JPH01211560A - Production of beta-lactam derivative - Google Patents

Abstract

PURPOSE:To obtain the title substance through a one-step process from readily available feedstock, by reaction an amide such as N-(t-butoxycarbonylmethyl)- N-(4-methoxyphenyl)butanamide with an oxidizing agent in the presence of a base. CONSTITUTION:A compound of formula I (R<1> is H, alkyl, alkenyl, alkinyl, alkoxy, substituted amino; R<2> is aryl, alkoxy, substituted amino; R<3> is protecting group for amino group is allowed to react with 1.0-2.5 equivalent amount of an oxidizing agent such as halogen, N-haloimide, copper acetate in the presence of 2.0-3.5 equivalent amount of a base such as an organolithium compound or sodium hydroxide at -120-50 deg.C to give the compound of formula II. The reaction is preferably carried out in a solvent such as THF, and the addition of a tertiary amine and a quaternary phosphonium salt is preferred, because the yield is increased. The compound of formula II is used as an intermediate of beta-lactam antimicrobials.

Description

[Detailed description of the invention] [Industrial application field] The present invention is based on the following general formula (r) .

In formula C, R' is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, tm or an unsubstituted alkynyl group, an alkoxy group, or a substituted amino group. Rx represents an aryl group, an alkoxy group, or a substituted amino group, and R3 represents a protecting group for the amino group.]
The present invention relates to a novel method for producing a β-lactam derivative represented by formula C, in which R1, R1 and R3 have the same meanings as above, by reacting an amide represented by the above with an oxidizing agent in the presence of a base.

The method for producing the β-lactam derivative represented by the general formula (I[) can be a useful intermediate in the production of various β-lactam antibacterial agents such as carbapenem derivatives.

For example, the β-lactam derivative of (II) (R': hydrogen atom, Hz, benzyloxy group, R3: hydrogen atom) is used as a synthetic intermediate for the antibacterial agent chenamycin (T, N, Sa
l zmann et al., J. Am.

Chsm, Soc, 102.6163 (1980))
or as a synthetic intermediate for drugs with central nervous system effects (T., Tamura et al., European Published Patent No. 171)
No. 159) can be used.

[Conventional technology]

Conventional methods for synthesizing β-lactam derivatives having a carbonyl substituent at the 4-position represented by general formula (n) include i) cyclization reaction of β-amino a derivatives (Salzmann et al., J. Am, Chsm.

3oc,, 1st 2.6161 (1980))if)
Reaction of acid chlorides with imines in the presence of tertiary amines (B, AIcaide et al., Heteroyclsa,
2 Sat., 1597 (1986)) 1ff) Reaction of imines with ester enolates (D. J. Har t et al.
J.Am.

Cham, Soc, 108.6054 (1987))
lv) Intramolecular reaction between epoxide and ester enolate (H, Maruyama et al., Bul 1. Chem
,Soc,,Jpn,,58°3264 (1,98
5)), v) Cyclization reaction of β-tosyloxyamide derivative (A, Gateau-01eskar et al., Tatrah
edron Lett, 27°41 (1986
)), vi) Reaction of diketene and imine (Y, Ito et al., Tetrahsdron Lett, g. engineering, 5751
(1986)), but for 1), the types of β-amino acids that are easily available as starting materials are very limited, and for 11), 3
Unsubstituted β-lactam (R1 in general formula (11) is a hydrogen atom) cannot be produced; iii) requires a large number of reaction steps because 4-carboxyl-β-lactam derivatives cannot be directly synthesized; iv) and (ii) require multiple steps to synthesize raw materials, and vi) includes a step using chromium dioxide, which is problematic for waste disposal.

[Problem that the invention seeks to solve]

As a result of repeated studies to develop a method for more effectively producing the β-lactam derivative represented by the general formula (■), the present inventors discovered that -
The present invention was completed by discovering the fact that β-lactam derivatives can be obtained in the process.

[Means for solving problems]

The general formula (1) used as a raw material in the production method of the present invention
The amide represented by can be easily produced by acylating a primary amine, which is easy to do manually, and then alkylating it, or by alkylating and then acylating it. q can be obtained by reacting with
Lutidine, collidine, etc. can be used.

(reduction) As the glutinous material, dicyclocarbodiimide or N,N
'-carbonyl diimidazole and the like can be used. The base and condensing agent can be used in appropriate amounts. Alkylation of the amides produced by the above-mentioned method can be carried out using known methods (M, 5hlozakl et al., Heterocyclos
.

This can be carried out by reacting alkyl mezilad, alkyl mezilad, etc. The base used can be the same as in the case of acylation of primary amines described above.

Acylation of the secondary amine produced by this method can be carried out in exactly the same manner as the acylation of the primary amine described above. The acylation and alkylation reactions are preferably carried out using a solvent, and any solvent can be used as long as it does not directly participate in the reaction, but dichloromethane, tetrahydrofuran, etc. can be suitably used. The reaction greenhouse is -78℃~10
Although it can be carried out at a temperature in the range of 0°C, it is preferably in the range of 0°C to room temperature.

In the present invention, R in the above-mentioned formulas (1) and (ff)
I is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, an alkoxy group, a substituted alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-
Examples include butyl, pentyl, hexyl, hydroxymethyl, hydroxyethyl, l-hydroxy-1-methylethyl, etc. Substituted or unsubstituted alkenyl groups include:
ethynyl, propenyl, butenyl, phenylethynyl,
Examples include methoxyethynyl, substituted or unsubstituted alkynyl groups include ethynyl, propynyl, butynyl, phenylethynyl, propargyl, etc., and alkoxy groups include methoxy, isopropyloxy, t
-butoxy, 2-tetrahydropyranyl, etc.
Examples of substituted amino groups include dimethylamino, diethylamino, diisopropylamino, diphenylamino, and dibenzylamino.

