JPS6051171A - Production of beta-lactam compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is N-protecting group or substituent group; R<2> is H or OH-protecting group; R<3> is H, alkyl, aryl, aromatic heterocyclic group, halogen, acyl, substituted silyl, substituted hydroxy, substituted hydroxycarbonyl, substituted thio, substituted sulfinyl, substituted sulfonyl, cyano or nitro; A is -CidenticalC- or group of formula II). EXAMPLE:( 3S,4R )-1-[4-Methoxybenzyl]-4-phenylthioethynyl-3-[( 1R )-1-hydoxyethyl]-2-azetidinone. USE:Synthetic intermediate of a thienamycin compound (antibiotic substance). PREPARATION:The compound of formula I is produced by treating the compound of formula III (X is halogen) or the compound of formula IV with a base such as NaOH, KH, t-butyl lithium, etc. in a solvent such as benzene, toluene, etc. at -50-100 deg.C for 1min-24hr.

Description

[Detailed description of the invention] The present invention is based on the general formula The present invention relates to a compound having the following properties and a method for producing the same.

R1 in general formula (1) K is a nitrogen atom protecting group or substituent [aralkyl group (benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2.4.6-) dimethoxybenzyl, 2,
4.5-trimethoxybenzyl, 3,4.5-trimethoxybenzyl, 4-hydroxy-3I5-dimethylbenzyl, 3.5-tert-ph“tyl-4-hydroxybenzyl or 3.5-di-tert- Butyl roux 4~
methoxyben') kg), -OR" group in formula 1,
R4 is an alkyl group (methyl, ethyl, propyl, inpropyl, buty-A/or tart-butyl group), an aralkyl group (benzyl, 4-methoxybenzyl or 4-nitrohensyl group), or an aryl group (phenyl, ru, triethyl group). silyl, triisoglopylsilyl, tert-
butyldimethylsilyl or tert-butyldiphenylsilyl group), aryl group (phenyl, 4-methquinphenyl, 2,4-cymethquinphenyl, 3,4-dimethquinphenyl or 2.4.6-)rimethoxyphenyl group ), -CHR5CO2R6 group 1 where R5 is a hydrogen atom, hydroxyl group, halogen atom (chlorine, bromine or iodine atom), -8R group (wherein R is a hydrogen atom, methyl, ethyl, propyl, inpropyl, butyl, isobutyl,
tert-7'thyl, benzyl, phenyl, vinyl, allyl, metquinmethyl, methylthiomethyl, tetrahydropyranyl, trimethylsilyl or tert-butyldimethylsilyl group. )-(J R7 group (wherein, R
has the same meaning as above. ), -8eR group (wherein R indicates the same moiety as described above), aryl group (
phenyl, 4-methquinphenyl or 4-chlorophenyl group) or an alkyl group (methyl, ethyl, propyl, impropyl or butyl group), and R6 is a hydrogen atom, methyl, ethyl, propyl, tert-7'thyl , benzyl, diphenylmethyl, 4-nitrobenzyl,
2-nitrobenzyl, allyl, 2-chlorallyl, 2-
Methylallyl, 2,2.2-trichloroethyl, 2.
2.2-)ribromoethyl or 2-()limethylsilyl)ethyl group), R is methyl, ethyl, propyl, impropyl, butyl, phenyl, 4-methoxyphenyl, methoxy, ethquin, propoxy, impropoxy, butyloxy, phenoxy, 4-methoxyphenoxy, dimethylamino, diethylamino, dipropylamino, diisoglotide, and R and R are the same or different hydrogen atoms, methyl, ethyl, or R and R11 together are Vc. a ring-forming group -(CH2)4- or -
(CH)- group. ). R2 is.

5 Protecting group for hydrogen atom or hydroxyl group [alkyl group (methyl,
ethyl, propyl or isopropyl group), aralkyl group (benzyl, 4-nitrobenzyl, 2-nitrobenzyl or 4-methocinobenzyl group), acyl group (formyl, acetyl, chloroacetyl, trifluoroacetyl, telluryl, triethylsilyl, triethylsilyl,
tert-phthyldimethylsilyl, tert-butyldiphenylsilyl or U triethylsilyl group), CO
2R group (wherein R is methyl, ethyl, butquine, te
rt-butquin, 2,2.2-trichloroethyl, 2.
2.2-Tribromoethyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, allyl, 2-chlorallyl, 2-methylallyl, diphenylmethyl or 2-()
rimethersilyl)ethyl group), ether group (ethoxyethyl, ethoxymethyl, 1-ethoxyethyl, benzyloxymethyl, tetrahydropyranyl or 2-()rimethersilyl)ethoxymethyl group) or thioether group (methylthiomethylethylthiomethyl, propylthio methyl-benzylthiomethyl, 2-nitrobenzylthiomethyl, or 4-nitrobenzylthiomethyl group)].

