JPH02193964A - Production of 3,4-trans-beta-lactam derivative - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound useful as an intermediate for the synthesis of various beta-lactam antibiotics such as monobactams by using an easily available 3,4-cis-beta-lactam derivative as a raw material and treating the material with an acid. CONSTITUTION:The objective compound of formula II (R<4> is H or carboxyl- protecting group) can be produced by using a 3,4-cis-beta-lactam derivative of formula I [R<1> is amino or protected amino; R<2> is H or carboxyl-protecting group; the steric configuration of 3- and 4-positions is (3S*, 4S*), (3S, 4S) or (3R, 4R); R<3> is H or amino-protecting group] as a raw material and treating the material with an acid. The acid is preferably trifluoroacetic acid, oxalic acid, etc., and its amount is from 0.1 equivalent to excess amount, preferably in excess (>=2 equivalent). The reaction temperature is -78-+100 deg.C. The starting compound of formula I is synthesized by using a primary amine as a raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to the following general group 2 (where R1 represents an amino group or a protected ``amino group'', and R1 represents a hydrogen atom or a protecting group for a carboxyl group). The configuration of the 3rd and 4th positions is (3S", 4S"),
(3S, 4S) or (3R24R). R3 represents a hydrogen atom or a protecting group for an amino group.]
General formula (■) characterized in that a 3,4-cis-β-lactam derivative represented by is treated with an acid [wherein R1 and Rs represent the same meanings as above].

R4 represents a hydrogen atom or a carboxyl group protecting group,
The configuration at the 3rd and 4th positions is (3R", 43"), (3R, 4S) or (3S, 4R), respectively, corresponding to the notation order of the configuration in the (+) formula. 3 represented
, 4-) relates to a method for producing a lance-β-lactam derivative.

The β-lactam derivative represented by the above-mentioned linear formula (n) can be a useful intermediate in the production of various β-lactam antibacterial agents such as monobactams. For example, in (II>, R ' is a dibenzylamino group, R'' is (
(33,4R)-β-lactam derivatives in which S)-1-phenylethyl group and R4 are t-butyl groups are used as antibacterial agent aztreonam (Kuchi, M., Floyd et al., J. Org, C.
hem, 4e, 5160 (1982)') (see reference side below), or as a synthetic intermediate for various 3-7 mino N-substituted 3,4-trans-β-lactams.

[Conventional technology]

Conventional methods for synthesizing 3,4-trans-β-lactam derivatives having an optionally protected amino group at the 3-position include i) ring-closing reaction of β-hydroxy-α-amino M & derivatives <D, M, Floyd et al., J, Org, Chem.
47, 176 (1982)).

+i) Isomerization reaction of s, t-cis-β-lactam derivatives with sodium hydroxide (B, Alcalda et al.) 1
eterocycles, 24.1579 (1986
)) Mt. a) 1. of 3.4-cis-β-lactam derivatives.
Isomerization reaction with 5-diazabicyclo(4,3,0)-nonan-5-ene (A, Bose et al., Ches+, C
omm, 975 (1970)).

1v) Isomerization reaction of 3.4-cis-β-lactam derivative with sodium bis(trimethylsilyl)amide (M
, Kitch et al., Tetrahedron, 42.
2677 (1986)).

etc. are known, but regarding i), it is not possible to synthesize various derivatives because the types of β-hydroxy-α-amino acids that can be used as starting materials are extremely limited, and various derivatives cannot be synthesized. , As the isomerization of the 3rd and 4th positions on the β-lactam stage progresses, the product becomes a mixture of stereoisomers (see comparative example below). The reaction does not proceed (
(See Comparative Examples below) and IV) require conversion of the nitrogen protecting group for the isomerization reaction, and have drawbacks such as partially recovering the cis isomer.

[Problems to be solved by the present invention]

The present inventors have discovered that 3, 4-) represented by the -wire formula (n)
As a result of repeated studies to develop a method to more effectively produce lance-β-lactam derivatives, we found that the above-mentioned -
In one step, from the 3,4-cis-β-lactam derivative represented by the linear formula (1), and without racemization even when (1) is an optically active form, the -linear formula (11) can be obtained. It was discovered that a 3,4-trans-β-lactam derivative represented by the following formula could be obtained, and the present invention was completed.