R1 is an aryl group, an alkoxy group, or a substituted amino group. Examples of the aryl group include phenyl, p-methoxyphenyl, p-tolyl, 2,4,6-drimethylphenyl, and examples of the alkoxy group include methoxy, ethoxy, isopropoxy, t-butoxy, menthyloxy, Examples include 8-phenylmenthyloxy, norbornyloxy, and examples of substituted amino groups include dimethylamino,
R3 is a protecting group for an amino group, and examples of the protecting group include p-methoxyphenyl, 0-methoxyphenyl, 2.4-dimethoxyphenyl, 3.4.5-trimethoxyphenyl, 2- pyridyl, 2-pyrimidyl,
Examples include trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like.

The present invention requires a base and an oxidizing agent. As the base, any base used in the organic reaction of the will can be used, but organic magnesium compounds such as butyllithium, S-butyllithium, t-butyllithium butylmagnesium, sodium hydride, potassium hydride, etc. are preferably used. be able to. The amount used is 2.0-10
The range of equivalents is 2.0 to 3.5 equivalents, and preferably 2.0 to 3.5 equivalents are used.

The reaction temperature is in the range of -120°C to 50°C, and in this range, deprotonation occurs from the general formula (1) and dianions are easily produced, but preferably -100'C
It is in the range of ~-50°C.

Examples of the oxidizing agent used in the present invention include halogens such as iodine and bromine, N-haloids such as N-iodosuccinimide, N-bromosuccinimide, and N-chlorosuccinimide, copper acetate, copper benzoate, steel chloride, W4(II) salts such as copper bromide or copper trifluoromethanesulfonate can be used. The amount used is in the range of 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents. The β-lactam derivative of the general formula (U) is produced by the reaction of these oxidizing agents with the dianion described above, but this reaction
It can be carried out in the range of ℃ to 50℃, but preferably = 100℃
It is in the range of -30°C.

It is preferable to use a solvent in these reactions.Any solvent can be used as long as it does not directly participate in the reaction, such as ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, hexane, heptane, cyclohexane, pentane, etc. □ Aliphatic hydrocarbons, aromatic hydrocarbons such as benzene, toluene, and xylene, and solvents such as dimethylformamide, isobutyronitrile, and bivalonitrile can be used alone or as a mixture thereof.

In the present invention, it is preferable to add a tertiary amine, a quaternary phosphonium salt, or a quaternary ammonium salt in order to improve the yield.

As a tertiary amine, it does not have active hydrogen,
Examples include optically active amines such as 1,4-diazabicyclo(2,2,2)octane, tetramethylethyldiamine, and sparteine.

Any quaternary phosphonium salt and quaternary ammonium salt can be used as long as they do not have active hydrogen, but preferred examples include tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, bistriphenylphosphoranylidene ammonium chloride, etc. It can be used. The amount used is in the range of 0.5 mol to 5.0 mol, preferably 2.0 to 3.0 mol.

The present invention will be described in detail below with reference examples and examples, but the present invention is not limited thereto in any way. The meanings of the abbreviations in the reference examples and examples are as follows. .

A, njs: p-methoxyphenyl group t-Bu: t-butyl group THF: Tetrahydrofuran n-BuLI Nibutyllithium t-BuLl: t-Butyllithium NTS diN-9-tosuccinimide DMF Nidimethylformamide CLI (OAC )t'Copper(II) acetateCu(O
BZ)s: Benzoic acid! ! (!I) DABCO: 1
,4-diazabicyclo(2,2,2)octane Reference Example 1 p-anisidine (2,06 g, 17 mmol), butanoyl chloride (2,61 ml, 1.25 mmol) triethylamine (4,66 ml, 33 mmol) and dichloromethane (30 ml) ) was stirred at 0°C for 2 hours. The reaction solution was diluted with ethyl acetate and mixed with IM-hydrochloric acid,
It was washed successively with water, saturated aqueous sodium carbonate solution, and saturated brine. Organic butanamide (3.12 g, yield 97
%) was obtained.

'H-NMR (CDCI delta: 0.97 (t.

J=6.8Hz, 3H), 1.6 2.0 (m.

2H), 2.29 (t, J=6.8H32H).

3.76 (s, 3H), 6.82 (t, Js-
s, sHz, 2H), 7.40 (d, J=8.8Hz
.

2H).

Of this, 1.84 g (9.5 mmol) was dissolved in dichloromethane (30 ml), and bromoacetic acid t was added under ice cooling.
-butyl (4,62ml, 29mmol), triethylbenzylammonium bromide (0,45g).

1.7 mmol) and 50% aqueous sodium hydroxide solution <
The reaction mixture was stirred at room temperature for 40 hours, poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed successively with water, IM-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ether:hexane-45:55) to obtain N-(t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)butanamide (2.80 g, yield 93%). ) was obtained as colorless plate crystals.

Melting point: 96-97.5°C (isopropyl ether).

Rf O, 44 (Ether: Hegyu San-2: 1)
.

'H-NMR (CDC13) δ+0.84 (t.

J-1,3Hz, 3H), 1.46 (s, 9H).

1.5-1.8 (m, 2H), 2.0-2.2 (m,
2H), 3.82 (s, 3H), 4.21 (s, 2H
), 6.89 (d, J = 9.0Hz.

2H), 7.25 (d, J=9.0Hz, 2H).

rR (KBr) C:2990.1745°1660.
1'515.1225.1155cm-'.