R5 is a hydrogen atom, an alkyl group (methyl, ethylglobil, isopropyl, butyl or tert-butyl group), an aryl group (phenyl, emethoxyphenyl, 4
-nitrophenyl group),
Aromatic heterocyclic group (chenyl, furyl, triazinyl, or pyridyl group λ halogen atom (chlorine or bromine atom)
, -COR15 group (wherein R is a hydrogen atom, methyl, ethyl, propyl, isopropyl, hydroxymethyl, methoxymethyl, tetrahydropyranyloxymethyl, benzyloxymethyl, benzyl, tetralyl group (trimethylsilyl, triethylsilyl, trimethylsilyl) isopropylsilyl,
tert-butyldimethylsilyl or tert-butyldimethylsilyl group X-substituted oxy group -OR (in the formula, R is
Methyl, ethyl, propyl, butyl, tert-butyl, phenyl, benzyl, 4-methoxyphenyl ik is 4
-methquinbenzyl group), substituted oxycarbonyl group -C02R (wherein R is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2.2.
2-Trichloroethyl, 2゜2,2-) v Fromethyl, benzyl, 2-nitrobenzyl 1 ft B
4-nitrobenzyl group), substituted thio-8R (wherein R is methyl, ethyl, propyl, isopropyl,
Benzyl, phenyl, 4-methoxyphenyl, 2-nitrophe (in the formula, R has the same meaning as above), substituted sulfonyl group -8o2R (R has the same meaning as above), 7-ano There are no particular limitations on the group or nide, and it represents a single type of isomer or a mixture of isomers.

The compound having the general formula (1) obtained by the present invention may have various isomers, or may be one of them or a mixture thereof.

In recent years, chenamycin, an antibiotic that exhibits excellent antibacterial activity against a wide range of pathogenic bacteria, including Durham-positive bacteria and Gram-negative bacteria, has been discovered, and a method for its total synthesis has also been reported (Japanese Patent Application Laid-Open No. 1983-1972). No. 65892). As a result of intensive research into the synthesis of β-lactam compounds as part of the research and development of pharmaceuticals with antibacterial activity, the present inventors discovered that a novel compound represented by the general formula (1) was discovered as an intermediate in the synthesis of chenamycin compounds. Is it a compound that is useful for the body?
This discovery led to the complete completion of the present invention.

The novel compound (1) of the present invention is a compound having the general formula (wherein R1, R2, a5 and A are as defined above, Q't=k, or is a chlorine, bromine or iodine atom) or General formula (where R, R
and A have the same meanings as described above. ) with a base (sodium hydride, potassium hydride, sodium amide, potassium amide, 1,5-diazabicyclo (: 4.3.0 Enon-5-ene, 1,5-diazabicyclo[5,4,0]]undec-5-enebutyllithium, tert-butyllithium, lithium diisogropyramide or lithium hexamethyldi Silazide) at -50°C to -100°C for 1 minute to 24 hours, and after the reaction is completed, the mixture is separated from the reaction mixture according to a conventional method.

All examples of compound helmets obtained by the present invention are shown in Table 1.

Table 1 1-CH, @j-OCH3H, 5ph 2〃〃〃H 3〃〃-[302Ph 4'/I IF -0Ph 5〃〃N02 (i〃I　-CN 7 // tl -Co2Bu 8 // tt -5t (ca3).

10 # /F -f3φ and t ll p tt -8CH2Ph 12 tt tt -0CH3 13-cH2()OcH,, -co2ca min No2 →
ph14 // -(11(CH3)2Bu' -8P
h16 tl tt H IT〃〃-So,, Ph 18 # tl -8OPh 19〃〃-Co2cH2Ph 1? @OCH3〃5Ph 20 1 // R 241tt -8i(CH3)3 22 〃II -COCH 3 231# -0Buf' 24 0CR5H-CM.