(Means for solving the problem) In the present invention, R1 in the -wire formulas (1) and (Ir)
is an amino group or a protected amino group. Protected amino groups include dibenzylamino, benzylamino, 3,4-dimethoxybenzylamino, di(4-methoxyphenyl)methylamino, 2-nitrobenzylamino, triphenylmethylamino, 4-methoxyphenylamino, dimethylamino, phenacylamino, acetamide, trifluoroacetamide, 1,2-benzenecarboximide, benzyloxycarbonylamino,
Examples include [-butyloxycarbonylamino.

Rt and R4 are hydrogen atoms or carboxyl groups! !
It is the basis. Protecting groups for carboxyl groups include methyl,
Examples include ethyl, isopropyl, t-butyl, benzyl, 4-nitrobenzyl, trimethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl.

Rz is a hydrogen atom or a protecting group for an amino group.

The protecting group for the amino group is an aryl group, a substituted silyl group, or a substituted alkyl group represented by (R)- or (S)-CHR'Ar.

Examples of the aryl group include 4-methoxyphenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-pyridyl, 2-pyrimidyl, etc., and examples of the substituted silyl group include trimethylsilyl, triethylsilyl, triisopro and lucilyl, [ Examples include -butyldimethylsilyl, t-butyldiphenylsilyl, and the like. (R) - or (
Regarding the substituted alkyl group represented by S)-〇HR'Ar,
R% is a hydrogen atom or a lower alkyl group. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. As Ar, phenyl, 2-methoxyphenyl, 4
-methoxyphenyl, 2,4-dimethoxyphenyl, 2
Examples include -tolyl, 4-tolyl, 2,4.6-trimethylphenyl, 1-naphthyl, 2-naphthyl, and the like.

The above-mentioned -wire formula (1) which is a raw material in the production method of the present invention
The 3,4-cis-β-lactam derivative represented by It can be easily produced by treating the tertiary amide obtained by the above reaction with an oxidizing agent in the presence of a base (see Reference Examples below).

Next, a method for producing 3,4-trans-β-lactam (II) from 3,4-cis-β-lactam (1) will be described.

This step can be carried out by treating the 3,4-cis-β-lactam derivative represented by the general formula (RI) with an acid in the presence or absence of a solvent.

Any acid used in ordinary organic reactions can be used, but trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, nitric acid, Cheryl acid, benzenesulfonic acid, and 4-toluenesulfone are preferable. acids, protonic acids such as trifluoromethanesulfonic acid, benzoic acid, 4-nitrobenzoic acid, aluminum chloride, aluminum bromide, titanium tetrachloride, titanium tetrabromide, tin tetrachloride, tin tetrabromide, boron trichloride Lewis acids such as trifluorofluorinated methyl ether, trimethylsilyl chloride, and trimethylsilyl trifluoromethanesulfonate can be used. The amount used ranges from 0.1 equivalent to an excess amount, and preferably an excess amount of 2 equivalents or more is used.6 The reaction temperature is from -78°C to 10°C.
It is in the range of 0°C, preferably in the range of 0°C to 10°C. This reaction can also be carried out in the presence of a solvent9
Any substance can be used as long as it does not participate in the reaction, such as dichloromethane, chloroform, 1.2
- Halogenated hydrocarbons such as dichloroethane, aliphatic hydrocarbons such as hexane, pentane, and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, Alcohols such as methanol, ethanol, isopropyl alcohol, and 2-methyl-2-propanol, and solvents such as dimethylformamide, acetonitrile, and nitromethane can be used alone or as a mixture thereof.

By the above reaction, 3.4-cis-β-lactam derivative (
The position-specific isomerization reaction at position 3 of 1) proceeds, and 3,4-
A trans-β-lactam derivative (■) is obtained. 3.
When R4 of the 4-trans-β-lactam derivative (II) is hydrogen, the reaction residue is made into an ether solution or a tetrahydrofuran solution, and then treated with diazomethane to form 3,
The 4-trans-β-lactam derivative (■) can be easily isolated.

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. .

t-Bu: t-butyl group THF: Tetrahydrofuran n-BuLi Nibutyl lithium t-BuLl: t-butyl lithium NIS + N-iodokoha (acid imide, Ants: p-methoxyphenyl group TMEDA: N, N, N', N'-tetramethylethylenediamine (R)-1-phenylethylamine (1,66 g.

14 mmo+) of THF (40 ml) i solution under water cooling.
Triethylamine (3,82ml 1,27mmol) and t-butyl bromoacetate (3,32ml 1.21mmol+)
was added and stirred at room temperature for 24 hours.