Mass m/z (relative strength) 307 (M”, 15), 237 (14).

181 (94), 136 (10G).

Elemental analysis value: Calculated value as C1 Ht s N Oa: C, 66,42; H, 8,20i N, 4.56%.

Actual value: C, 66,40; H, 8,09i N, 4.56%.

Acetyl chloride (0.32 ml, 4.5 mmol) was added to a solution consisting of p-anisidine (0.37 g, 3.0 mmol), ethylamine (0.83 ml, 6.0 mmol) and dichloromethane (3.0 ml) over water cooling. was added and stirred at the same temperature for 1.5 hours. The three reaction solutions were diluted with ethyl acetate and washed sequentially with Q, IMtllfll, saturated aqueous sodium bicarbonate solution, and saturated brine.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield pure N-(4-methoxyphenyl)-acetamide (
0.50 g, quantitative) was obtained.

'HNMR (CDCIs) δ: 2.12 (s.

3H), 3.7? (s, 3H), 6.83 (d.

J-9.0Hz, 2H), 7.38 (d, J-9.0
Hz, 2H).

Of this, 0.20g was dissolved in dichloromethane (4.0ml), and t-butyl bromoacetate (0.62ml) was cooled on ice.
1, 3.5 mmol), triethylbenzylammonium bromide (50s, 0.18 mmol) and 50% aqueous sodium hydroxide solution (0.20 ml) were added, and the mixture was stirred at the same temperature for 1 hour. After further stirring at room temperature for 17 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane-7=3) to obtain N-(t-butoxycarbonyl methyl)-N-(4-methoxyphenyl)-acetamide (0.28 g, yield 84%) was obtained as colorless crystals.

Melting point: 58-60°C (isopropyl ether).

Rf O, 33 (ethyl acetate:hexane-1j 1)
.

'HNMR (CDCIs) δ: 1.45 (s.

9H), 1.88 (s, 3H), 3.81 (s.

3H), 4.21 (s, 2H), 6.89 (d.

J=9.01 (z, 2H), 7.26 (d,
J-9.0Hz, 2H).

IR(KBr)y:2990.1745°1660.1
515.1375.1250゜1225.1150am
-'.

Massm/z (relative intensity) 279 (M”, 69), 237 (16).

223 (30), 206 (40), 181 (100
).

Elemental analysis (1: Calculated as CIs Hz + NO-: C, 64,49; H, 7,58i N, 5.01%.

Actual value: C, 64,26: H, 7,70: N, 4.95%.

Reference example 3 2-aminopyridine (1,11IC, 12mmol)
Triethylamine (3.29 ml, 24 mmo +) and acetyl chloride (1.26 ml, 8 mmo I) were added to a dichloromethane (20 ml) solution under water cooling, stirred at the same temperature for 1 hour, and then stirred at room temperature for 5 hours. The resulting 0 reaction solution was diluted with ethyl acetate and washed successively with water and IM-hydrochloric acid/saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain pure N-(2-pyridyl)-7cetamide (1.51 g, yield 94%).

'H-NMR (CDCIs) δ: 2.28 (s.

3H), 7.2-8.7 (m, 4H), of which 1.49g (11mmo +) was added to dichloromethane (2
1-butyl bromoacetate (5 ml) and 1-butyl bromoacetate (5 ml) under ice cooling.
, 31ml, 33mmol I), triethylbenzylammonium bromide (0.50g, 19mmol) and 50% aqueous sodium hydroxide solution (2.0ml) were added and stirred at the same temperature for 2 hours, then stirred at room temperature for 20 hours. The liquid was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed successively with water, LM-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (ether:hexane-4:l) to give N-(t-butoxycarbonylmethyl)-N-( 2-pyridyl)-acetamide (1.82 g, 66% yield) was obtained. Colorless oil.

Rf O, 44 (ether).

' HN M R (CD CI s) δ: 1.45
(s.

9H), 2.13 (s, 3H), 4.4'7 (s.

2H), 7.1-8.5 (m, 4H).

IR(neat) shi;2990,1?40°1675
．． 1590.1470,1370゜1210.1155
cm-'.

Mass m/z (relative intensity) 250 (M”, 1.1), 208 (2,
5).

194 (2,5), 177 (7,5), 107 (1
00).

Reference example 4 p-anisidine (0.75 g, 6.1 mmol)) ethylamine (2.54 ml 1.18 mmol) and TH
Phenacyl bromide (1
, 82 g, 9.2 mrnol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate and
．． The mixture was washed successively with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown solid (1.56 g). 1.30g of this was added to dichloromethane (20ml)
Dissolve triethylamine (2,25ml + 16mm
o l) and acetyl chloride (0,77ml1.11mm
o 1) was added under water cooling, and after stirring at the same temperature for 5 hours, the reaction solution was diluted with ethyl acetate and washed successively with IM-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetic acid ether:hexane-1:1) to obtain N-benzoylmethyl-N-(4-methoxyphenyl). -acetamide (0.61 g, yield 43%) was obtained. Pale yellow oil.

Rfo, 32 (ethyl acetate:hexane-2:1).

'H-NMR (CDCIs) δ: 1.96 (s.

3H), 3.81 (s, 3H), 5.07 (s.

2H), 6.89 (d, J-9,0H32H)
.

7.31 (d, J=9.0Hz, 2H), 7.4-8
．． 1 (m, 5H).

IR(neat)y:2935.1700°1660.
1510.1250cm-'.

Massm/z (relative intensity) 283 (M”, 76), 241 (28).