25 II H-CN 26 // H-No2 27 II -co2cHeo2-sphza tt
-5t(aH3)2Bu' -5ph30 // I
H 31-0Bu' n-5o2ph 32-CH,, Co2ButHH 'aha /J w -5ph 34 tt # CN 35 tt tt -at (aH3) 33B-CH2C
o2ButH-Co2CH2Ph39 # tt -8
1 (CN5).

40〃〃 Seven (CH3) 2 pieces 41 tt p -0CH3 42#-COCH<EkaNo2-8Pb2 43 # -Ell(CH3)2Bu' -APh45
' II # -Co,, Bu'46 1 1 -C
N 47 tt tt -61 (C2H5) 3 Compound (1) obtained by the present invention is an important intermediate leading to the carbapenem derivative. For example, in the general formula (where R is a hydrogen atom, R is 4-benzyloxycarbonyl, R is thiophenyl, and A is a -CmiC- group, the water utilization reaction of acetylene in compound (1), After acylation with MHI alkoxyoxalyl chloride, the fucarbapenem derivative (4) is obtained by heating with triethyl phosphite.

The compounds having the general formulas and the general formulas used in the present invention can be produced by the method shown below.

That is, butyric acid derivative odor (in the formula, R and X have the same meanings as described above) CN5CHCHC! 02H or or or carboxylic acid of (6) or their acid chloride or mixed acid anhydride and amine rust conductor (1) (in the formula, R
, R and A have the same meanings as described above. ), (2) is obtained from (5), and (3) is obtained from (6).

Compound (3) can also be obtained by the method shown below.

(8) That is, ebok-7butyric acid derivative (8) (wherein R1 has the same meaning as described above) K propargyl halide (
9) (in the formula, R and Xt! have the same meanings as those described above? are shown) to obtain the compound (3).

Examples and reference examples are given below to specifically illustrate the present invention.

Example 1 (3 days, 4R)-1-(4-methoxybenzylcou 4-
Phenylthioethynyl-3-[(1R)-1-hydroxyethyl]-2-acetedinone (1) Amide compound obtained in Reference Example 3 (6) 393111p (0,876zm
ot) 0.0 mg of lithium hexamethyldisilazane was dissolved in s mg of dry tetrahydrofuran and stirred under cooling with water.
39 mJ3 (0,175m+notf of hexamethyldisilazane and 15g6butyllithium L1BM (0
, 175 mmol) was added dropwise. After stirring for 5 minutes under water cooling, the remaining half of lithium hexamethyldisilazane was added dropwise while stirring at 22 to 25C. After stirring at room temperature for 30 minutes, dilute hydrochloric acid was added, followed by extraction with 100% ethyl acetate, water, 5% sodium chloride solution,
Wash sequentially with saturated saline. After drying over anhydrous magnesium sulfate and distilling off ethyl acetate, the obtained oil was subjected to Rover column chromatography and eluted with ethyl acetate-cyclohexane (1at) to obtain the desired azetidinone compound tl+94 (29 , 2ch) were obtained.

NMR spectrum (CDCt,) δppm'128 (3
H, +i, J = 6.5Hz).

3.35 (IH, ad, J-3,4,5Hz) 3.75
(3H, s) 4.10, 4.67 (2H, AB'-q, J-15Hz
) 4.25 (IH, m) 4.33 (?H, d, J-3Hz) s, 5o (za, a, J-9Hz) 7-19 (2H, d, J-9Hz) Otsu 28 (5H ,s) Example 2 (38,4R)- and (as,4s)-t-(p-methoxybenzyl)-s-(jlu) kudzu bitroxyethyl)
-Mixture of 4-trimethylsilylethynyl-2-azetidinone +21 +31 Epoxide compound obtained in Reference Example 5 +2i o, I
Butyllithium D, 8 mff1 (
1.3 mmol) k was added and stirred at the same temperature for 1 hour.

Water and ethyl acetate were added to the reaction mixture, washed with aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent was completely evaporated under reduced pressure, the residual oil was subjected to rapid chromatography on silica gel and eluted with cyclohexane-ethyl acetate (7-3). As a result, 0.03 f of a cis-trans mixture of ring-closed azetidinone compound (3) was obtained.

