JPS6229577A - Oxazolidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is H or carboxy- protecting group; R2 is N-protecting group; R3 is OH-protecting group). EXAMPLE:2-Benzyl-4-benzyloxycarbonyl -3- [(2'-t-butyldimethylsiloxy-1'- methyl) ethyl]-5-methyl-isooxazoline. USE:A drug and a raw material for synthesizing simply a beta-lactam derivative containing 1'-beta-methyl group at the side chain of the 4-position of the formula II (R4 is OH-protecting group) useful as an intermediate for synthesizing 1-beta- methylcarbapenem having improved antibacterial action. PREPARATION:OH of optically active methyl (S)-(+)-3-hydroxy-2-methyl propionate shown by the formula III is protected to give a compound shown by the formula IV, which is reduced to give a compound shown by the formula V. Then this compound is reacted with a compound shown by the formula IX to give a nitron derivative shown by the formula VI. This compound is reacted with a compound shown by the formula VII to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the general formula (1) [wherein R□ represents a hydrogen atom or a carboxyl group protecting group, R2 represents a nitrogen atom protective group, and R3 represents a hydroxyl group protective group. ] This invention relates to a novel oxazolidine derivative represented by the following and a method for producing the same.

The oxazolidine derivative represented by the general formula (1) can be produced by cleavage of the nitrogen-oxygen bond and nitrogen-carbon bond by reduction, followed by a cyclization reaction, and protection of the secondary hydroxyl group.
General formula [wherein, R4 is a hydroxyl group protecting group]. ] 4
This can lead to a β-2cutam derivative having a 1β-methyl group in the side chain at the position (see reference side below).

The β-lactam derivative represented by formula (n) having a 1'β-methyl group in the side chain at the 4-position has an excellent antibacterial effect.
It can be used as an important synthetic intermediate for β-methylcarbapenem (D, H, 5h1h, etc.).

Heterocycles, 21.29 (198
4). ).

Conventionally, in order to obtain a β-lactam derivative having a 1'β-methyl group in the 4-position side chain, which is represented by 2(n), the hydrogen atom at the 1'-position present in the acetic acid residue at the 4-position was strongly It was synthesized by abstracting it with a base and then introducing a methyl group.

However, this method uses lithium diimpropylamide, which is industrially difficult to handle, and must be carried out at a low temperature of -78°C.
It has the disadvantage that a large amount of β-lactam derivatives having an α-methyl group are produced (1'β/1'α=y4), and it is clear that it is very difficult to implement it industrially.

As a result of intensive studies to overcome the drawbacks of the conventional art, the present inventors found that the oxazolidine derivative (1) of the present invention is an important synthetic intermediate for easily obtaining a β-lactam derivative having a 1β-methyl group. They discovered this and completed the present invention.

The method for synthesizing the oxazolidine derivative of general formula (1) according to the present invention is as follows: (1) Optically active (S) -(+) -3 that can be obtained at low cost
Using methyl -hydroxy-2-methylpropionate as a raw material, an anomer having an unnecessary 1'α-methyl group is not produced.

(2) The reaction can be achieved using reagents that are easy to handle.

(3) Reaction operation is simple.

It has the following characteristics.

R□ in the above general formula [E] represents a hydrogen atom or a protecting group for a carboxyl group.

The protecting group for carboxyl group is not particularly limited as long as it is commonly used, but suitable examples include evahensil,
p-methoxybenzyl, 2,4-dimethoxybenzyl,
0-nitrobenzyl, p-nitrobenzyl, p-chloro (substituted or unsubstituted monoarylmethyl group such as methyl, etc. Straight chain or branched chain such as methyl, ethyl, inpropyl, tθrt-butyl) C□-C4 lower alkyl groups, such as 2-methyl iodide, 2,2,2-trichloroethyl, etc.
-C2 lower alkyl group, e.g. 01-C4 lower alkoxymethyl group, such as methoxymethyl, ethoxymethyl, imbutoxymethyl, e.g. 1-C0-C3, such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl Lower alkoxycarbonyloxyethyl groups, such as allyl, 2-methylallyl, 3-
Substituted or unsubstituted 03-C6 such as methylallyl
lower alkenyl groups, e.g. diphenylmethyl, cyp
Examples include substituted or unsubstituted diarylmethyl groups such as -ayucylmethyl, substituted or unsubstituted aryl groups such as phenyl, 4-nitrophenyl, and 2,6-dimethylphenyl.