178 (72), 136 (100).

(S)-4-isopropyloxazolidin-2-one (
264 mg, 2.0 mmol) of THF (25 m
l) Cool the solution to -78°C and add a hexane solution of n-BuL (1,53M, 1.47ml, 2.2mmol).
was added and stirred at the same temperature for 20 minutes. Bromoacetyl chloride (0.22 ml, 2.7 mmol) was added and the reaction solution was gradually heated to 0° C. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oil.

'H-NMR (CDCIs) δ! 0.90 (d.

J=6.5Hz, LH), 0.92 (d, J-6,5
Hz, 3H), 2.2-2.6 (m, IH).

4.1-4.6 (m, 3H), 4.53 (ABq.

Jam"13.0H2, ΔM-13.9Hz, 2H).

This was dissolved in THF (4 ml), triethylamine (0.57 ml, 4.1 mmo I) and p-anisidine (302 m, 2.5 mmo I) were added, and the reaction mixture was stirred at room temperature for 9 hours and diluted with ethyl acetate. Dilute and IM
- Washed sequentially with hydrochloric acid, water, saturated IR# sodium hydrogen aqueous solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oil.

'H-NMR (CDCIs) δ: 0.83 (d.

J-6.0Hz, 2H), 0.91 (d,
J-6,5Hz, 3H), 2.1-2.5
(m, IH).

3.75 (S, 3H), 4.1-4.6
(m, 3H).

4.46 (s, 2H), 6.76 (A
Bq, JAI-9.0Hz, Δy=13
．． 2Hz, 4H).

This was dissolved in dichloromethane (10 ml), and triethylamine (0.57 ml, 4.1 mmol) was added under water cooling.
) and butanoyl chloride (0.32ml, 3.1mmol
) and stirred at the same temperature for 2 hours.

The reaction solution was diluted with ethyl acetate, and the residue obtained by the same treatment as above was purified by preparative TLC (ether).
N-((S)-4-isopropyloxazolin-2-one-3-carbonylcomethyl-N-(4-methoxyphenyl)-butanamide (R list 0.43.0.45 g, 3
A stepwise yield of 61%) was obtained. Pale yellow oil.

[α)”+47.5' (c=0.38.CHC13
).

'H-NMR (CDC13) δ: 0.84 (t.

J-7.5Hz, 3H), 0.88 (d,
J-6.8Hz, 3H), 0.91
(d, J-7,0Hz, 3H), 1.4-
1.8 (m, 2H).

2.12 (d, J-6,6Hz, 2H),
2.2-2.6 (m, IH), 3.82
(s, 3H).

4.1-4.5 (m, 3H), 4.89
(ABq.

Ja*=17.0H2, ΔC 10.5Hz, 2H
).

6.89 (d, J-9,0Hz, 2H),
7.28 (d, J-9,0H2,28).

ER(neat) C:2970. 1780°17
15, 1660. 1510. 1390°1250
am-'.

Mass m/z (relative intensity) 362 (M”, 8.3), 292 (3
2).

163 (17), 136 (100).

Reference example 6 (-)-8-phenylmenthol (E, J.

1::orey et al., J. Am. Chem. Soc.

To a solution of bromoacetyl chloride (154, 0.66 mmol I) obtained by the method described in Uni.
82 μm, 0.99 mmo I) and triethylamine (0.18 mm 1.1.3 mmo I) were added and stirred at the same temperature for 10 hours, then stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate and diluted with IM-hydrochloric acid. , water, saturated aqueous sodium bicarbonate solution and saturated brine.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oil.

'H-NMR (CDCI,) δF 0.86 (
d.

J-6.0Hz, 3H), 1.18 (s.

3H), 1.29 (s, 3H), 1.4-2.2(
m, 8H), 4.22 (ABQ, JAw-15, I
Hz, Δj'-29.3Hz, 2H).

4.8-5.1 (m, IH), 7.1-7.5 (m,
5H).

Of this, 80 µ was dissolved in dichloromethane (1, Qm I ), and N-(4-methoxyphenyl)-acetamide (see Reference Example 2) (56 µ, 0.34 mm o 1 ) was dissolved.
, triethylbenzylammonium bromide (15■, 0
．． 05 mmo +) and 50% aqueous sodium hydroxide solution (0.1 ml) were added and stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was transferred to a preparative TL.
Purified with C (ethyl acetate:hexane-3=2) and purified with N-(
8-phenylmenthyloxycarbonyl)-N-(4-
methoxyphenyl)-acetamide (R-〇, 51゜5
6■, two-step yield 57%) was obtained. Colorless oil.

'HNMR (CDCIs) δ: 0.85 (d.

J=5.9Hz, 3H), 1.67 (s.

3H), 1.25 (s, 3H), 1.5-2.2 (m
, 8H), 1.85 (s, 3H).

3.66 (A Bq+ 'J *s-17,1) (z
.

ΔC 59.8Hz, 2H), 3.84(s, 3MaI)
, 3.86 (td, J-10,01(z, 4.
5Hz, IH), 6.9-7.3 (m, 9H).

rR(neat)y:2960.1?40°1665.
1510.1200c11-'.

Massm/z (relative intensity) 437 (M”.

22), 395 (9,5), 224 (50).

181 (87), 136 (100).

(R)-(-)-3-hydroxybutanoate methyl (1,
Triethylamine (3.38ml 1.24mmol) in DMF (60ml) solution of 90g, 16mmol)
, 4-dimethylaminopyridine (196g, 1.6mm
o l) and t-butyldimethylsilyl chloride (2
92 g, 19 mmol) were added sequentially, and 55 g of
The reaction solution was stirred for 4 hours, diluted with hexane, water and 0.5
Washed with M-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.85 g of a pale yellow oil.