The reaction solution was poured into ethyl acetate and washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine.

After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a pale yellow oil. Add this to dichloromethane (
30rnl) and cooled to -20°C. Triethylamine (2.84 ml, 21 mmol) and bromoacetyl bromide (1.42 ml, 17 mmol I) were added and stirred at the same temperature for 1 hour.

The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. AJI was washed sequentially with IM-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a brown oil. This product was dissolved in THF (30 ml), triethylamine (3,79 ml, 27 mmol) and dibenzylamino (3,92 ml, 21 mmol 1) were added under water cooling, and the mixture was stirred at room temperature for 15 hours.The reaction solution was diluted with ethyl acetate. It was diluted and washed successively with water, IM-hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone:dichloromethane-0.5-119.5-99) to obtain N-([ -butoxycarbonylmethyl)-N-(
(R)-1-phenylethyl)-(N',N'-dibenzylamino)acetamide (5,81 g, 3 steps yield 9
0%) was obtained as colorless crystals.

Melting point 69-70°C (isopropyl ether-hexane) Rf O,37 (ether; hexane-1:1) [α
)” +47.2” (C-0,83,CHCl-H-NMR (CDCi calculation) 61.18.1.37 (
2S9 intensity ratio -3:2,9H).

1.40 (d, J-7, OH2, 3H).

3.25. 3.37 (2ABg, JAM-1
3,4°13.5Hz, Δ'am-91,0,10
,8Hz.

Intensity ratio -3F 2, 2H), 3.33, 3.35 (2d
, J=16.7, 18.4Hz, intensity ratio -2:3.
IH), 3.93.4. IT(2d, J=16.
7,18.4Hz, intensity ratio -2! 3. IH)
, 3.93.4.17 (2d, J=16.7, 18.
4Hz, intensity ratio -2:3. IH), 3.45
(d, J-i 3.3Hz, 1.2H),
3.74 (S.

1.68), 3.80 (d, J-13,3
Hz.

! , 2H), 5.29. 6.03 (2q, J
-7,0,7,0Hz, intensity ratio -2:3. IH).

7.0-7.4 (m, 5H).

I R (KB r) 2970. 1? 40.
1655°1445, 1150811-' Elemental analysis value: Calculated value as C3°Hs h N x Os: C, 76,24; H, 7,68, N, 5.
93%.

Actual value +C, 76,22; H, 7,70; N, 5
．． 89%.

Reference example 2 ψ ψ N-(t-butoxycarbonylmethyl)-N((R)-
1-phenylethyl)-(N',N'dibenzylamino)acetamide (93■, 0.20 mmol) in THF
(5 ml)'fJ solution was cooled to -78°C, and TMEDA
(65111,0.44mmol) was added, and then a hexane solution of n-BuLI (1,61M, 0.49mmol) was added.
The reaction solution was stirred at the same temperature for 1 hour, and then cooled to -95°C.
A HF (3 ml) solution was added at once to the reaction mixture, and the temperature was gradually raised to -70° C. over 1 hour while stirring.

Methanol (about 1 ml) was added at the same temperature, and the mixture 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.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to preparative TLC (ethyl acetate:hexane-1
:3) to give 4-(L-butoxycarbonyl)-
A mixture of four stereoisomers of 3-N,N-dibenzylamino-1-((R)-1-phenylethyl-2-azetidinone (54w, yield 58%) was obtained.Production of isomers The ratio was determined by 400MHz'H-NMR measurement of the above mixture: 3,4-cis form: 3.4-trans form = 171, (3
S,4S) body: determined to be (3R,4R) body-18:1. These isomers were further purified by preparative TLC (acetone:dichloromethane-〇, 5:99.5) to obtain each pure isomer.

(3S, 4S) body; RfO, 45 (acetone: dichloromethane = 0.5:9
9.5) [α)■ +36.0” (C-1,86,CHCl5
)'H-NMR (CDCIs) 61.54 (S.

9H), 1.65 (d, J=7.1Hz.

3H), 3.72 (d, J=5.3Hz.

IH), 3.91 CAB g, Ja*
=13.9)(z.

ΔI'am-29,7Hz, 4 f(), 4
．． 33 (d, J=5.3Hz, IH), 5.03 (q,
J-7, 1Hz, IH), 7.1-7.5 (m, 15H
).