R2 represents a nitrogen atom protecting group. Preferably, substituted or unsubstituted monoarylmethyl groups such as hahanzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, 0-nitromethyl, and p-nitrobenzyl are used; - Substituted or unsubstituted diarylmethyl groups such as p-ayucylmethyl, e.g. trityl groups, e.g. p-methoxyphenyl, 2.4-)methoxyphenyl, o-=)ophenyl, p-nitrophenyl, 2.4- Substituted aryl groups such as dinitrophenyl can be mentioned. ' R3 represents a hydroxyl group-protecting group, and any commonly used hydroxyl-protecting group can be used, but preferred examples include trimethyl7lyl, triethylsilyl, and t-1.
Trialkylsilyl groups such as tildimethylsilyl, t-7'tyldiphenyl7lyl, e.g. methoxymethyl, methylthiomethyl, benzyloxymethyl, t-
Alkoxy or aralkoxy substituted methyl groups such as butoxymethyl, 2-methoxyethoxymethyl, e.g. tetrahydropyranyl groups, e.g. benzyl, p-methoxy(methyl, 2,4-dimethoxybenzyl, 0-nitrobenzyl, p-nitrobenzyl, etc.) Examples include substituted or unsubstituted monoarylmethyl groups such as acyl groups such as a7tyl and indiyl.

The method for producing the compound of the present invention will be described below.

The oxazolidine derivative represented by the general formula (1) of the present invention can be produced, for example, by the following method.

[In the formula, R, R2 and R3 have the same meanings as above. ] [First step] This step protects the hydroxyl group of the optically active (S) -(+) -3-hydroxy-2-methylpropionate methyl (m) to form the (S)-methyl propionate derivative (IV). It manufactures. This step can be carried out according to a conventional method.

[Second Step] In this step, the ester group of (iV) obtained in the first step is reduced to produce an aldehyde derivative (V)t-. In this step, M can be obtained by converting the ester group (IV) into an aldehyde group in one step, or by reducing the ester group (IV) to a hydroxyl group and then oxidizing it to an aldehyde group again. As the reducing agent used in the one-step conversion, ordinary reducing agents can be used, but
Inbutylaluminum hydride is preferably used. The reaction temperature is preferably -60°C or lower.

As an alternative method for the second step, the ester group in (IV) is reduced to a hydroxymethyl group to obtain lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride, which are then converted into pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide oxidation,
It is also possible to oxidize to (v) with manganese dioxide or the like.

Although the alternative method requires a two-step reaction operation, it has the advantage that the reaction can be carried out at room temperature.

[Third Step] In this step, the aldehyde derivative (V) obtained in the second step is reacted with a hydroxylamine derivative to produce a nitrone derivative (Vl). The hydroxylamine derivative used is a compound that can be easily synthesized from the corresponding oxime derivative (R.

F., Borch et al., J. Am, Chem.
Soc,, 93. See 2897 (1971). )
. This step is preferably carried out in a solvent using calcium chloride, molecular sieve, or the like as a dehydrating agent. Solvents include aromatic solvents such as benzene and toluene, and ether.

Ether solvents such as THF' and dioxane can be used.

The reaction proceeds smoothly at 0°C to room temperature.

[Fourth Step] In this step, the nitrone derivative (Vl) obtained in the third step is reacted with crotonic acid or crotonic acid ester to produce an oxazolidine derivative represented by general formula (1).

This step can be performed without a solvent or in a solvent. When a solvent is used, aromatic solvents such as benzene, toluene and xylene, ether solvents such as ether, THF' and dioxane, and polar solvents such as DMF and DMSO can be used. The reaction proceeds smoothly at 0°C=100°C.

In addition, when reacting using crotonic acid, N,N-
It is effective to add an organic base such as dimethylaniline to crotonic acid in its own amount.