1.30~L60 (3H+mlCHs)32
5-3.55 (IH, m, 3-H) 3.76 (3H,,
s, OMe) 4.15-4γ5 (I H, m, 4-H, Mei
-) 6.84 (2H, cl, J-9Hz) Otsu 42 (2H, ci, J-1]Hz) IR spectrum L1qcrIV1: 3480.2200, 1750, 1530MS spectrum m/: 317 (M+), 232 Reference Example 1 N-globalgyl-4-methoxybenzylamine (4) yOMe p-methoxybenzylamine 2.741 (20mmot
) was dissolved in 50 m of tetrahydrofuran, 2.029 m of triethylamine (20 mmot) was added, and while stirring at room temperature, 2.38 m of glovargylbromide was dissolved.
(20mmoL) of THFI01r17? Add the entire solution dropwise. After standing overnight at room temperature, the triethylamine hydrochloride i7 produced was removed and tetrahydrofuran was distilled off. Add and dissolve 300 i of ethyl acetate to the residue, wash with 50 M water and 50 ml of saturated brine, and dry over anhydrous magnesium sulfate. After all ethyl acetate was distilled off, the resulting oil was subjected to Roper column chromatography and eluted with ethyl acetate-cyclohexane (1:1).
106 F (30.24%) was obtained.

NMR spectrum (CDCl2) δppm '1.52
(IH, a) 2.25 (IH, t, J-10Hz) 7.79 (2H, d, J-2,0Hz) 3γ3 (3Hz
s) 3.80 (2H, s) 6.6-7.35 (4H, m) MS spectrum / : 175 (M+) Reference example 2 N-(3-phenylthioglopargyl)-4-methoxybenzylamine (5) Reference example, the amine obtained in (411,75? (10 m
mot) k Dissolved in 25% of tetrahydrofuran and 78%
Cooled to 10°C and stirred butyllithium (6.25 mg of 15 flfffi in thihexane) in tetrahydrocra2.
Add all of the 5M bath solution dropwise. Furthermore, a 10M solution of diphenyl disulfide 2.18 F (10 mmot) in tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at room temperature for 30 minutes. After the reaction is complete, dissolve in ethyl acetate 300~ and water 100~
- three times, then washed with saturated brine, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off. The obtained oil was subjected to Rover column chromatography and eluted with ethyl acetate-cyclohexane (1:1) solution to obtain 2.5Of (88.2%) of the desired amine (5).

NMR spectrum/l/(CDCl2)δppm '1
60 (IH, s) 3.1i3 (2H, s) 3.97 (3H, s) 3.84 (2H, s) 6, γ~Otsu 5 (9H, m) Reference example 3 (28, 3R) N -(3-phenylthioglobargyl)
-N-(4-Methoquinbenzyl)-2-bromo-3-hydroquine butyric acid amide (6) M6 Amine f51185 obtained in Reference Example 2? (6,5
119 f (28,3R)-2-bromo-3-hydroxybutyric acid (6,5 mmot) was dissolved in 20 m of dry methylene chloride, and 1.35 f (6,5 mmot) of synchlohexylcarbodiimide was dried under water cooling. Add methylene chloride (10M) solution dropwise.

After stirring at room temperature for 2 hours, methylene chloride was distilled off, 20M1 of benzene was added, and the mixture was left overnight. After removing the precipitated dicyclohexyl urea from P, the benzene was distilled off and 10% of ethyl acetate was added.
0d and washed sequentially with 5% sodium chloride solution and saturated saline. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off, and the residue was subjected to Roper column chromatography and eluted with ethyl acetate-cyclohexane (1:2) to yield the desired amide f6) 2.53 f (86,4%). )
was gotten.

NMR spectrum (CDCt,) δppm: 1°2
0 (3H, d, J-6, 5Hz) 3.76 (3H, s) 3.9-5.0 (6H, m) 6, T-7.4 (9H, m) MS spectrum 1/: 447 (M+) Reference Example 4 (2R,3R)-N-P-methoxyphenyl-N-propargyl-2,3-epoxybutyrylamide 8) Epoxide compound (715? (24,1 mmoL)
), glopargyl bromide B, 6'? (72,3
mmot) and human ethylbenzylammonium iodide 0.77? To a solution of (2,41 imol) in methylene chloride (80% red) was added 50% sodium hydroxide solution at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After the solvent was completely evaporated under reduced pressure, the residue was subjected to rapid chromatography using silica gel and eluted with cyclohexane-ethyl acetate (65-35). As a result, the desired propargylamide compound (8) was found as an oil with a weight of 5.7? Obtained.