IR(neat)2980.1755°1145cm-
'(3R,4R) form: 0.50 (acetone: dichloromethane-〇, 5j 9
9.5) [α)” -17,3” (c-0,81,CHC
l'H-NMR (CDCIs) δ1.50 (S.

9H), 1.80 (d, J=7.1Hz.

3H), 3.84 (d, J-5, 3Hz.

lH), 3.92 (ABg, Jas=13.8Hz
.

ΔyAm-44.5Hz, 4H), 4.38(d, J-
5.3Hz, IH), 4.62 (Q, J=7.1Hz,
IH), 7.1 7.5 (m, 15H).

IR(neat)2980, 1755°1150cs-
'f Reference Example 3 p-anisidine (10L■, 0.89rr+mo
l), L-butyl bromoacetate (0.29ml, 1.8ml
mol) and triethylamine (0.37ml, 2.7
mmol) in THF (10 ml) was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed successively 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 dissolved in dichloromethane (4 m
1) and cooled to -10°C. Triethylamine (0.25 ml, 1.8 mmol) and bromoacetyl bromide (0.12 ml, 1.3 mmol) were added and stirred at the same temperature for 40 minutes. The reaction solution was diluted with ethyl acetate.
Washed sequentially with IM-hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying the separated layers over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a pale yellow oil.

This product was dissolved in THF (2 ml), triethylamine (0.25 ml, 1.8 mmol) and dibenzylamine (0.26 ml, 1.3 mmol) were added, and the reaction mixture was stirred at room temperature for 17 hours with ethyl acetate. It was diluted and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to preparative TLC (ether:
N-(t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)=(
N',N'-dibenzylamino)acetamide (276
(2) 3-step yield of 68%) was obtained.

Colorless crystals (isopropyether).

Melting point: 123-124°C.

RrO,46(ether:hexane-3:2)'HNM
R(CDCIs) 61.46 (S.

9H), 3.09 (S, 2H), 3.
76 (S, 3H), 3.84 (S, 4
H).

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

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

7.3 (brs, l0H).

IR(KBr)2990. 1740. 1660°1
510, 1150cm-' Massm/z (relative intensity): 475 (Ml"
.

17.3>, 383 (89,5>, 210
(100).

Elemental analysis value Calculated value as Cx*HxaNtOa: C
,73,39; H,? , 22; N, 5.90%
.

Actual value! C,? 3.37; H,7,34i N
, 5.79%.

Reference example 4 N-<t-butoxycarbonylmethyl)-N-(4-methoxyphenyl)-(N', N'-dibenzylamino)
Acetamide (69 mg, 0.15 mmol) in THF
(4 ml) solution was cooled to -78°C, t-l3uL,
Pentane solution of i (0.20m 1.0.32mmo
I) was added and stirred for 1 hour.

This solution was cooled to the same temperature, and tetraphenylphosphonium bromide (134@II, 0.32 mmol) was added to THF.
(Pour 1 ml into the suspension and stir for an additional 30 minutes,
Cooled to -95°C. N cooled to the same temperature as this
IS (43m, 0.19mmo 1) of THF (1
ml) solution was added all at once, and the reaction solution was gradually heated to -20°C while stirring. After adding methanol (1 ml), the reaction mixture 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. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified by preparative TLC (ether:hexane-3:2).

3.4-cis- and 3.4-1-lance-4-butyloxycarbonyl-3-N,N-dibenzyl7mi/-
A mixture of 1-(4-methoxyphenyl)-2-azetidinone (33 µ, yield 48%) was obtained. The production ratio of 3,4-cis and 3,4-trans isomers is 7 according to IH-NMR;
It was decided to be 1.

This stereoisomer mixture was purified by preparative TLC (ethyl acetate:hexane-1:9.multiple development) to obtain pure 3.4-
) The lance isomer and the 3,4-cis isomer were obtained, respectively.

3.4-trans form RfO, 50 (ether:hexane-3:2)' H-
NMR (CD Cl s) δ 1.35 (
S.

9H), 3.80 (ABq, J□謹13.2Hz,
Δνam” 14.1 Hz, 4 kl>.

3.76 (S, 3H), 4.41 (S, 2H)
.

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

7.1-7.5 (m, I2H).

IR(KBr)2990,1745.1735°151
5, 1250. 1145cm-'Mass m/
z (relative intensity): 472 (M.