The present invention will be described in detail below using Examples and Reference Examples.
The present invention is not limited to these.

The meanings of the abbreviations are as follows.

TBDMS: t-butyldimethylsilyl group THP
: Tetrahydropyranyl group Z : Benzyloxycarbonyl group Bu: n-butyl group Ph: Phenyl group Me; Methyl group Reference example 1 (S) -(+) -3-hydroxy-2-methylpropionate methyl 1.001 ( 8,47nvnol)
and imidazole 1.15 E (16,9 mmol)
was dissolved in 10 trrl of anhydrous dimethylformamide, and t
-Butyl-dimethylchlorosilane 1.30,! i'
(8.62 mmol) was added at room temperature. 1.5 at room temperature
After stirring for an hour, add 10ml of water and 20ml of hexane to the reaction solution.
ILl was added. After separating the organic layer, the aqueous layer was diluted with hexane 10
Extracted twice with m1. Hexane extract 'tt and water 5
ml three times, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give (S) −(+) −3−(
1.9111 (97% yield) of methyl t-butyldimethyl-siloxy)-2-#-propionate was obtained as a colorless oil. A portion of this (179cm) was distilled using Kugelrohr (registered trademark) to obtain a purified product of 176 m'? (Bath temperature:
120°C/14 mmHg) was used as the sample for analysis.

[α), +18.9° (C=1.00. CHCl3
) ;Eng R(neat): 1740cm= ;Ma
889'e: 175 (M-Bu)";"HN!
Il! R(CD(J3): δ= 0.03 (6H,
s), 0.87 (9H, s), 1.13 (3H, (1
, J = 7Hz), 2.64 (IH, q, J =
7Hz), 3.66 (3H, s).

Reference example 2 (S)-(+)-a-(t-butyldimethylsiloxy)-2-methylpropionate methyl 1.31, li
' (5.6 mmol) in anhydrous ether 18.5 tt
8.4 m of a hexane solution of 1M diimbutylaluminum hydride 9 at −78°C under an argon atmosphere.
1 (8.4 mmol) was added dropwise over 5 minutes. After 30 minutes, 90 ml of methanol and 0.84 mA' of water were added, the mixture was allowed to reach room temperature, and the mixture was further stirred at room temperature for 1 hour. The gel-like reaction solution was filtered, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was transferred to a silica gel column (hexane: ethyl acetate = 9:1
) and purified with (S)-(+)-3-(t-butyldimethylsiloxy)-2-methylpropionaldehyl'0.
Obtained 89 g (78% yield) as a colorless oil. To obtain a sample for analysis, 1 g of 57W was distilled using a 7-gel roll to obtain a purified product of 53 cm (bath temperature: 110°C/14 mmH).
g) Got f.

[α]. +37.8° (C=1.20.CHCl3)
; Engineering R (neat): 1735cm +1H
NMR (CDC13): δ= 0.06 (6H,S
), 0.88 (9H,s), 1.09 (3H,d,
J=7Hz), 2.57 (LH, tq, J=7Hz
and 6Hz), 3.84 (2H, d, J = 6Hz)
, 9.74 (IH, d, 1.5Hz).

Reference example 3 N-benzylhydroxylamine (R,F, Eorch
et al., J. Am. Chem. Soc., 93.28
97 (1971)) 368 mV (
3,0 mmol), chloride power JLt sium 330 m
9 (3.0 mmol) was added with 30 ml of anhydrous ether under a stream of argon, and while stirring at 0°C (S)
-(+)-3-(t-butyldimethylsiloxy)-2-
Methylpropionaldehyde 600”9C3, Ommo
l) was added dropwise. After stirring at 0° C. for 1 hour, the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:5 →
R)-(-)-N-(3-t)
-butyldimethylsiloxy-2-methylpropion)-
Benzylamine-N-oxide 658 ■ (yield: 64)
I got it.

