49.0 mmol) in tetrahydrofuran solution
Add 140 ml dropwise at -65°C or lower over 10 minutes.
After stirring at the same temperature or lower for 20 minutes, the resulting mixture was added to the methyl-3-benzyloxycarbonylamino-2,3,6-trideoxy-α-D-arabino-hexopyranoside-4- obtained in Example 2.
A solution of 7.0 g (23.9 mmol) of ulose in 60 ml of tetrahydrofuran is added dropwise at −65° C. or lower over 20 minutes. After stirring for 1.5 hours at the same temperature or lower, -
Raise the temperature to 10°C, add 100 ml of 10% citric acid aqueous solution (W/W) while stirring, and separate the organic layer. Extract the aqueous layer three times with 100 ml each of ethyl acetate.
The previously separated organic layer and extract are combined, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent; benzene/
If purified with ethyl acetate), amorphous crystals of methyl-3-benzyloxycarbonylamino-4-diphenylphosphinoylmethoxymethyl-2,
11.9 g (yield 92.3%) of 3,6-trideoxy-α-D-arabino-hexopyranoside are obtained. The amorphous crystals are a mixture of two diastereomers, which can be separated by medium pressure column chromatography (silica gel, 25 μ; eluent: ethyl acetate), and the upper isomer (Rf = 0.61; eluent: ; ethyl acetate) to the lower isomer (Rf = 0.56; eluent; ethyl acetate) was 3:1. [Upper isomer] IR (KBr) cm ^-1 ; ν _NH , _OH 3300 (broad), ν _C=0
1705, ν _P=0 1125, 1110 Optical rotation; [α] ²⁰ _D +60.6° (C1.04, CHCl ₃ ) Mass spectrometry; (m/z) 539 (M ⁺ ) NMR (CDCl ₃ ) δ value; 1.15 (3H, d, J=7Hz, C6 _- H), 1.67-2.10 (2H, m, C2 _- H), 3.23 (3H, s,

[Formula] ), 3.26 (3H, s, -OCH ₃ ), 3.78-4.72 (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,

[Formula] ) [Lower isomer] IR (KBr) cm ^-1 ; ν _NH , _OH 3300 (broad), ν _C=0
1708, ν _P=0 1127, 1111 Optical rotation; [α] ²⁰ _D +72.2° (C1.00, CHCl ₃ ) Mass spectrometry; (m/z) 539 (M ⁺ ) NMR (CDCl ₃ ) δ value; 1.19 (3H, d, C ₆ -H), 1.70-2.10 (2H, m, C ₂ -H), 3.15 (3H, s,

[Formula] ), 3.20 (3H, s, -OCH ₃ ), 3.70-5.20 (7H, 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] ) Example 5 480 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 the methyl-3-benzyloxycarbonylamino-4-diphenylphosphinoylmethoxymethyl-2,3 obtained in Example 4 was added. A solution of 747 mg (1.38 mmol) of the upper isomer of ,6-trideoxy-α-D-arabino-hexopyranoside in dimethylformamide was added dropwise under ice cooling over 20 minutes. After stirring at the same temperature for 1 hour, 20 ml of water was added to the reaction mixture, and the mixture was extracted four times with 50 ml of ethyl acetate each time. 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 (eluent: benzene/ethyl acetate) and then recrystallized from hexane to produce methyl-3-benzyloxycarbonylamino in the form of needles with a melting point of 66-67°C. -4-methoxymethylene-2,3,4,
333 mg (yield 74.9%) of 6-tetradeoxy-α-D-arabino-hexopyranoside are obtained. IR (KBr) cm ^-1 ; ν _NH 3325, ν _C=0 1700 Optical rotation; [α] ²⁰ _D +86.9° (C1.04, CHCl ₃ ) Elemental analysis; C ₁₇ H ₂₃ NO ₅ calculated value (% ) C; 63.54 H; 7.21 N; 4.36 Actual value (%) C; 63.49 H; 7.26 N; 4.34 Mass spectrometry; (m/z) 521 (M ⁺ ) NMR (CDCl ₃ ) δ value; 3.39 (3H, d , J=6Hz, _C6 -H), 1.70-1.85 (1H, m, _C2- Ha), 2.12 (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, _-OCH3 ), 3.57 (3H, s, _CH3O -CH=), 4.12-4.38 (1H, m, _C3 -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−C H =), 7.35 (5H, s,