NMR spectrum (cDct3) δppm'1.35
(3H+d, J = 5 Hz, CHs) 117
(I H, da, J-2,5Hz, 15Hz
, -C=CH) 2.95 (IH, q, d, J-5Hz, 5Hz) 3.2
0 (1H, d,, r-5Hz) 3.83 (3H, s, OMe) 4.28, 4.58 (2H, AB-q, J=16.5H
z.

2.5Hz, CH2) 6.65-7.30 (4H, m, phenyl)I
R spectrum shim 1qcrn-1=2120.167
0 M S he I) /l/m/: 245 (M+)
Reference Example 5 (2R,3R)-N-1)-Methoxyphenyl-N-t'J methylsilylpoxy-2,3-epoxybutyrylamide (2) (81(21) Glopargylamide compound (815,7 (23,2
Butyllithium 22M (34,0 mmol) was added to a solution of dry tetrahydrofuran (70 mA) under cooling at -78°C.
8 mmot) and then 10.8 mmot of trimethylsilyl chloride. I P (92.8 mmot) was added. Next, the temperature of the reaction solution was raised to 0° C., and then stirred for one hour while cooling with water. After evaporation of the solvent under reduced pressure, the residue was subjected to rapid chromatography on silica gel, eluting with cyclohexane-ethyl acetate (7-3). As a result, the desired trimethylsilyl compound (212,33
t was obtained.

NMR spectrum (CDCl2) δppm '0.12
(9H, s, Mg2Si) 1.35 (3Hrd, J = -5Hz e CH
5) 2.97 (IH, q, d, J-5Hz, 5Hz)
3.20 (IH, d, J-5Hz) 3.80 (3H, s, OMe) 4-47 (2H, s, CH2) 6.80-1.40 (4H, m, phenyl) IR spectrum A- 1/L1qn': ax 2200.1680.1510 MS spectrum mml 317 (M+), 232 Reference example 6 (38,4R)-1-(p-methoxybenzyl)-3-
[(IR)-1-(p-nitropenzylox7carponyloxy)ethyl]-4-phenylthioethynyl-2-
Azetidinone CI) Ig) Azetidinone derivative fl) 128 obtained according to Example 1
ml (0,35 mmot) f dry methyl chloride 5
p-Nitrobenzylox7carponyl chloride 225~(1,05 mmol) was dissolved in M and stirred while cooling with water.
Dry methylene chloride 2M solution of t) and dimethylaminoviridi>127 ml (105 mmol, 30f) of dry methylene chloride 2M solution are sequentially added dropwise. 3 at room temperature
After stirring for an hour, methylene chloride was distilled off and cyclohexane
After dissolving in 10ml of ethyl acetate (2:1) and removing insoluble matter, it was subjected to Rover column chromatography and eluted with cyclohexane-ethyl acetate (1 yam) to obtain the desired azetidinone compound 19+ 96~(50.4%). ) i'i
Obtained.

NMR spectrum (cvct,)δppm'1.3
(3H,eL,J-6,5'Hz)3.35(1u
, ad, J-3,6,5Hz) 3.75 (3H, s) 4.1.4.7 (AB-q, 16Hz) 4.35 (lH
,d,,r-3H2) 3.9~4.4(1H,m) 6.8(2H,(1,J-7,5Hz)TO~7.5(
7H, m) MS spectrum ml: 54 s (M+) Reference example T (3s, 4R)-1-Cp-methoxybenzyl) -
3-[(IR)-1-(,p-nitrobenzyloxycarbonyloxy)ethyl)-4-phenylthiocarbonylmethyl-2-azetidinone derivative (+oJ Azetidinone compound f9+ obtained in Reference Example 6) 96 In
9 (0,H6 mmol) was dissolved in 2M dry methylene chloride, and while stirring under water cooling, 0.1°f (0.88 mmol, 5 eq) tl of trifluoroacetic acid was added thereto, and the mixture was stirred and reacted under water cooling for 5 hours. 5 of the reaction solution
Adjust the pH to 7 with % hydrogenated sodium chloride water, and add ethyl acetate too.
miv and washed sequentially with water and saturated saline. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off and subjected to Rover column chromatography.
Elution with ethyl acetate (2:1) yielded the desired azetidinone compound (1130m9 (30.2%)).