[α) D-37,7° (C=0.89, CHCa
3); Engineering R (neat): 1595cm +
Mass rVe: 307 (M”): Elemental analysis value: Calculated value as C1□H290°NSi: C; 66
．． 40, H; 9.51, N; 4.55% Planting value: C;
65.86, H; 9.25, N; 4.46 Section 1
HNMR(CD(J3): δ=-0,02(3H,S
), 0.00 (3H,S), Q,84 (9H,S)
, 1.10 (3H, d, J= 7Hz), 3.1
0-3.40 (LH, bm), 3.63 (2H, t, J
=5Hz), 4.87 (2i(,S), 6.59
(IH, d, J = 7Hz), 7.37 (5H,
S).

Example 1 (R)-←)-N-(3-t-butyldimethylsiloxy-2-methyl-1-propylidene)benzylamine-N
- Dissolve oxide '469 W (1,53 mmol) in anhydrous toluene, add crotonic acid and add L08 g.
(6.14 mmol) was added and stirred at 80°C for 10 hours. The solvent and excess benzyl crotonate were heated at 120°C.
Distillation was performed using Torr, and the obtained oil was subjected to silica gel column chromatography (hexane: ethyl acetate = 95:
5), 2-benzyl-4-bandyloxycarbonyl-3-((2'-t-butyldimethylsiloxy-1
443 m9 (60% yield) of 7-methyl)ethylcy5-methyl-inoxazolidine was obtained as a colorless oil.

Engineering R: 1738cm.

Mass %: 483 (M") y"HNMR(
CD(J3): δ= 0.00-0.05 (6H,
S), 0.88 (9H, S), t, 35 (3H, b
d), 5.21-5.24 (2H, s), 7.30-7
．． 41 (IOH, s).

Reference example 4 (1) 2-hensyl-4-benzyloxycarbonyl-
3-((2'-t-butyl-dimethylsiloxy-17-
methyl)ethylc-5-methyl-inoxazolidine 1
75mg (0.36mm0l) of methanol 3.6m
10% palladium carbon 52 = 9 was added thereto, and the mixture was stirred for 40 hours under a hydrogen atmosphere of 5 atm. The reaction solution was filtered through Celite to remove the catalyst, and the solvent was distilled off under reduced pressure to give 3-amino-5-t-butyldimethylsiloxy-2.
110 ml of -(1'-hydroxyethyl)-4-methylbentanoic acid was obtained.

(2) 110 mg of the obtained β-amino acid was dissolved in 30 ml of anhydrous acetonitrile, 91 mg (0.41 mm) of 2,2'-dipyridyl disulfide was added, and 110 t of latriphenylphosphine was heated under reflux.
A solution of ny (0.42 mmol) dissolved in 6.2 volumes of anhydrous acetonitrile was slowly added dropwise. 3 more
After heating under reflux for an hour, the solvent was distilled off under reduced pressure and the product was
It was separated into two fractions at C.

(3) 21.0 ml of the more polar fraction (0,073
mmol) in 1 ml of anhydrous dichloromethane,
-dimethylaminopyridine 26■ (0.21 mmol
) and be/zyl chloroformate 30 m! ! (0.21mm
ol) under ice-cooling, stirred at room temperature for 1 hour, and then added p
-dimethylaminopyridine 267'9 (0,21rr
artol) and chloroformic acid are undil 301a (0,2
1rurLol) was added and stirred for 1 hour. The solvent was distilled off under reduced pressure and purified by TLC (hexane: ethyl acetate = 8:2) to give (3S, 4R) -3-((1'R)-1'
-(benzyloxycarbonyloxy)ethyl) -4
-((1'R)-1-(t-butyldimethylsiloxymethyl)ethyltuazetidin-2-one 24.9■(1
6.4% yield).

[α) +10.2° (C=1.10, CH(J3)
; Engineering R: L760crn.

Mass “g, : 422 (M”) r”HN
MR(CD(J3): δ=0.03(6H,s), 0
．． 88 (9H, S), 0.95 (3H, d, J = 6.
8 Hz), 1.44 (3H, d, J = 6.4 Hz)
, 1.50-2.00 (LH, m), 3.15 (IH,
ba), 5.15 (2H, S), 7.36 (5H, S
).