Of this, 3.75g was added to potassium hydroxide (1.30g).

23 mmo+) in methanol (20 ml) and stirred at room temperature for 17 hours. Methanol was distilled off under reduced pressure, and the residue was dissolved in water and washed three times with ether. The aqueous layer was made acidic with IM-hydrochloric acid while cooling with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain pure (3R)
~t-butyldimethylsilyloxybutanoic acid (3,15
g, 2-step yield 69%) was obtained. Colorless oil.

'T-I-NMR (CDC11) δ, Q, 09 (1
3H), 0.10 (s, 3H), 0.89 (s, 9H
), 1.25 (d, J-6, 4Hz, 3) 1), 2.
49 (d, J-5, 9Hz, 2M), 4.0-4.4
(m, IH).

The above product (410m, 1.9mmo 1), N-(4
-methoxyphenyl)-glycine t-butyl (535g
A reaction solution consisting of LtrH diimide (465Q+, 2.3 mmol), 4-dimethylaminopyridine (23 g, 0.19 mmol 1) and dichloromethane (5Q+) was heated at room temperature for 12 min.
Stir for hours. Insoluble matter was filtered off with a filter paper and washed with ether. The filtrate was diluted with ether and washed successively with 0.1M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the resulting residue was purified by silica gel column chromatography (acetone:dichloromethane-〇, 2299.8).
3R) -N-(t-butoxycarbonylmethyl)-N-
(4-methoxyphenyl)-3-1-butyldimethylsilyloxybutanamide (735*, yield 89%) was obtained as a colorless oil.

'H-NMR(CDCls)δ: 0.0
2 (s.

6H), 0.84 (s, 9H), 1.
11 (d, J-5, 9Hz, 3H), 1.
45 (s, 9H), 2.12 (dd,
J-18.0Hz, 6.6Hz, IH),
2.42 (dd, J-18,0Hz, 6.6H
z＞.

3.83 (s, 3H), 4.20 (A
Bq.

Jam-16.7Hz, Jas=37.2Ht.

2H), 4.1-4.5 (m, LH),
6.89 (d, J=9.0Hz, 2H),
7.25 (d, J-9,0Hz, 2H).

IR(neat)y:3040. 1740°16
85, 1510. 1250°1 055csi-'.

Massm/z (relative intensity) 437 (M″″.

1.7), 422 (3,0), 380 (1
00).

[α) V+21.2° (c-1,36, CHCl5)
,.

Elemental analysis value Calculated value as CssHs*N0sS l
C, 63,12i H, 8,98i N.

3, 20%.

Actual measurement value C, 63,08i H, 8,97; N.

3.01%.

The above product (203*, 0.46 mmo 1), THFifi of tetrabutylammonium fluoride (IM, 0
．． 70m1, 0.70mmo I), and THF (
A reaction solution consisting of 3.0ml) was stirred for 10 hours under water cooling and then for 2 hours at room temperature.The reaction solution was diluted with ether and washed with water. After drying the organic layer with anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent under reduced pressure was purified by preparative TLC (ethyl acetate:hexane-2:1) to give (3R)-N
-(t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)-3-hydroxybutanamide'(
R♀0.45.145■, yield 97%) was obtained as a colorless solid.

'HNMR(CDClx)δ! 1.08 (d.

J-6, 4Hz, 3H), 1.46 (s.

9H, ), 2.18 (d, J-8,4Hz
.

IH), 2.21 (d, J=4.0Hz.

IH), 3.82 Cs, 3H), 4.
1 (brs, IH, OH), 4.1 4.3 (
m, IH), 4.21 (s, 2H).

6.90 (d, J-9, 2Hz, 2H).

7.23 (d, J-9, 2Hz, 2H).

Mass m/z (relative intensity) 323 (M”.

8.4), 237 (9,4), 18]
(77>.

136 (100).

Example 1 N-(t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)butanamide (55 ■.

0.18 mmol) in THF (4.0 ml) solution =
Cool to 78°C and add t-BuLl in pentane solution (1,4
Add 1M, 0.28m1, 0.39mmo 1), 3
Stirred for 0 minutes. This solution was cooled to -78°C and dissolved in tetraphenylphosphonium bromide (173w, 0.41mmol).
The reaction mixture was added to a THF (1 ml) suspension of 1) and stirred for an additional 30 minutes, and then cooled to -95°C.

0.23 mm o l) of THF (1.0 m1)
The fil solution was added all at once. After stirring for 30 minutes, the reaction solution was
The reaction solution, which had been heated to -70°C over a period of time, was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate.

The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (acetone:dichloromethane-2:98) to give cis-4-(t-butoxycarbonyl)-3-ethyl-1-(4-methoxyphenyl)-2-7. Zetidinone (Rmine 0.48.28■,
(Yield 51%) was obtained as colorless crystals.

Melting point: 92-93°C (isopropyl ether).

'H-NMR (CDCIs) δ+ 1.11 (t.

J=7.3Hz, 3H), 1.46 (a.

9H), 1.6-1.9 (m, 2H).

3.45 (dt, J-6, 2, 8, 0Hz.

IH), 3.78 (s, 3H), 4.45 (d, J=
6.2Hz, IH), 6.84(d, J-9,0Hz,
2H), 7.24(d, J-9, 2Hz, 2H).

IR(KBr)u:2990,1745°1?35,1
510.1240°1170 csi-'.

MB 33 m/z (relative strength) 305 (M.

16), 249'(100).