NMR spectrum (CDCl2) δppm '1.3
5(3H,a,J-6,5Hz)2.8(2H,d,J
-2,0Hz) 3.15 (IH, dd, J-2,0Hz, 'J-7
．． 0Hz) 3.75 (3H, s) 4.1, 4.5 (2H, As-q, 14.5Hz) 3
B-4,1(IH,m) 5.1(2)1. S) 6.75 (2a, a, J-Otsu 5Hz) 7.1 (jH, d, Jl-Otsu 51 (z) Otsu 3 (5H, s
) 7.38 (2H, d, J-9,5Hz) 8.1 (2H
, d, J-9,5Hz) MS spectrum m/: 564 (M+) Patent applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashi De Shoji Page 1 continued 0 Inventor: Hide Masuko - Tokyo Parts Co., Ltd. Uchikawa 1-2 Seki Sankyo Co., Ltd. Chemical research procedure amendment form (
Voluntary) November 13, 1980 Mr. Manabu Shiga, Commissioner of the Patent Office ■, Indication of the case 1983 Patent Application No. 1583γ6 2, Name of the invention Process for producing β-lactam compounds 3, Person making the amendment , Patent Applicant Address: 3-1 Nihonbashi Honmachi, Chuo-ku, Tokyo 103 Name 6 (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4, Agent Residence 1-2 Hiromachi, Honbashiwa-ku, Tokyo 140 No. 58 Sankyo Co., Ltd. 6 Subject of amendment Detailed explanation of the invention in the specification Column 1,
“Njil group)” and f--OR on page 6, line 1T of the specification
Add the following token between 'base].

"Acyl group (acetyl, benzoyl, 4-nitrobenzoyl, methoxyoxalyl, t-butoxyoxalyl,
N,N-dimethylaminooxalyl, N,N-diethylaminocarbonyl, benzyloxycarbonyl, methoxycarbonyl or t-butoxycarbonyl),” 2. “is)” and “ma” on page 6, line 1T of the specification. Add the following words in between.

"Alkenyl group (allyl, 1-propargyl is 2-butenyl)" 3 r-(3s l 4R) J on page 6, 1T of the specification
Correct it to r (3s, 48) J.

4. Add the following phrase between page 6, line 1T and line 14 of the specification.

"Example 3 (2R,3R) -N-allyl-N-(3-phenylpropargyl) -'2,3-epoxybutyramide 56
1 g (0.22 mmole) f A 0.5 M solution of lithium hexamethyldisilazide [hexamethyldisilazane 403 II? (2,50 mmole
) in tetrahydrone run 31- and 155 ml (2,48 mm
ole) at 0℃] is 0.50
Add ml (0.25 mmole). After 10 minutes, add 1 drop of acetic acid and then dilute the reaction with ethyl acetate. After washing with water, the organic layer is dried, the bath medium is distilled off, and the resulting residue is separated and purified using Rover Column A. Chloroho kl
Elute with a mixed solvent of h-methanol (30:3) to obtain cis-azetidinone ((3s, JR)-isomer) in 9 tries (
yield 16%) and trans-azetidinone ((38,48
)-isomer) 17Q (yield 3o%) were obtained as oils.

trans-azetidinone [(38,4S)-isomer];
IR spectrum νCHCt5 cm-': 359
0,3420.

2230, 1γ2O NMR spectrum (CDCtR) δppm 71.34
(3H.

a, J = 6.5 t(z), 2.15
(I H, br,) , 3.32 (I I(, dd
, J-5, 2,5Hz), 3.66 (IH
.

dd, J = 16, 6 Hz), 3.9
~4.4 (2H.

m ), 4.4'2 (I H, d, J =
2.5 Hz), 5.0-6.2 (3[(, m
), 7.32 (5[(,m)cis-azetidinone [(38,4R)-isomer]; IR spectrum ν
CHCl1(7)-” 73580, 3440.

2230, 175O NMR spectrum (cDc15) δppm: 1.4
2 (3H.