Optical purity is determined by subjecting quartz crystals to a reduction reaction using palladium carbon as a catalyst in a hydrogen atmosphere to remove benzyloxycarbonylation. It was determined by measuring 'H-NMR using fluoropropylhydroxymethylene)-d-can-7-orato]λ-ropium (111) (Eu (hfbc) 3 ).

As a result, the optical purity of the main island was found to be 95% ee or higher.

Reference example 5 (33,4R) -3-C(1'R) -1'-(benzyloxycarbonyloxy)ethyl) -4-((1
'R) -1'-(butyldimethylsiloxymethyl)ethyl)-azetidi/-2-one 26.418g (0
,063mmol) in acetic acid 0.4rrtl, THF'
0.2ml! , water and 0.1 rne of water, and stirred at 70°C for 3 hours. After distilling off the solvent, silica gel chromatography (hexane: ethyl acetate = 426 →
(3S, 4R)-3-
[(1'R) -1'-(benzyloxycarbonyloxy)ethyl)-4-((1'R)-1'-(hibiloxymethyl)ethyl di-azetidin-2-one 12.5
Tq (65% yield) was obtained.

[α] +10.1° (C= 1.26, CHC
l3); Engineering R (neat): 1743 crn.

Mass%: 307 (M”); IHNMR (C
DC13): δ = 0.94 (3H, a, J = 7Hz
), 1.46 (3H, a, J=6Hz), 3.19 (IH, dd, J==9Hz, IHz), 5.
07 (2H, S), 6.10 (IH, bs), 7.35
(5H, S).

Reference example 6 (33,4R) -3-((1'R) -1'-(benzyloxycarbonyloxy)ethyl) -4-C(
t'R) -1'-punishment'Droxymethyl)ethyl]azetidin-2-one 52.511 g (0.17 mm01
) was dissolved in acetone l11Le, and Jones reagent was added dropwise at room temperature. Stop dripping when it stops discoloring,
Remove inorganic salts with a silica gel short column (3S,
4R) -3-C(1'R) -1'-(benzyloxycarbonyloxy)ethyl) -4-[(1 chain-1'
-Ruboxyethyl]azetidin-2-one 52.3
mg (95% yield). In order to obtain a sample for analysis, it was purified using a silica gel column (navel+t>: I!!IP!i-t:IJ gland=3:7:0.01).
42.671fl, 78%).

mp 112-114℃; [α]ゎ +665°(C=1.05, CH(J
3); Engineering R (KBr): 1755.1730.1
675cm.

Mass %: 321 (M+):1HNMR(
CDC13): δ= 1.20 (3H, a, J=
7.0 Hz), 1.40 (3H, d, J=6.4Hz
), 2.66 (IH, dq, J=6.8Hz), 3.1
9 (LH, da, J=1.6Hz, 7.6Hz), 3.
83 (LH, aa, J=2.2 Hz, 5.7 H
z), 5.14 (2H, 5), 6.42 (IH, bs)
, 7.34 (5H,S).

Example 2 (R)-(→-N-(3-t-butyldimethylsiloxy-2-methyl-1-propylidene)benzylamine-N
-Oxide'658m1i+ (2,14mm0(4)
was dissolved in 2.1 mA' of anhydrous l-toluene, 2.28 ml (21,47 Hylol) of methyl crotonate was added, and the mixture was heated to 80 mA'.
The mixture was stirred at ℃ for 10 hours. The solvent and excess methyl crotonate were distilled off under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain 2-benzyl-3-((2'-t- Butyl-dimethylsiloxy-17-mefyl)ethyl)-4-methoxycarbonyl-5-methylinoxazolidine was obtained as a mixture of four diastereomers in an amount of 654 m'i (yield: 75%).

IR," 1740cm * Maes%: 407 (M") ;'HNMR(C
D(4!3): δ=-0.02-0.03 (6H,
s), 0.86 (9H, S), 0.97 (3H, a),
1.30-1.40 (3H, d), 3.73.3.72
．． 3.76.3.78 (3H, S), 7.32 (5H,
S).