[Formula] ), Incidentally, if the lower isomer obtained in Example 4 is similarly operated, methyl-3-benzyloxycarbonylamino-4-methoxymethylene-
2,3,4,6-tetradeoxy-α-D-arabino-hexpiranoside is obtained. 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-arabino-hexopyranoside
Add 550 ml of carbon tetrachloride to 10.0 g (34.3 mmol) and add 7.3 g of N-bromosuccinimide.
(41.2 mmol) and barium carbonate 10.0 g (50.7
mmol) and reflux for 40 minutes. After cooling, insoluble materials were removed and the solvent was distilled off under reduced pressure.
The resulting residue is dissolved in 200 ml of chloroform, washed successively with a 5% aqueous sodium bisulfite solution, a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting oil was purified by column chromatography (eluent: hexane/ethyl acetate) to obtain 11.1 g of white crystals. Furthermore, if recrystallized from isopropyl alcohol, methyl-3-azido-4-O-benzoyl-bromo-2,3,6 prismatic crystals with a melting point of 65 to 65.5°C can be obtained.
9.2 g (yield 76.4%) of -trideoxy-α-D-arabino-hexopyranoside are obtained. IR (KBr) cm ^-1 ; ν _N3 2105, ν _C=0 1722 Optical rotation; [α] ²⁰ _D +41.9° (C1.00, CHCl ₃ ) Elemental analysis; C ₁₄ H ₁₆ N ₃ O ₄ Br calculation Value (%) C; 45.42 H; 4.36 N; 11.35 Actual value (%) C; 45.50 H; 4.33 N; 11.37 NMR ( _CDCl3 ) δ value; 1.50-2.45 (2H, m, C2 _- H), 3.41 (3H, s,
−OCH ₃ ) 3.30 to 3.60 (2H, m,, C ₆ −H), 3.69
~4.35 (2H, m, _C3 -H, _C5 -H), 4.87 (1H,
m, _C1 -H), 5.06 (1H, m, _C4 -H), 7.10~
8.20 (5H, m,

[Formula] ) Reference Example 2 Methyl-3-benzyloxycarbonylamino-4-methoxymethylene- obtained in Example 5
2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside 250 mg (0.78 mmol)
is dissolved in 2.5 ml of methylene chloride, 503 mg (2.33 mmol) of pyridinium chlorochromate is added to this solution, and the mixture is stirred at room temperature for 1 day. Add 10 ml of diethyl ether to the reaction mixture, stir for 15 minutes, filter through a glass filter lined with silica gel G to a thickness of about 3 cm, and wash the residue with 100 ml of diethyl ether. The solution obtained earlier and the washing solution are combined, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (eluent: benzene/ethyl acetate) to produce white crystals.
Obtain 78.6 mg (30% yield). Further, when this is recrystallized from diisopropyl ether, methyl-3-benzyloxycarbonylamino-4-methoxycarbonyl 2,3,
4,6-tetradeoxy-α-D-arabino-hexopyranoside is obtained. IR (KBr) cm ^-1 ; ν _NH 3320, ν _C=0 1718, 1680 Optical rotation; [α] ²⁰ _D +79.6° (C1.06, CHCl ₃ ) Elemental analysis; C ₁₇ H ₂₃ NO ₆ calculated value (%) C; 60.52 H; 6.87 H; 4.15 Actual value (%) C; 60.61 H; 6.93 H; 4.39 Mass spectrometry; (m/z) 337 (M ⁺ ) NMR (CDCl ₃ ) δ value; 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, _C2 −
He, _C4- H), 3.36 (3H, s, _-OCH3 ), 3.60 (3H, s, _-COOCH3 ), 3.80~4.46 (2H, m, J _C4-H , _C5-H = 10Hz, C ₃ −
H, _C5 -H), 4.75 (1H, d, J=3Hz, C1 _- H), 4.93 (1H, bd, J=10Hz, NH), 5.02 (2H, s,