3.7), 444 (4,7), 371
(3,3).

343 (21,0), 237 (67,6).

91 (100).

3.4-cis Rfo, 48(ether:hexane-3:2)'HNM
R(CDCIson δ 1.51 (S.

9H), 3.77 (3,3■(), 4.44(d,
J-5,5Hz, fH), 6.84(d, J-9,0
Hz, 2H), 7.1-7.5 (m, 12H).

IR(KBr)2940.1?45.1515°124
5, 1150Cs-' Masam/z (relative intensity): 472 (M''.

2.9), 444 (3,5), 371
(2,4).

343 (8,9), 237 (66,5).

91 (100).

Example 1 (3R,4R)-4-(t-butoxycarbonyl)-3
-N,N-dibenzylamino-((S)-1-phenylethylcou-2-azetidinone (36■).

Trifluoroacetic acid (1 ml) was added to a solution of 0.077 mmol) in dichloride methane (1 ml) under water cooling, and the mixture was stirred at the same temperature for 30 minutes. Toluene (5 ml) was added to the reaction mixture, which was stirred at room temperature for 10 hours. The solvent was then distilled off under reduced pressure at 35°C or lower. Toluene (5 ml) was added and the solvent was distilled off in the same manner, and ether (1 ml) was added to the resulting residue.
An ether solution of diazomethane was added under ice cooling. After raising the temperature to room temperature, the mixture was stirred for 2 hours. The residue obtained by distilling off the ether was purified by preparative TLC (ethyl acetate:hexane-11) to obtain (3S,4R)-4-methoxycarbonyl-3
-N,N-dibenzylamino-1-((S)-1-phenylethylcou-2-azetidinone (27 5 yield 82%)
) was obtained as a single stereoisomer.

Colorless crystals (isopropyl ether).

Melting point: 121-122°C.

Rfo, 37 (ethyl acetate; hexane-1:3).

[α] Low’ +4.9 (C1,00, CHCl5).

'H-NMR (CDCI 61.55 (d.

J-7, 3Hz, 3H), 3.57 (ABQ.

J Al-13,4Hz, Δl'as=29.1Hz
.

4H), 3.64 (S, 3H), 3.91 (d, J-
2.0Hz, LH), 4.23(d, J=2.0Hz,
LH), 5.04 (q, J=7.3Hz, IH), 7.
23 (brs, 10H), 7.31 (brs.

5H).

IR (KBr) 3040.2945.1750゜Actual 1735, 1380.　1205゜ 1145cm-' Massm/z<relative intensity)j 428 (M”.

0.2), 323 (0,5), 2
37 (8,4).

1 90 (9,3), 1 05 (19,0
).

91 (100).

Elemental analysis value C*tH□0. Calculated value FC as N8
,75,67i H,6,59+N, 6.54%.

Actual value: C, 75,65i H, 6,62; N,
6.54%.

Male side 2 Trifluoroacetic acid (lff) was added to a solution of non (32 mg, 0.068 mmol) in methane (1 ml) under water cooling.
ll) and stirred at the same temperature for 30 minutes, then stirred at room temperature for 12 minutes.
Stir for hours. By the same post-treatment and purification as in Example 1
(3R,43)-4-Methoxycarbonyl-N,N-dibenzylamino-1-((R)-1-phenylethylcou-2-azetidinone (26■, yield 89%) was converted into a single stereoisomer The instrumental data of this product were consistent with those obtained in Example 1 except for the specific rotation.

[α)” -4,0° (C1,03,CHCl5)
.

Example 3 ψ ψ le) (33,43)-4-(t-butoxycarbony3-N
, N-dibenzylamino=1-ψ ψ [(R)-1-phenylethyl]-2-azetidi(33,
43)-4-(t-ptoxycarbonyl)-3-N,N
-dibenzylamino-1-((R)-1-phenylethyl)-2-azetidinone (53*, 0.11 mmol
) was dissolved in formic acid (3ml) and stirred at room temperature for 60 hours. Formic acid was distilled off under reduced pressure, ether (2 ml) was added to the resulting residue, and then an ether solution of diazomethane was added under ice cooling. After raising the temperature to room temperature, stirring for 2 hours and distilling off the clam ethyl, the resulting residue was purified by preparative TLC (ethyl acetate:hexane-1:3) to obtain (3R,43)-4
-methoxycarbonyl-N.

N-dibenzylamino-1-((R)-1-phenylethyl-2-azetidinone (30 µ, yield 62%) was obtained as a single stereoisomer. Instrumental data for this were given in Example 2. Consistent with that obtained Example 4 cis-4-(t-butoxycarbonyl)-3-N,N-
Dibenzylamino-1-(4-methoxyphenyl)-2
-Azetidinone (26 ml, 0.55 mmol) in dichloromethane (Hml) was added with trifluoroacetic acid (1 ml) under water cooling.
ml) and stirred at the same temperature, followed by stirring at room temperature for 6 hours. Trifluoroacetic acid was distilled off by the same operation as in Example 1, and trifluoroacetic acid was added to the residue obtained by treatment with diazomethane, followed by heating under reflux for 10 hours.

After cooling the reaction solution to room temperature, trifluoroacetic acid was distilled off in the same manner as in Example 1. The residue was purified by preparative TLC (ether:hexane-3:2) to give 4-methoxycarbonyl-3-N,N-dibenzylamino-1-(4-
methoxyphenyl)-2-azetidinone (18 g, yield 76%) was obtained.

The production ratio of the 3.4-trans isomer to the 3,4-cis isomer was determined to be 6.7:I by 'H-NMR.

Rfo, 41(ether:hexane-3:2)'HNM
R(CDCIs) δ3.72, 3.77 (2B5 intensity ratio -6.7F 1.3H).

3.7B, 3.81 (25, intensity ratio -6,7:1°3H), 3.81, 3.94 (2ABq.

Jam= 13.4.14.0Hz, Δ”Al-1
33,9,37,1Hz, intensity ratio -6,7:L4H),
4.44, 4.55 (2d, J-2, 1, 5, 6Hz
, intensity ratio -6,71°IH), 4.52,4.72 (
2d, J-2,1,5,6Hz, intensity ratio -6,7i1゜iH), 6.85 (d, J-9,IHz.

2H), 7.2-7.4 (m, 12H).

IR (CHCIs) 3010. 1750°15
10, 1245011-' Mass m/s (relative intensity): 430 (M".

3.3), 343 (3,6), 31
1 (4,8).

237 (51,4), 91 (100).

Reference example 5 (33,4R)-4-methoxycarbonyl-3-N,N
-dibenzylamino-1-((S)-1-phenylethyl)-2-azetidinone (376■.

0.88 mmol) in ethanol (16 ml)
0% palladium hydroxide (70 cm) was added, and the mixture was heated under reflux for 1 hour under a hydrogen atmosphere. Insoluble materials were collected by filtration and washed with warmed ethanol. The filtrates were combined and the solvent was distilled off under reduced pressure. Dissolve this in dichloromethane (3.0ml),
Triethylamine (0.20ml, 1.4mm) was added under water cooling.
ol) and 2-(t-butoxycarbonyloxyimino)-2=phenylacetonitrile (Boc-ON) (2
After stirring at room temperature for 24 hours, add triethylamine (0.20ml, 1.4mmol).
and Boa-ON (264 w, 1.1 mmol 1) were added and stirred for further 18 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to preparative TLC.
Purified with (acetone:dichloromethane-5:95),
(33,4R)-4-methoxycarbonyl-3-t-butoxycarbonylamino-1-((S)-1-phenylethylgo-2-azetidinone (196μ, 2-step yield 6
4%).

'HNMR (CDCIs) 61.36 (S.

9H), 1.57 (d, J-7,0Hz.

3H), 3.58 (S, 3H), 3.79 (d, J-
2.0Hz, LH), 4.57(dd, J-1,1,2
, 0Hz, IH).

4.87 (q, J=7.0Hz, IH).

5.54 (d, J-1, 1Hz, LH).

7.27 (S, 5H).

(33,4R)-4-methoxycarbonyl-3-t-butoxycarbonylamino-1-((S)-1-phenylethylgo-2-azetidinone (190w, 0.55mm
o 1) was dissolved in THF (10 ml), and sodium borohydride (207 w, 5.5 mmo I) was added under water cooling.
A water (5 ml) solution was added thereto, and the reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (ether) to obtain <33.4R)-4-hydroxymethyl-3-1.
-butyloxycarbonylamino-1-((S)-1-
Phenylethyl go 2-azetidinone (90μ, yield 5
6%).

Colorless crystals (isopropyl ether) R (0,5? (ethyl acetate:hexane-9:1) [α)
” +22.1° (cl, 27.CHClm).

'HNMR (CDCIs) δ1.42 (S.

98), 1.63 (d, J-7,0Hz.

3H), 3.2・-3,8(m, 4H), 4.28(d
d, J-5,1,1,5Hz, IH).

4.87 (Q, J=7.0Hz, IH).

5.1-5.4 (brs, IH), 7.34 (S, 5
H).

TR(KBr)3360.2995.1?25°171
0.1540,1270゜1255.11?0,1155cs-'Massm/z
(Relative intensity): 321 (MH'''.

0.1) 265 (0,7), 247
(4,6).

173 (11,6), 117 (48,3)
.

105 (41,7), 73 (30,9).

57 (100).

Reference Example 6 (33,4R)-4-hydroxymethyl-3-t-butoxycarbonylamino-1-((S)-1-phenylethylgo-2-azetidinone (9,0*, 0.028mm
p-) toluenesulfonyl chloride (27 μm) in 1 ml of pyridine solution.

0.14 mmol) was added under water cooling, stirred at the same temperature for 1 hour, and stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, and diluted with saturated aqueous sulfuric acid, saturated aqueous sodium bicarbonate, and saturated brine. Washed sequentially. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (ether) to obtain (33
,4R)-4-(4-toluenesulfonyloxymethyl)-3-t-butoxycarbonylamino-1-((S)
-1-phenylethyl]-2-azetidinone (13■,
A yield of 98% was obtained.

Rf O,52 (ether) (α)"-35,9'" (C1,25,CHCl
,).

'H-NMR (COCl) 61.38 (S.

9H), 1.59 (cl, J-7,5Hz.

3H), 2.44 (S, 3H), 3.4-3.6 (m
, IH), 3.8-4.2 (m, 2H).

4.27 (dd, J-6,6,2,2Hz.

IH), 4.89 (q, J=7.5Hz.

IH), 4.9-5.2 (br s',
IH).

7.30 (S, 5)1), 7.31 (
d, J-8,8H32H), 7.71 (d
, J-8, 8Hz, 2H).

TR(KBr)3410. 2995, l 760°17!5. 1600. 1510°1370, 1180csi-' Masim/z (relative strength): 475 (MH'
.

0.1) 419 (1,6), 327
(6,8).

271 (29,2), 227 (34,1)
.

172 (19,7), 146 (48,7>
.

105 (100).

Reference example 7 (33,41)-4-(4-)luenesulfonino 1-
((S)-1-phenylethyl)-2-azetidinone (
80wK, 0.17mmo 1) acetone (3ml)
Add sodium iodide (254N, 1.7mm) to the solution.
o I) was added and stirred at 70°C for 5 hours. After cooling to room temperature, 1. Dilute with ethyl acetate and saturated thiosulfate)
It was washed successively with an aqueous IJum solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution.

After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified by preparative TLC (ether 8 hexane-4=1) to obtain (3S).

4R)-4-iodomethyl-3-t-butoxycarbonylamino-1-((S)-1-phenylethyl-2-
Fuzetidinone (70 μ, yield 96%) was obtained.

Rf O, 43 (ether: hexane-4+ 1)
.

Cα)” +7.9’ (C1,24,CHCl,)
.

'H-NMR (CDCIg) 61.44 (S.

9H), 1.72 (d, J=7.0Hz.

3H), 3.8-4.4 (m, 3H),
4.26 (dd, J-6,3,1,3Hz, I
H).

4.91 (Q, J=7.0Hz, LH).

4.8-5.1 (br s, ] H), 7
．． 36 (S, 5H).

IR(neat)3340. 2995. 1?50°1710, 1510. 1370°1160cm-' Massm/z (relative intensity): t3i (MH-.

0.1), 375 (2,8), 357 (
6,1).

156 (58, 2), 105 (100).

Reference Example 8 (:3S,4R)-4-iodomethyl-3-t-butoxycarbonylamino-f-((s)-1-phenylethyl-2-azetidinone (2(Ig.

0.047 mmol) was dissolved in hexamethylphosphoric triamide (0.5 ml), sodium cyanoborohydride (15N, 0.24 mmol) was added, and 90
The 8 reaction mixture was stirred at ℃ for 4 hours, cooled to room temperature, diluted with ether, and washed 3 times with water.

After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (ether) to obtain (3S,4S)-4methyl-3-t-butoxycarbonyl. Amino-1-((S)-1-phenylethyl-2-azetidinone (12w, yield 81%) was obtained.

Colorless oil.

R(0,63(ether) [α)” -26,8° (C1,16,CHCl5
).

'H-NMR (CDCIs) δ 1.30 (
d.

J=6.2H33H), 1.42 (S.

9H), 1.64 (d, J-1,0Hz.

3H), 3.34 (dd, J-6,2,1
, 8Hz, IH), 4.18 (dd,
J=6.9゜1.8H2, IH), 4.91 (
q, J -7.0Hz, IH), 4.8-
5.1 (brs.

IH), 7.33 (S, 5H).

IR(CHCl3)3455. 2985. 2945
゜1745, 1715. 1500. 1370°1
160cm- Mass m/z (relative intensity): 305 (MH
”0.1), 249 (0,6), 231
(1,1).

157 (3,8), '14? (3,9
), 132(11,7), 105
(30,9>, 57 Reference Example 9 (3S,43)-4-methyl-3-t-butoxycarbonylamino-1-((S)-1-7dynylethyl)-2
-T of azetidinone (3,6■, 0.012mmo+)
HF-2-methyl-2-propertool (10:1.
Sodium (0.3 ml) solution was cooled to -78°C.
5.4 g, 0.23 mrnol)-ammonia (1 ml) was added and stirred at the same temperature for 1 hour. Powdered ammonium chloride was added, and when the blue color of the reaction solution disappeared, dichloromethane was added and the reaction solution was brought to room temperature to vaporize ammonia. Water was added and the dichloromethane layer was separated.

The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (ether), and (
33,43)-4-Methyl-3-t-butyloxycarbonylamino-2-azetidinone (1,4■, yield 59
%) was obtained.

Specific optical rotation [α)”-67,1° (C0,1
4゜M e OH) and device data described in the literature (
(α), -68,4° (C2,8,MeOH)) (0
, M. Floyd et al., J. Org. Chem., 47
．． 5160 (1982)).

Comparative example 1 ψ ψ (33,43) -4-(t-butoxycarbonyl)-
3-N,N-dibenzylamino-1-((R)-1-phenylethyl)-2-azetidinone (22sir,
0.047 mmo J) was dissolved in ethanol (0.5 ml), IM-sodium hydroxide <0.35 ml) was added, and the mixture was stirred at 70°C for 1 hour.

After cooling to room temperature, IM-hydrochloric acid was added under water cooling to adjust the pH to about 3, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in THF (
1 ml). An ether solution of diazomethane was added under ice cooling, and the mixture was heated to room temperature and stirred for 2 hours. After distilling off the ether, the resulting residue was purified by preparative TLC (ethyl acetate; hexane-1:3) to obtain (33,4R)- and (3
R,4S)-4-methoxycarbonyl-3-N,N-dibenzylamino-1-((R)-1-phenylethyl]-2-azetidinone mixture (16■, yield 80%)
I got it. The production ratio of the (3S,4R) body and the (3R,43) body is 'H-Comparative Example 2 of the mixture <33.43)-4-(t-butoxycarbonyl)-3
-N,N-dibenzylamino-1-((R)-1-phenylethyl]-2-azetidinone (33 mg, 0.0
70 mmo 1) under the conditions of Bose et al. (AJ, Bosa
(1,5-diazabicyclo(4,3,0)-nona-
When treated with 5-ene/benzene under heating under reflux for 24 hours, a starting material of 28* was recovered (recovery rate: 85%), which had an H-NMR (90 MHz) of 3.4-).
The abundance ratio of lance isomers was 10% or less.

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼-(I) [In the formula, R^1 represents an amino group or a protected amino group, and R^2 represents a hydrogen atom or a protecting group for a carboxyl group. represents. The configurations of the 3rd and 4th positions are 3S^*, 4S^*), (3
S, 4S) or (3R, 4R). R
^3 represents a hydrogen atom or a protecting group for an amino group. ) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ - (II) [In the formula, R^1 and R^3 represents the same meaning as above. R^4 represents a hydrogen atom or a protecting group for a carboxyl group. The configurations at the 3rd and 4th positions are (3R^*, 4S^*) and (3R, 4), respectively, corresponding to the order of notation of the configuration in formula (I).
S) or (3S,4R). ] A method for producing a 3,4-trans-β-lactam derivative.