Elemental analysis value: C + qH * Calculated value as 5 NOa + C
,66,86+H,7,59,N,4.59%.

Actual value: C, 66,701, 7,43, N, 4.57%
8 Example 2 υ N7 (t-butoxycarbonylmethyl)-N-(4-
methoxyphenyl)butanamide (56■.

A solution of 0.18 mmol) in THF (5,0 ml) was cooled to -78°C, and a solution of t-BuLl in pentane (1,0 ml) was cooled to -78°C.
41M, 0.28m1.0.39mmol) was added,
Stirred for 30 minutes. Cu(OBz)m cooled to the same temperature
(139*, 0.45 mmon DMF-THF
(1: 1.8.0 ml) @ suspension was added all at once and stirred for 1 hour. The same post-treatment and purification as in Example 1 were carried out to obtain 4-(
t-butoxycarbonyl)-3-ethyl-1-(4-methoxyphenyl)=2-azetidinone (22■, yield 4
0%) was obtained.

The ratio of 3.4-cis form and 3.4-trans form is 'H-N
It was determined to be 1.4+l from MR.

Colorless oil.

R40,48 (acetone:dichloromethane-'H-NM
R(CDCIs)δ: 1.11 (br t.

J-1.3Hz, 3H), 1.45.1.46 (239
Intensity ratio -121,4,9)1).

1.6-2.0 (m, 2H), 3.1-3.3 (m,
0.41 (), 3.45 (d t, J
-6,2,8,0Hz, 0.6H), 3.78 (a
.

3H), 4.05.4.45 (2d, J Temple 2.5
．． 6.2Hz, intensity ratio -1F 1.4゜IH),
6.84 (d, J=9.0H32H), ?
, 24. 7.26 (2d, J-9,0,J=
9.0Hz, intensity ratio -t, 4+1°2H).

IR(neat)El:2990. 1?45°151
5, 1245. 1155cm-'.

Example 3 N-(t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)acedo, mido (75■.

0.27 mmol) and DABCO (66+qr.

A solution of THF (0.59 mmol) (0.5 ml) was cooled to -78°C, and t-13 ul, l of a pentane solution (
1,41 M, 0.42 ml, 0.59 mmol 1) was added and stirred for 30 minutes. Cu (OAc)x (146w, 0.80mmol) cooled to -78℃ was added to this solution.
A DMF (4 ml) solution was added at once to the reaction mixture, which was stirred at the same temperature for 3 hours, poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure. The obtained residue was purified by preparative TLC (ethyl acetate:hexane-1:2) to obtain 4-(t-
butoxycarbonyl)-1-(4-methoxyphenyl)
-2-Azetidinone (Ren 0.39..31■, yield 4
1%) was obtained as colorless crystals.

Melting point: 93.5-95°C.

'H-NMR (CDCI,) δ: 1.44 (s.

9H), 3.05 (dd, J=14.4Hz.

3.0Hz, LH), 3.33 (dd, J-14, 4
Hz, 5.5Hz, IH), 3.78(s, 3H)
, 4.33 (dd, J-5,5Hz,
3.0Hz, LH), 6.85 (d.

J-9, 2Hz, 2H), 7.28 (d.

J=9.2Hz, 2H).

IR (CHCIs) υ: 2990. 1750
゜1515, 1245cm-'.

Massm/z (relative intensity): 277 (M”.

20), 221 (100).

Elemental analysis value C+ s Hlq N Calculated value as Oa: C, 64,96; H, 6,91; N.

5.05%・ Actual value: C, 65, 03,! (,7,08;N.

5.03%.

Example 4 THF (
The solution (5 ml) was cooled to -78°C, a hexane solution of n-BuLl (0.37 ml, 0.52 mmol) was added, and the mixture was stirred for 1 hour.

The reaction solution was cooled to -95°C, and N I was cooled to the same temperature.
THF (70ar, 0.31mmo 1)
1.0 ml) solution was added all at once. After stirring at the same temperature for 1 hour, the mixture was further stirred at -78°C for 1 hour.

The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer is a saturated sodium thiosilicate aqueous solution,
It was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. After drying over anhydrous magnesium acid, the solvent was distilled off under reduced pressure and the resulting residue was purified by preparative TLC (acetone:dichloromethane-3:97) to give 4-(t-butoxycarbonyl)-1-( 2-pyridyl)-2-azetidinone (R size: 0.34.22 mm, yield: 37%) was obtained.

Colorless oil.

'H-NMR (CDC11) δ: i, 44 (s.

9H), 3.03 (dd, J=15.OHz.

2.9Hz, IH), 3.35 (dd, J-15, O
Hz, 6.0Hz, IH), 4.53
(dd, J=6.0Hz, 2.9Hz, IH).

6.9-8.3 (m, 4H).

IR(neat) υ:2990.1770°1?4
0.1590,1480°1435.1155cm-'.

Mass m/z (relative intensity): 248 (M'.

1.1), 175 (9,3) 147 (
51).

57 (100).

Example 5 N-benzoylmethyl-N-(4-methoxyphenyl)
-acetamide (64■, 0.23 mmol) and DA
BCO (j6sir, 0.50 mmol) in THF (
2.0 ml 1) solution of lithium diisopropylamide (0.25 mmol) was cooled to -78°C in THF (5,
0ml) solution and stirred for 30 minutes. n-Bu
Li hexane solution (1,56M, 0.16ml 1.0.
25 mmol) was added, and after further stirring for 1 hour, the temperature was reduced to -78°C.
Cu (OAc)t (103w, 0.58
mmol) of TI(F (5.0 ml)) was added all at once. After stirring at the same temperature for 3 hours, the reaction mixture was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was diluted with a saturated sodium thiosulfate aqueous solution, Washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified using preparative TLC (ethyl acetate:hexane-3:2). and 4-benzoyl-1-(4-methoxyphenyl)
-2-Azetidinone (8 articles 0.43.7.1■, yield 1
1%). Colorless oil.