(1, J -6Hz), 2.4 (I H, br
, ) , 3.32 (I H, dd , J = 9
, 5 Hz), 3.61 (1H1ad, J
= 16, 6 H2), 3.85-4.5 (2
H.

m), 4.49 (I Fl, d, J
= 5 Hz), 4.9~62 (3H, m)
, 7.32 (5H,8-1ike) Example 4 (38,48) -1-allyl-3-[:(R)-1-
Hydrogen (2R,3R) -N-allyl-N-[3-(phenylthio)propargyl]-2,3-epoxybutyramide 460ml (1,60mmote) Totally dissolved in tetrahydrofuran 5rnlK and stirred at 0°C. , 0.5 M solution of lithium hexamethyldisilazide [hexamethyldisilazane 40319 (2,50 mmole
) in 3.11 nl of tetrahydrofuran, 1.
6M butyllithium hexane solution 1.55 me (2
, 4Brrnote) at 0°C]
3.52 mj! (1,75 mmole) is added. After stirring for 1 minute, 200 mg of acetic acid is added and the reaction mixture is diluted with ethyl acetate. After washing with water, the organic layer is dried and the solvent is completely distilled off. The resulting residue was subjected to preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (
1:1)] to obtain 125μ of azetidinone (yield: 2
γ%) was obtained as an oil. This is a mixture of cis and trans isomers, but it was further separated using a Rover column [chloroform-methanol (30:1
)), cis-azetidinone [: (3El, JR)-isomer] 31 (yield T) and trans-azetidinone (
: (38,48)-isomer 387119 (yield 1B
%) was obtained as a pure product.

trans-azetidinone ((38,4Sl)-isomer)
;IR spectrum k v "HCt! cm-' : 3
H.O., 2170.

143 Specific rotation [α] +29° (C-0,81, CHCL3
) NMR spectrum (CDCz δI) pm: 1
．． 30 (3H.

d, J = 6 Hz), 2.88 (I
H, br, ), 3.29 (IH, dd, J=4.3
Hz), 3.64(1)1゜dd, J=16.6Hz)
, 3.85-4.4 (2H.

m), 4.46 (I H, d, J = 8
Hz), 5.0~6.2 (3[(,m)
, 7.32 (5H, 8-1ike) cis-azetidinone [(38,4R)-isomer]; IR spectrum k v
"Ct'ctn-': 3220, 2160
.

1γ45 NMRX pectk (cDcts) δppm: 1.
41 (3H.

d, J = 6 Hz), 2.25 (I
H, br, ), 3.32 (I H, dd, J
-9,5Hz), 3.61 (IH.

dd, J=16.6Hz), 3.85~4.5 (2H
.

m), 4.52 (I H, d, J = 5
Hz), 4.9-6.2 (3H, m),
7.35 (S H, m) J5, Specification No. 35
Add all of the following words between the 14th and 15th lines of the page.

“Reference Example 8 Allylamine 49T II9 (8,7mmote)
f dimethylformamide 5- and tetrahydrofuran 5
- 340 mg of 3-phenylbropargyl bromide (1,74mnote) at 0°C.
't-Add and stir for 15 minutes. After the reaction is completed, diluted 1 water is added and extracted with benzene. The solvent was completely distilled off, and the residue was purified by silica gel dispersion chromatography [developing solvent: hexane-ethyl acetate (6:1)] to obtain 2 mg (yield: 58 mm) of the desired product as an oil.

NMR spectrum (cvct5) δppm: 1.4
1 (I H, s), 3.35 (2H, dt,
J = 6, I Hz), 3.61 (2H
, s), 4.95-5.4 (2H, m),
5.93 (I H, ddt, J-17, 10,
6Hz), 7.3 (5H+m) Reference Example 9 Allyl(3-phenylpropargyl)amine 150 Toxic 9 (0.88mmole), (2R,3R)
-2,3-epoxybutyric acid 132 ■(1,29mmo
le ), N,N'-dicyclohexylcarbodiimide 266 Rg (1,29+nmole )4-(dimethyl9 aminopyridine 6 m9 (0,05 mmole
) in methylene chloride 2- and stirred at room temperature for 1 hour.

After the reaction is complete, 100 ml of water is added and stirred for 30 minutes, and the insoluble matter is removed by filtration and the solvent is distilled off. The residue was purified by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (2:1)] to obtain the desired product (142m9).
(yield 63%) was obtained as an oil.