【formula】 ), 7.30 (5H, s,

[Formula]) Reference Example 3 36 mg (0.11 mmol)
Dissolve in 0.7ml of tetrahydrofuran and add
Add 0.7 ml of 0.6N hydrochloric acid and reflux for 3 hours. Add 3 ml of water to the reaction mixture and extract twice with 15 ml each of ethyl acetate. Combine the ethyl acetate layers, add saturated brine,
Wash sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. If the obtained residue is washed with diisopropyl ether,
3-Benzylcarbonylamino-4-methoxycarbonyl-2, a white crystal with a melting point of 184-187°C.
34 mg (yield 98.4%) of 3,4,6-tetradeoxy-α-D-arabino-hexopyranose is obtained. IR (KBr) cm ^-1 ; ν _OH 3410 (shoulder), ν _NH 3320,
ν _C=0 1720, 1677 Optical rotation; [α] ²⁰ _D +36.5° (C1.20, MeOH) Mass spectrometry; (m/z) 323 (M ⁺ ) Reference example 4 3 obtained in Reference example 3 -benzyloxycarbonylamino-4-methoxycarbonyl-2,3,
30 mg (9.28 x 10 ^-5 mol) of 4,6-tetradeoxy-α-D-arabino-hexopyranose was dissolved in 1.5 ml of acetone, and 0.04 ml of 8N Jones reagent (1.06 x 10 ^-4 mol). After stirring for 40 minutes under ice-cooling, 0.02 ml of isopropyl alcohol is added and stirred at the same temperature for 10 minutes. Add 10 ml of ethyl acetate to the reaction mixture, 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 (eluent: benzene/ethyl acetate) to give 15.2 mg of white crystals (yield: 50.7 %). Furthermore, if this is recrystallized from benzene/diisopropyl ether, needle-shaped crystals (4R,
5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6-methyl-δ-lactone is obtained. IR (KBr) cm ^-1 ; ν _NH 3365, ν _C=0 1720 Optical rotation; [α] ²⁰ _D +2.2° (C1.20, CHCl ₃ ) 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 Mass spectrometry; (m/z) 321 (M ⁺ ) NMR (CDCl ₃ ) δ value; 1.38 (3H, d , J=6Hz, _-CH3 ), 2.38-2.79 (2H, m, J _C4-H , _C5-H =10Hz, _C2-
Ha, _C4 -H), 3.00 (1H, dd, J _C2-He , _C2-Ha = 15Hz,
J _C2-He , _C3-H =7Hz, C2 _- He), 3.69 (3H, s, _-COOCH3 ), 4.13-4.62 (2H, m, J _C4-H , _C5-H =10Hz, _C3-
H, _C5 -H), 5.08 (2H, s,

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

[Formula] ), ¹³ C-NMR (CDCl ₃ ) δ value; 19.6 (Q, C-6), 35.4 (T, C-2), 47.3 (D, C-3), 52.4 (D, C-4 ), 52.8 (Q, −OCH ₃ ), 66.8 (T,