'H-NMR (CDCIs) δ: 3.0? (dd.

J-14,4833,0Hz,IH).

3.58 (dd, J=14.4Hz, 6.0Hz
, IH), 3.77 (s, 3H).

5.41 (dd, J=6.0Hz, 3.0Hz.

LH), 6.86 (d, J=9.0Hz.

2H), 7.26 (d, J-9,0Hz.

2H), 7.4-8.1 (m, 5H).

IR(neat) u+2945. 1750°1
510, 1250am-'.

Masam/z (relative intensity): 281 (M”.

64), 176 (38) 148 (6'
? ).

134 (100).

Example 6 N-((S)-4-isopropyloxazolidine-2-
[on-3-carbonyl]methyl-N-(4-methoxyphenyl)butanamide (57■.

A solution of t-BuLi in pentane (1,6 mmol) was cooled to -78°C in THF (4,0 ml)
0M, 0.22ml, 0.35mmol), and
Stirred for 0 minutes. This solution was cooled to -78°C and mixed with tetraphenylphosphonium bromide (152 mg, 0.36 mm).
o 1) into a THF (1,0 ml) suspension, and after further stirring for 30 minutes, Cu(OAc)t(72*, 0
．． A solution of 40 mmol 1 ) in DMF (2.5 ml) was added all at once at the same temperature. After stirring for 4 hours, the reaction solution was gradually heated to room temperature, and the reaction solution was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. After drying with anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent under reduced pressure was purified by preparative TLC (ether) and further purified by preparative TLC (acetone:dichloromethane-5:95) to obtain 3-ethyl-4-
((S)-4-isopropyloxazolidin-2-one-3-carbonyl)-1-(4-methoxyphenyl)-
Four stereoisomers of 2-azetidinone were obtained. (30■
, yield 52%).

The isomers were determined by TLC (Slot, ether) as isomers 1, 2, and 3.4 in order of decreasing polarity, and the production ratio was determined to be t, 3: t, s: t, and 2: 1 from their isolated yields. . Isomer 1, colorless oil.

0.61 to R (ether).

(α)’d-169@(c=0.31.CHCIs).

'H-NMR (CDCta) δF 0.93 (d.

J-7.0Hz, 3H), 0.95 (d.

J-6,8Hz, 3H), 1.11 (t.

J-1,3Hz, 31(), 1.4-1.8 (m.

2H), 2.2-2.6 (m, IH).

3.5-3.8 (m, IH), 3.77 (s.

3H), 4.3-4.6 (m, 3H).

5.62 (d, J-5, 9Hz, LH).

6.84 (d, J-9, 2Hz, 2H).

7.20 (d, J=9.2Hz, 2H).

I R(CHCl s) υ :2975. 17
80°1750, 1715. 1515°1390, 1245(2)i.

Ma s s m/z (relative intensity) = 360 (M”
37), 149 (74), 134 (10G
).

C+ *H□N, as 06 Calculated value: M”, 360.1683° Actual value: m/z 360.167? .

Isomers 2. Colorless oil.

R♀0.54 (ether).

(α) v +194@ (C-0,19,cHcls
>.

'H-NMR (CDCI2) δ: 0.90 (d.

J=7.0Hz, 3H), 0.92 (d.

J=7.0Hz, 3H), 1.10 (t.

J=7.3Hz, 3H), 1.8-2.2 (m2H)
, 2.1-2.5 (m, IH).

3.21 (td, J=7.0Hz, 2.4Hz.

IH), 3.77 (s, 3H), 3.
2-3.6 (m, 3H), 5.53 (d
, J-2,4Hz, IH), 6.84
(d, J -9,0Hz, 2)1), 7
．． 23 (d, J -9,0Hz, 2H).

IR(CHCIs) υ :2970. 1780
゜1750.1710, 1515゜1390, 1245c*-'.

Massm/z (relative intensity): 360 (M′″41),
176 (84), 149 (100).

Calculated value as C+ q H* a N * Os: M”
, 360.1683° Actual value: m/z 360.1679, isomer 3. Colorless oil.

R90,46 (ether).

(α)V+211” (c-0,11,CHCl5)
.

'H-NMR (CDCIs) δ; 0.92 (d.

J=6.8Hz, 3H), 0.93 (d.

J=7.5Hz, 3H), 1.18 (t.

J-7.0Hz, 3H), 1.5-1.9
(m2H), 2.2-2.6 (m, IH)
.

3.6-3.9 (m, LH>, 3.77
(s.

3H), 4.0-4.4 (m, 3H).

5.45 (d, J-5,9Hz, IH).

6.84 (d, J-9, 2Hz, 2H).

7.22 (d, J=9.2Hz, 2H).

IR (CHCIs) (1:2950, 1780°1750, 1?10. 1515°1390° 1 25 Qcm-'.

Ma s s m/z (relative intensity): 360 (M”
49), 176 (54), 134 (100
).

Calculated value as C+ e H a N s Oa - M'''
, 360.1683° actual measurement? 1: m/z 360.1684° isomer 4.
Colorless crystal.

Melting point: 189-190℃ R given 0.41 (ether).

(”) “D-72-5” (c-0,32, CHCI
J-'H-NMR (CDC1s) δ+ 0.91 (
d.