Reference Example 7 (1) 9 2-benzyl-3-((2'-t-butyldimethylsiloxy-1-methyl)ethylcou 4-methoxycarbonyl-5-methylinoxazolidi/(117m9) obtained in Example 2 .0, 2
9 mmol) was added with 1.3 mg of a methanol solution of IM potassium hydroxide, and after stirring at 60°C for 3 hours,
IM aqueous solution of hydrochloric acid 1.3 mJ and dichlorometh/3 at room temperature
trtl was added. After separating the organic layer, the aqueous layer was extracted with dichloromethane. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 2-benzyl-3-((2'-
t--1Tyldimethylsiloxy-1'-methyl)ethylcy4-carboxy-5-methylinoxazolidine 1
02.5 mV (91% yield) was obtained.

(2) Dissolve this in 4 ml of methanol and
% palladium on carbon was added and the mixture was reacted for 40 hours under 5 atmospheres of hydrogen. The following process was carried out in the same manner as in Reference Example 4, and (3
S, 4R) -3((1'R) -1'-(benzyloxycarbonyloxy)ethyl)-4-((1'R)
-1'-(t-butyldimethylcyvoxymethyl)ethyltuazetidin-2-one 19.2 hours was obtained.

[α) +10.1°(c 1.os CH(J3
); D-notechnical R, NMR, and Masθ spectra were consistent with those of Reference Example 4.

Example 3 (R) -(→-N-(3-t-butyldimethylsiloxy-2-methyl-1-7'rohyritene)benzylamine-N-oxy7' 130 mg (0,42 mail
) anhydrous toluene solution C3ml1) VC crotonic acid 72
mg (0.84 mmol) and 7107 μll (0.84 mm01) of N,N-dimethylanili were added thereto, and the mixture was stirred at 90° C. for 10 hours. 1N to the reaction solution under water cooling,
14 acid (0.85 rtte) was added and extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off to obtain 1176 mg of crude 2-benzyl-3-(2-butyldimethylsiloxy-1-methylethyl)-5-methylinoxazolidine-4-carboxylic acid. Ta. This egg (24 mii') was taken, treated with diazomethane in ether, purified by silica gel column chromatography (hexane:ethyl acetate = 9:1),
-benzyl-3-(2-t-butyldimethylsiloxy-
15.4 mLj (yield: 65%) of a mixture of four diastereomers of (1-methylethyl)-5-methyl-4-methoxycarbonyl isoxazolidine was obtained.

Reference example 8 2-methylpro/+? Ndiol 1.0,! i' (
0,011 mol) and dibutyltin oxide 2.76
g (0,011 mol) in 30 ml of anhydrous benzene
! The mixture was stirred under reflux for 72 hours while removing water. After removing a small amount of insoluble matter, the F solution is concentrated to give 2,2-dibutyl-5-methyl-2-stunner 1,3-dioxane 3
．． 53.9 (quantitative yield) was obtained as a white solid. Dissolve 1 g of this in 20 ml of chloroform, add 0.32 ml of crotonic acid chloride (3.2 mmol
After refluxing for 1 hour, 5 parts of dioxane containing 10 parts of water was added, and the mixture was refluxed for an additional hour. After cooling, it was washed successively with saturated brine, saturated sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was distilled using 7-gelcol (registered trademark) (bath temperature: 170°C/12 Torr) L,2-methyl-3-crotonoyloxypropanol't35 (17
(71%) obtained.

'HNMR (CDC/3): δ = 0.97 (3) (
, d, J = 6.5 Hz), 1.87 (3H, dd, J
=5H2 and 1.5Hz), 1.75-2.35(lH,
m), 2.70 (IH, brs), 3.50 (2H, t
, J=6Hz), 4.10 (2H, d,, J=6Hz)
, 5.85 (IH, dq , J = 16Hz and 1.5
Hz), 7.00 (IH, dq, J = 16Hz and 6Hz).

Reference example 9 Pyridinium chlorochromate 500 mg (2,32
711@ol) and 2.5I of anhydrous Celite were suspended in 10 me of anhydrous dichloromethane, and 2-methyl-3-crotonoyloxypropanol 246T? g (1,56mm
A dichloromethane solution of No. 02) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/benzene-3/4) to obtain 121η (50%) of 2-methyl-3-crotonoyloxypropanal.