【formula】 ), 74.8 (D, C-5), 127.9, 128.4, 136.0 (

[Formula] ), 155.3 (S, -COO-), 169.3, 170.8 (S, C-1, -COO CH ₃ ) Reference Example 5 Obtained by the method of Reference Example 4 using 25 mg of 5% palladium-carbon. (4R,5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6-methyl-δ-lactone 65mg (2.02×10 ^-4
mol) is catalytically reduced in a 3 ml methanol solution under a hydrogen atmosphere for 1 hour. After removing 5% palladium 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%). Without purifying the resulting residue, add 1 ml of concentrated hydrochloric acid and reflux for 40 minutes. The solvent is distilled off under reduced pressure, benzene is added to the resulting residue, and benzene azeotropy is performed three times to obtain crude (4R,5S,6R)-4-amino-5-carboxylic amorphous crystals. -6-methyl-δ-lactone hydrochloride
Obtain 42 mg (100% yield). Add 0.3ml of benzyl alcohol to this and stir at 70℃ for 7 hours.
Benzyl (3R,4S,5R)-4-amino-4-carboxyl-5-hydroxy-hexanate hydrochloride is obtained. Without purifying the reaction mixture, add 0.3 ml of benzyl alcohol and 42 mg (2.02 x 10 ^-4 mol) of dicyclohexylcarbodiimide.
and 0.028 ml (2.02×10 ⁻⁴ mol) of triethylamine are added and stirred at 55° C. for 5.5 hours. After cooling, the precipitated crystals are removed and the liquid is purified by column chromatography (eluent: benzene/ethyl acetate) to obtain an oily (3S,4R)-3-[(1'R)-1'-
23 mg of hydroxyethyl]-4-benzyloxycarbonylmethyl-2-azetidinone are obtained [yield from (4R,5S,6R)-4-benzyloxycarbonylamino-5-methoxycarbonyl-6-methyl-δ-lactone; 43.2%]. Optical rotation: [α] ²⁰ _D +9.9° (C2.3, CHCl ₃ ) Mass spectrometry: (m/z) 263 (M ⁺ ) NMR (CDCl ₃ ) δ value: 1.27 (3H, d, J=6.3 Hz,

[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 , _C1 ′ _-H
= 6.7Hz, _C3- 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 _C1 ′ _-H , _C3-H = 6.6Hz, J _C1 ′ _-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 value; 21.3 (Q, CH ₃ ), 3.4 (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 formula "In the formula, R ¹ and R ² , one represents a hydrogen atom and the other represents an alkoxy group; R ³ and R ⁴ , one represents the formula [formula] (in the formula, R ⁶ represents an aryl group; and R ⁷ represents an alkyl group, and the other represents a hydroxyl group; R ³ and R ⁴ together represent the formula =
Forms a group or an oxo group represented by CH~ ^OR8 (in the formula, ^R8 represents an alkyl group; and ~ indicates that it may be a cis or trans form, or a mixture thereof.) You can leave it there. R ⁵ is an amino group having a protecting group;
Each indicates that it may be axial or equatorial, or a mixture thereof. A D-hexopyranose derivative represented by 2. The D-hexopyranose derivative according to claim 1, wherein R ³ and R ⁴ together form an oxo group. 3. The D-hexopyranose derivative according to claim 2, which is methyl-3-benzyloxycarbonylamino-2,3,6-trideoxy-α-D-arabino-hexopyranoside-4-ulose. 4 One of R ³ and R ⁴ is a group represented by the formula [Formula] (wherein R ⁶ represents an aryl group; and R ⁷ represents an alkyl group, respectively), and the other is a hydroxyl group. A D-hexopyranose derivative according to claim 1. 5. Claim 4, which is methyl-3-benzyloxycarbonylamino-4-diphenylphosphinoylmethoxymethyl-2,3,6-trideoxy-α-D-arabinohexopyranoside.
D-hexopyranose derivatives described in Section 1. 6 R ³ and R ⁴ are combined to form the formula = CH ~ OR ⁸ (in the formula,
R ⁸ represents an alkyl group; and ~ each represents a cis or trans form, or a mixture thereof. ) The D-hexopyranose derivative according to claim 1, which forms a group represented by: 7. The D-hexopyranose derivative according to claim 6, which is methyl-3-benzyloxycarbonylamino-4-methoxymethylene-2,3,46-tetradeoxy-α-D-arabinohexopyranoside.