IR Suhe/t/l/v”””＆an-': 1
62ONMR spectrum (CDC15) δppm 71
．． 31 (3H.

d, J = 5 H2), 3.3 (I H,
m ) , 351 & 3.72 (I H, 1: 1
, d & d, J = 4 Hz).

4.2 (2H, m), 4.35 (I H, s
), 4.28 (1/2 H, d, J-1γ
Hz), 4.51 (1/2H, d, J =
17 Hz), 4.9~5.4 (2[(, m
), 5.4-6.2 (I H, m), 7.3
(5H, s) Reference Example 10 Amine allylamine 920 mg (16,1 mmote)
k dimethylformamide 5Tn1. 3-(phenylthio)propargyl bromide 733 mW (3,23 m
Add all mole) and stir for 1 hour and 15 minutes. After the reaction is complete, diluted sodium carbonate solution is added, extracted with ethyl acetate, and the organic layer is washed with water. The solvent was distilled off, and the resulting residue was purified using silica gel 15
Subjected to column chromatography using 1/f. Target compound 4 was eluted with hexane-ethyl acetate (4:1) mixed solvent.
rs*y (yield T2%) was obtained as an oil.

IR spectrum νCHCt5 cm-': 333
0,2180.

644 NMR spectrum (CDC43) δppm: 1.3
3 (IH.

s), 3.31 (2H, br, d, J-
5Hz).

3.60 (2H, s), 4.9~5.4 (2
H, m).

5.88 (I H, dat, J = 17, 9
, 5 Hz).

71-7.6 (5H, m) Reference Example 11 Lumidoallyl[3-(phenylthio)glopargyl]amine 4
70 m9 (2,32mmole), (2R,3R
) -2゜3-epoxybutyric acid 370 M9 (3,63
mmote ), N, N'-dicyclohexylcarbodiimide 75019 (3,63 mmote ), 4-
(dimethylamino)pyridine 20wag (0,16r
nrnole) in methylene chloride 5- and stirred at room temperature for 30 minutes. After the reaction is complete, 300 ng' of water is added, and after stirring for 30 minutes, insoluble matter (rif') is removed and the retention medium is distilled off.The residue is subjected to column chromatography using silica gel 1519.

The crude product 54Qw+gf obtained by bathing out with a mixed solvent of benzene-ethyl acetate (5:1) is then subjected to fiV using Lorber column B. Benzene-ethyl acetate (3:
1) Elute with a mixed solvent to obtain the target product 3s5try (yield 5
6) was obtained as an oil.

IRxHCl4 an-': 318
[1, 1662aX NMR spectrum (CDCl2) δppm: 1.2
6 (3H.

d, J = 5 Hz), 3.26 (I
H, m), 3.56 & 3.65 (I H, 1
: 1, ci & d, J = 4.5Hz)
.

4.15 (2H, br, d), 4.29 (1
/2 H, d, J co1γHz), 4.56
(1/2 H, d, J = Hz).

4.39 (I H, s), 4.9-6.2 (
3H, m).

7.31 (5H, m). ” that's all

Claims (1)

[Claims] +l) General formula [In the formula, R1 is a nitrogen atom protecting group or a substituent, R
2 is a hydrogen atom or hydroxyl group protection group, a ru group, a substituted oxy group, a substituted oxycarbonyl group, a substituted thio group, a substituted sulfinyl group, a substituted sulfo group (2) General formula [wherein R1 is a nitrogen atom protecting group or Substituent i, R
2 is a hydrogen atom or hydroxyl group protection fund\# group, [substituted oxy group, substituted oxycarponyl group, substituted thio group, substituted sulfinyl group, substituted sulfo general formula [wherein al is a nitrogen atom protecting group or substitution] The group, R
3 is a hydrogen atom, an alkyl group, an aryl group, a ') group,
rftFJJ Oxy group, substituted oxycarbonyl group, substituted thio group, substituted sulfinyl group, substituted general formula [wherein, Rf is a nitrogen atom protecting group or a substituent, R
2 is a protecting group for a hydrogen atom or a hydroxyl group, +M, a directly substituted oxy group, a substituted oxycarbonyl group, a substituted thio group, a substituted sulfinyl group, a substituted sulfonyl group.