'HNMR (CD (J3): δ = 1.15 (3H,
d, J=7Hz), 1.86 (3H, dd, J=7H
2 and 1.5Hz), 2.52-2.95 (IH, m),
4.35 (2H, a, J = 6Hz), 5.83 (IH
, dq.

J = 16 Hz and 1.5 Hz), 6.98 (IH, d
q, J=16Hz and 7Hz)-9,70(IH,d,
J=1.5Hz).

Reference example 10 Indylhydroxylamine 23.8m'! (0,1
93 mmol) and powdered calcium chloride 22 mV (0
, 20 mmol) was suspended in 0.5 me of anhydrous ether and cooled to 0°C, 26.8"Is' (0,1
0.5 g of an anhydrous ether solution of 73 mm 01) was added dropwise. The reaction was carried out at 0°C for 1 hour and then at room temperature for 1 hour, and the reaction mixture was separated and purified by thin layer chromatography (silica gel-ethyl acetate) to obtain N-(3-crotonoyloxy-2
-methylpropylidene)benzylamine-N-oxy)
-'33.1 ~ (74 嬬) was obtained.

IHNMR (CDC13): δ = 1.14 (3H,
d, J = 7.0 Hz), 1.87 (3H, dd,, T
= 6.8Hz and 1.6Hz), 3.23-3.68(l
H, m), 4.17 (2H, d, J=6.0Hz), 4
．． 88 (2H, s), 5.78 (LH, dq, J=15
．． 5Hz and 1.6Hz), 6.60(d,, T=7.0
Hz), 6.92 (IH, dq, J=15.5Hz and 6
．． 8Hz), 7.38 (5H, S).

Reference example 11 2.2-dibutyl-5-methyl-2-stunner 1.3-
Dioxa 71.47 my (4.57 mmol) in anhydrous chloroform 30 m/! Dissolve R-nozoyl chloride 6437n! (4.57 mmol) was added and allowed to flow ↑-7L for 1 hour. Dioxane 5 containing 10 t water
ml was added, and the mixture was further refluxed for 1 hour. After the reaction solution was treated in the same manner as in Reference Example 8, the residue was subjected to silica gel thin layer chromatography (ff) [ethyl/Hansenault V3].
The product was separated and purified to obtain 741 ml of 2-methyl-3-pendiyloxypronominol (section 84).

1H NMR (CD (J3): δ = 1.07 (3H,
d, J=6Hz), 1.6-2.2 (2H, m), 3
．． 36-3.62 (2H, nn), 4.2o-43z (
2H, m), 7.25 7.55 (3H, m), 7.9
0-8.13 (2H, J2)).

Reference example 12 2-methyl-3-diyloxypropanol 369
W (1,9 mmol), dihydropyran 273 m
y(3,2sy1@ol), pyridinium paratoluenesulfonate 50 ``!'! (0,2mmol)
was stirred in anhydrous dichloromethane ZLOxl at room temperature for 2 hours, and 20014 g (2,381 H1 ol) of dihydropyran was added.
and pyridinium paratoluenesulfonate 50■ (0,
2 mm01 ) was added and stirred for further 3 hours.

Add 50 td of ether to the reaction solution, wash with brine,
It was dried with anhydrous magnesium sulfate. The residue obtained after evaporating the solvent was separated and purified by silica gel thin layer chromatography (ethyl acetate/benzene = V4) to obtain l-tetrahydrobylanyloxy-2-methyl-3--? 466.3 m9 (section 88) of polypropane was obtained.

'HNMR (CD (J3): δ = 1.07 (3H,
a, J=6Hz), 1.4-1.8 (6H, m), 2
．． 00-2.55 (IH, m), 3.30 3.65
(LH, m), 3.70-3.95 (IH, m), 4.
26-4.43 (2H, m), 4.63 (IH, b
rs), 7.35-7.65 (3H, m), 7,9
6 8.17 (2H, m).

Reference example 13 1-tetrahydropyranyloxy-2-methyl-3-benzoyloxypropane 460 m9 (1,65 mmol
) Dissolved in total methanol loz, yg, added 3rnl of 1M thorium aqueous solution and 10mJe of water at room temperature.
Stir for hours. The reaction solution was extracted with ethyl acetate and washed with water.

After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was subjected to silica gel column chromatography (ethyl acetate/
Purification with benzene=[) gave 3-tetrahydropyranyloxy-2-methylpropanol (254-, 88-th).

"HNMR (CDC13): δ = 0.90 (3H,
d, J=6Hz), 1.3-2.3 (7H, m),
2.56 (1B, brs), 3.2-4.1 (6
H, m').

4.60 (IH, brs).

Reference Example 14 A dichloromethane solution of 250 mm (1,4 mm) of 3-tetrahydropyranyloxy-2-methylpropatol (4 rILt) was suspended in dichloromethane/10 nA' with 500 kg of pyridinium chlorochromate (2,32 mmol) and 2.5 g of Celite. The mixture was stirred at room temperature for 3 hours. After adding 100 ml of ether to the reaction solution, it was filtered and the p solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/(benzene=%), and 17
8 (73%) of 3-tetrahydropyranyloxy-
2-Methylpro.ξnal was obtained.

HNMR (CDCe3): δ = 1.13 (3H, d
, J = 6Hz), 1.40-1.85 (6H, m)
, 2.45 2.90 (IH, m), 3.40 4.
13 (4H, m), 4.62 (IH, brs), 9.7
5 (LH, d, J=1.0Hz).

Reference Example 15 Ether solution of 3-tetrahydropyranyloxy-2-methylpropanal 37.9 M (0.20 mmol) Lrn1f Benozylhydroxylamine 28.7 m
g (0,23711m01) and powdered calcium chloride 2
2.211ii+ (0.20 mmol,) of ether 0.5 meg? The mixture was added dropwise to Shu liquid at 0°C and stirred for 1.5 hours. The reaction mixture was subjected to thin layer chromatography on licage gel (
Ethyl acetate) minutes + 'J611'J? sk, N-(
3-tetrahydropyranyloxy-2-methylpropylide/)benzylamine-N-oxide 9349m1i+
(57%)' was obtained.

"HNMR (, CD (J3): δ = 1.15 (3H
, d, J=6Hz), 1.35 1.80 (6H, m)
, 3,25 3.90 (5H, m), 4.55 (IH
, brs), 4.90 (2H, s), 6.67 (LH,
d, J=6Hz), 7.40 (5H,S).

Example 4 N-(3-tetrahydropyranyloxy-2-methylpropylidene)benzylamine-N-oxy)” 135
mf (0,49mrrLol), methyl crotonate 490"? (4,9mmol), toluene (5m
The mixture was stirred at 105° C. for 3.5 hours. After distilling off the solvent and excess methyl crotonate under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate/kundan = 1/4), and 2-
'-Tetrahydropyranyloxy-4-methoxycarbonyl-5-methylinoxazolidine 1071 nV (58 units) was obtained.

IR: 1740cm.

! , Its%: 378 (M+).

Reference Example 15 2-Benzyl-3((2'-tetrahyto90vilanyloquin-1'-methyl)ethyl]=4-methoxycarbonyl-5-methylinoxazolidine obtained in Example 4 was treated in the same manner as in Reference Example 4. , (3S,4R)-3((1'R
)-1'-(benzyloxycarbonyloxy)ethyl)-4-((1'R)-1'-tetrahydropyranyloxymethyl)ethylcouazetidin-2-one was obtained.

Engineering R: 1752cm.

Mass %: 391 (M”); 1HNMR (C
D(J3): δ=0.96.1. o O(3H, a
, J=6. BHz), 1.43 (3H, d, J
=6.4Hz), 4.50 (IH, brs'), 5.1
4 (2H, S), 5.93 (IH, brs), 7
．． 35 (5H, S).

Director General of the Patent Office Michibe Uga Oxazolidine derivatives Full statement

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a hydrogen atom or a carboxyl group protecting group, R_2 is a nitrogen atom protecting group, and R_3 is a hydroxyl group protecting group. ] An oxazolidine derivative represented by