J-1.0Hz, 3H), 0.92 (d.

J=6.8Hz, 3H), 1.09 (t.

J-7, 3Hz, 3H), 1.8-2.1 (m.

2H), 2.2-2.5 (m, 1) 1).

3.26 (td, J=6.5Hz, 2.2Hz.

IH), 3.78 (s, 3)? ),
4.2-4.6 (m, 3H), 5.56 (d, J-
2,2Hz, IH), 6.84 (d, J-9,2Hz
, 2H), 7.22 (d, J-9, 211, 2H)
.

Summer R (CHCIs> a: 2980. 178
0°1750.1710.1515°1390.1245cm-'.

Massm/x (relative intensity): 360 (M'44),
176 (89), 134 (10G).

Calculated value as C, H car 4N proverb 0$: M”+ 360.1683°Actual measurement value: m/z
360.1675° Example 7 N-(8-phenylmenthyloxycarbonyl)methyl-N-(4-methoxyphenyl)acedoad(224
,0,050mmo 1) and DABCO (13w, 0
．． A solution of 12 mmol I) in THF (1.5 ml) was cooled to -78°C, and a solution of t-BuLi (1.
60M, 0.069 ml, 0.11 mmol 1) was added and stirred for 30 minutes. This solution was cooled to the same temperature as Cu.
(OAC) g (27N, 0.15mmo 1) D
Added all at once to MF (1.0 ml) solution. After stirring at -78°C for 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to preparative TLC.
After purification with (ether:hexane-3=1), further purification with preparative TLC (acetone:dichloromethane-5:95) produced 4-(8-phenylmenthyloxycarbonyl).
-1-(4-methoxyphenyl)-2-azetidinone (
JO, 604.0■, yield 18%) was obtained.

Colorless oil.

'HNMR(CDCIs)δ! 0.82 (d.

J-5, 9Hz, 3H), 1.19 (s.

3H), 1.32 (13M), 1.5-2.2 (
m, 8H), 2.63 (dd, J-18,0
Hz, 3.0Hz, IH), 3.06(dd, J=18
．． 0Hz, 6.0Hz.

IH), 3.7-3.9 (m, IH).

3.770m, 3H), 4.91 (td, J-9,
1Hz, 4.0Hz, IH), 6.8-7.3 (m, 9
H).

IR (CHCIs) u:2960.1750゜1
510, 1240cm-'.

Mass m/x (relative strength): 435 (M”1
2), 221 (46), 119 (68).

Example 8 U (3R)-N-(t-butoxycarbonylmethyl)-N
-(4-methoxyphenyl)-3-hydroxybutanamide (46, 0.14 mmo+) in THF (2,0
m1) Cool the solution to -78°C and add a hexane solution of n-BuLI (1.48M, 0.32m 1.0.47mmol
1) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. Copper trifluoromethanesulfonate (170ar, 0.47mmo
A solution of (+) in isobutylene (1.0 ml) was added all at once, and the mixture was further stirred for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative TLC (
After purification with preparative TLC (acetone:
Purify with dichloromethane (5:95, developed twice).
'R)-4-(t-butoxycarbonyl)-3-
Four stereoisomers of (1'-hydroxyethyl)-1-(4-methoxyphenyl)-2-azetidinone were obtained.

(1'R, 3S.

43) body, J O, 29, 2, 0 Akebono, yield 5%; (1'
R, 3R, 4R) body, R♀0.3], 1.1■.

Yield: 3%; (1'R, 3R, 43) and (1'R.

3S, 4R) mixture, R60,34,1,6I11
r.

The yield was 4%. The (1'R,33,4S) isomer is a known compound, and the instrumental data for this compound is reported in the literature It (M.

5hlozakl et al., Tetrahadron.

40.1795 (1984)).

(1'R, 3R, 4R) body: colorless oil.

'HNMR (CDCI3) δ: 1.42 (d.

J=5.5Hz, 3H), 1.45 (s.

9H), 3.28 (dd, J=6.0Hz.

2.8Hz, IH), 3.78 (s, 3H).

4.0-4.2 (m, IH), 4.24 (d.

J=2.8Hz, IH), 6.86 (d.

J-9, OH32H), 7.27 (d.

J=9.0Hz, 2H).

IR(CHCI,) υ: 3soo, 174
5°1510cm-'.

Mass m/z (relative intensity); 321 (M”22)
, 265 (100).

(1'R, 3R, 4S) body and (1'R, 3S.

4R) mixture, colorless oil.

Todoroki H-NMR (CDC13) δ: 1.37°1.
47 (2d, J=6.4, 7.0Hz.

Intensity ratio -1: 2,3H), 1.47 (s.

9H), 3.52 (t, J-6,0Hz.

0.38), 3.55 (dd, J=10.0Hz.

6.0Hz, 0.7H), 3.78 (s, 3H).

4.0-4.2 (m, 11(), 4.47°4.
57 (2d,,1=-6,0,6,OH1 intensity ratio-
1: 2. 1H), 6.86 (d.

J-9.0Hz, 2H), 7.25 (d.

Jm9. OH32H).

IR (CHCIs) υ:3soo, 1745°1
510cm-'.

Massm/z (relative intensity): 321 (M”14), 2
65 (100).

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, an alkoxy group, or a substituted amino group. R^2 represents an aryl group, an alkoxy group, or a substituted amino group, and R^3 represents a protecting group for the amino group. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting an amide represented by the following with an oxidizing agent in the presence of a base ▼ [In the formula, R^1, R^2 and R^3 are as above. Represents the same meaning. ] A method for producing a β-lactam derivative represented by: