JPS6045559A - Beta-lactam compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or protecting group or substituent group of NH; R<2> is H or OH-protecting group; R<3> is H, alkyl or aryl; R<4> and R<5> are H, alkyl, substituted alkyl, alkoxy, alkylthio, arylthio, etc.). EXAMPLE:[3S-[3alpha-( S* ),4beta]]-1-( 2,4-Dimethoxybenzyl )-3-(1-t-butyldimethylsilyloxyethyl)-4-(2,2-bisphenylthiovinyl)-2-azet idinone. USE:An intermediate of a carbapenem derivative having strong antibacterial activity, e.g. thienamycin, etc. PREPARATION:The compound of formula I can be prepared by treating the compound of formula III-IV (R<7> is alkyl or aryl; R<6> is R<7>, OR<7> or NH2; X is halogen) with a base, and reacting the product with the compound of formula II. The hydrolysis of the product gives the compound of formula V (R<8> is R<4> or R<5>; Y is O or S), from which the above antibacterial agent can be produced.

Description

Detailed Description of the Invention The present invention is based on the general formula [wherein R1 is a hydrogen atom or a protecting group or substituent for an amide NH group, R2 is a hydrogen atom or a hydroxyl group, and R3 is a hydrogen atom] , an alkyl group or an aryl group, R4 and R5 are the same or different hydrogen atoms,
Alkyl group, substituted alkyl group, alkoxy group, alkylthio group, arylthio group, heterocyclic thio group, aromatic heterocyclic thio group, sulfinyl group, sulfonyl group, alkoxycarbonyl group, alkylthiocarbonyl group/acyloxy group, acylthio group, amino group , amide group, halogen atom, carboxy group, cyano group or nitro group. ] and its production method, as well as a compound having the general formula [wherein R1, R2 and R5 are the same as those described above] which is an important intermediate for the synthesis of cal-gubenem visiting conductor by hydrolyzing compound (V). Meaning R8 has the same meaning as R4 or R5 mentioned above, Y
represents an oxygen or sulfur atom. ] This relates to a manufacturing method leading to a compound having the following.

A compound having the general formula (II) is a compound having the general formula (1)', and a compound (R')2 having the general formula (n) or (110) is treated with CHR'R5(II) or a base. In order to react later, the general formula (
A compound with M is obtained.

0R2R5 R1 in the general formula (1) and in the formula (1) is a hydrogen atom or a protecting group or substituent for amide NH, such as an aryl group [phenyl, 4-methoxyphenyl, 3,4-
dimethoxyphenyl or 2.4-dimethoxyphenyl group], aralkyl group [hennol, 4-methoxybenzyl, 3.4-dimethoxybenzyl, 2.4-somethoxypendyl group, etc.], R9 is a commonly used carboxyl group-protecting group shows. For example alkyl groups (such as methyl to ethyl, propyl or jet-glutyl groups).

Aralkyl groups (such as benzyl, diphenylmethyl, 4-nitrohe/sol, or 2-nitrobenzyl groups), alkenyl groups (such as allyl, 2-chlorallyl or 2-methylallyl groups), halogenated alkyl groups (2,2 ,2-
)! It has the same meaning as J dichlorotyl, 2,2.2-)ribromoethyl group, etc.) or 2-(trimethylsilyl)ethyl group, etc. ], -cH2co2R
9 groups [wherein R has the same meaning as described above]. ].

Ether group [methoxy, benzyloxy group or ter
t-butoxy group], silyl group [trimethylsilyl,
tert-butyldimethylsilyl or tert-butyldiphenylsilyl group] or a herron atom [chlorine or odorant atom]. General formula〇) and (goods)
In, R2 is a hydrogen atom or a hydroxyl group protecting group [alkyl group (methyl, ethyl, propyl or inpropyl group, etc.)].

Silyl group (trimethylsilyl, triethylsilyl t
ert-butyldimethylsilyl, tert-butylnophenylsilyl or triethylsilyl groups), acyl groups (such as formyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, butyryl or benzoyl groups).

Aralkyl group (benzyl, 4-nitrobenzyl, 2-nitrobenzyl or 4-methoxybenzyl group), alkoxyl group (benzyloxycarbonyl, 4-methoxybenzyl group),
-Brompenzyloxycarbinyl, 4-nitrobenzyloxycarbinyl, 2-nitrobenzyloxycarbinyl, R2,2-)! j dichlorothoxycarvinyl,
Allyloxycarbonyl, 2-chloroallyloxycarginyl, 2-methylallyloxycarbonyl, t-butoxycarbonyl, diphenylmethyloxycarbonyl,
2-()limethylsilyl)ethoxycarbonyl group, etc.)
or an ether group (tetrahydropyranyl, methoxymethyl, 1-ethoxyethyl or 2-(trimethylsilyl)ethoxymethyl group, etc.).R5 in the general formula (1) and
ethyl or propyl group] or an aryl group [such as phenyl, 4-methoxyphenyl or 4-methylphenyl group].

R4 and R5 in general formula, (to) and (trans)
are the same or different hydrogen atoms, alkyl groups [methyl, ethyl or propyl groups, etc.], #-substituted alkyl groups (-CH
2CH□A, -CH(CH,)CH2A, CH
20COCH2A t or CH20COC) 12CH2
A (in the formula, R10 is a hydrogen atom or a general protecting group for an amino group (acyl group (formyl,
acetyl, chloroacetyl, trifluoroacetyl, propionyl, matahapenzoyl (nato), alkoxycarbonyl (ethoxycarbonyl, tert-butoxycarbonyl, 2.2.2-)lychloroethoxyruvenyl, 2,2.2-tri Bromoethoxylic is nil, 2
-(iJmethylsilyl)ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl, or allyloxycarbonyl group), aralkyl group (benzyl, diphenylmethyl, or triphenylmethyl group, etc.) ). ), -NR11R12 group (in the formula, R1
1 and R12, the same or different, hydrogen atoms, alkyl groups (eg, methyl, ethyl, propyl, or isopropyl groups, etc.).

Acyl groups (e.g., acetyl, globionyl, isobutyryl, or benzoyl), sulfoyl groups (tal(
! : EVA, methylsulfonyl, ethylsulfonyl, or phenylsulfonyl group) or a protecting group for amine group (
It has the same meaning as the protecting group for the amino group in R10. ). ).

A kill group (such as a methyl, ethyl, or propyl group) or an aryl group (such as a phenyl, p-methoxyphenyl or p-aminophenyl group). R14 is a hydrogen atom, an alkyl group (for example, methyl, ethyl, or propyl group), an amino group protecting group (same meaning as the amino group protecting group in R10), a phenyl group, or R15 and 1 (a group in which 14 together form a ring (for example, R and R are -(CH2)
5- or -(CH2)4- group, etc.). ).

is the same or different hydrogen atom, alkyl group (for example, methyl, ethyl, or propyl group, etc.), an amino group protecting group (same meaning as the amino group protecting group in R10), B10 and R17 together to form a ring (for example, R16, R+7, car(CH2)4-
1-(CH2)5-, Mata is -(CH2)6-, etc.)
, or a group in which R15 and 116 together form a ring (for example, I(15 and R16 are -(CH2)2-1-
(CH2)5- or -(CH2)4- group)], alkoxy groups [methoxy, ethoxy, glopoxy, tert-butoxy, methoxymethyloxy, methylthiomethoxy, 2-tetrahydropyranyloxy,
or -〇CH20COR'' group (in the formula, R1B is a hydrogen atom, methyl, ethyl, propyl, tert-butyl, phenyl or benzyl group, etc.) airkylthio group [methylthio, methoxymethylthio, methylthiomethylthio,
-8CH2CH2A group (in the formula, A is 1, the above-mentioned substituent A
does not show the same meaning. ), -8CH20COR group (in the formula, R has the same meaning as R described above), -8CH2SCO
R” group (in the formula, R18 has the same meaning as R18 described above)], arylthio group [phenylthio or 4-methoxy7x = ruthio group], heterocyclic thio group [pyrrolidinylthio, tetrahydrofuranylthio, thia zolidinylthio or 2-oxohexahydrobiliNF!15 has the same meaning as taR), -MatoNR16R17 group (wherein R15, R16 and H17 have the same meanings as described above), or nitrogen Atom-protecting group (same definition as the above-mentioned amine group-protecting group R10)].

R18 has the same meaning as described above. ].

-802R18 group [wherein R18 has the same meaning as described above]. : ] * Co2R18 group [wherein, R18 has the same meaning as described above. ), -CO8R1
8 groups [wherein R has the same meaning as described above]. ]−
0COR'' group [wherein R has the same meaning as defined above], -8COR18 group [wherein l718 has the same meaning as defined above]] r-NHrt21-g formula Among them, R21 has the same meaning as the above-mentioned R18 or the above-mentioned amino group-protecting group I (same as 10 and shows YAk).

-NHCOR'' group [wherein R18 has the same meaning as defined above], a halogen atom [fluorine, chlorine, bromine or iodine atom], a carboxy group, a cyan group or a nitro group.

R6 in the general formula (n) is an alkyl group [methyl, ethyl, propyl, impropyl or butyl group]. ], alkoxy group [methoxy, ethoxy, noropoxy, isopropoxy or butoxy group] aryl group [phenyl, 4
-methoxyphenyl or 4-methylphenyl group], an aryloxy group [phenoxy, 4-methoxyphenoxy or 4-methylphenoxy group], or an amine group [dimethylamino, dimethylamino or dipropylamino group].

R7 in general formula (g) is an alkyl group [methyl, ethyl, propyl, isopropyl or butyl group] or an aryl group [phenyl, 4-methoxyphenyl or 4-methylphenyl group].

Horner-Emm obtained by treating a compound having general formula (n) or (It) with a base
A compound having the general formula (1) can be obtained by reacting a compound having the general formula (1) with an ona or Wittig reagent. The bases used in this reaction are not particularly limited and include alkali metal hydrides [sodium hydride or potassium hydride], alkali metal amides [sodium amide or potassium amide], organic bases [triethylamine, pyridine, 4-dimethylaminopyridine] , 1,5-
diazabicyclo(4,3,O]]non-5-e or 1
, 4-diazabicyclo[2,2,2]octane] is a lithium compound [butyllithium, tert-butyllithium, lithium diisozolobylamide or (trimethylsilyl)lithium amide].

Solvents used in this reaction include aromatic hydrocarbons [benzene, toluene or xylene], ethers [diethyl ether, tetrahydroctane or dioxane], amides [dimethylformamide or dimethylacetamide] or dimethyl sulfoxide. reaction ff,
& is -78° to 120°C. The reaction time varies depending on the raw material compound, the type of base used, and the reaction temperature, but is from 10 minutes to 24 hours. The compound having the general formula W) obtained here can be isolated according to conventional methods. The general formula is shown in Table 1) The abbreviations in Table 1 are THP: Tetrahydropyranyl PNZ 24-ditropendyloxycarbonyl PNB
: 4-nitropendyl. All compounds in the table are new compounds. Various isomers can be considered with respect to the stereochemistry of the compound (transposition), and the general formula (product) represents one of the stereoisomers or a mixture thereof.

By decomposing a compound having the general formula
A compound having the general formula (Vlt-) is obtained.

In general formula (7), R', R2 and R3 have the same meanings as described above, R8 has the same meaning as R4 or R5 described above, and Y represents an oxygen or sulfur atom. This hydrolysis reaction is accelerated by acid or base catalysts. The acids used are sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, formic acid, aluminum chloride or boron trifluoride, etc., and the bases used are sodium hydroxide,
Potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine, bi-IJ&N, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,
3,O]non-5-ene or 1,4-diazabicyclo[2,2,23octane.

The solvents used in the reaction are alcohols [methanol, ethanol, propatool or butanol], acetone, ethers [diethyl ether, detrahydrofuran or dioxane], amides [dimethylformamide or dimethylacetamide dimethyl sulfoxide], halodanated It is a mixed solvent of water and hydrocarbons (methylene chloride, chloroform, or carbon tetrachloride) or aromatic hydrocarbons (benzene, toluene, or xylene), etc. On this occasion,
A mutual catalyst such as an ammonium salt can be used if necessary.

The reaction temperature is -78°C to 150°C. The reaction time is 1
It is 0 minutes to 24 hours. After completion of the reaction, the compound (■) can be isolated according to a conventional method.

The compound having the general formula (1), which is a starting material of the present invention, has the general formula [wherein R+, R2 and R3 have the same meanings as described above]. ] Compound 'I! : By oxidation or reduction or Grignard reaction, a compound having the general formula [wherein R1 and] (2 has the same meaning as defined above, and 2 represents a chlorine atom or an alkoxy group) can be obtained.

The compound having the general formula (9) obtained by the present invention is an important intermediate leading to carbapenem derivatives having strong antibacterial activity such as chenamycin.

That is, compound (V)U can be derived as a carbapenem derivative by various methods. One of the methods is to react a compound (R1: hydrogen atom) having the general formula (V) shown in Figure 1 with halogen chloride (Vi!l) to obtain a triethyl phosphite compound (T). A carbapenem derivative can be obtained by reacting with General formula (V
R9 in ID represents the aforementioned carboxy group protecting group, and R2 and R5 in general formulas (g) and (3)
, R8 and R9 have the same meanings as described above.

Figure 1 fart) The present invention will be specifically illustrated by giving examples below.

Example 1 [38-[3α-(S*), 4β] ) -1-(
2,4-Dimethoxybenzyl)-3-(1-t-butyldimethylsilyloxyethyl)-4-(2,2-bisphenylthiovinyl)-2-azetidinochloride under a stream of diethyl di(phenylthio)methylphos Huonate (
Butyl lithium (0.75 d of 1,6 M hexane solution) was added to a solution of 442 mg, 1.2 mmot) in tetrahydrofuran (10 mj) under ice cooling, stirred for 5 minutes, and then aldehyde (407.4 mg, 1.0 mmo
A solution of t) in tetrahydrofuran (5-) is added dropwise. 3
After 0 minutes, the temperature was raised to room temperature and stirred for an additional 30 minutes. Dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate, and brine, and dry with MgSO4. The solvent was distilled off under reduced pressure,
The remaining oil was purified by silica dull TLCK to obtain the desired product as a viscous oil with a yield of 511 mp (82%).

NMR spectrum (CDCLs) δppm: 0.
04 (6H, g), (1,84 (9H, s ), 1゜1
5 (3H, d, J=GHz), 2,80 (IH, dd
, 'J=2.3Hz), 3.79(6H,s), 4.2
2 (IH, dq, J=3.6Hz), 4.23 (21
1°B), 4.85(IH, ad, J=2.9.5H
z), 5.77 (IH, d, J = 9.5Hz
), 6.27-6.50 (2H.

m), 7.03-7.25 (IIH, m).

Actual elemental analysis value 2C, 64, 67; H, 7, 35SN, 2.2
0; S, 10.04 Theoretical value: C, 65,66;
H, 6,97:N, 2.25:S, IO, 31% Example 2 [3S-[3α(S*), 4α, 1 ml −1-
(2,4-dimethoxybenzyl)-3-(1-hydroxyethyl)-4-(phenylthiocarvinylmethyl)-
2-Azetidinone Vinyl phyto(2) 100 rag CF
The C00H-H2O3 (2:1) 3-solution is stirred at room temperature for 2 hours.

Diluted with ethyl acetate, washed with sodium bicarbonate solution and saline solution, and extracted with Mg
Dry with SO4. The solvent is removed under reduced pressure to obtain crude crystals. Purification by silica gel chromatography yielded 24 rng (36%) of the target product (3) and 7 mg of vinyl sulfide in which only desilylation occurred. Compound (3)
IR spectrum of Nujol I-1: 3310,
1777 rax 1745.1633, 1618.1588NMR (CD
Ct,) Spectrum δppm: 1.30 (3H.

d, J=6Hz), 2.12 (IH, dd, J=8.1
0Hz, Cs-H), 2.53 (IH, dd, J=6
．． 5.17Hz), 2.98 (IH, dd, J=6.
5.17Hz), 3.77 (LH, dt, J=8.6.
5Hz, C4-H), 3.78 (3H, s), 3.80
(3H, a), 4.1-4.8 (31Lm), 6.0-
6.5 (2H, m), 7.0-7.3 (6H, m), MS two vector m/e: 415 (M', 3
06, 260.

234...

Example 3 C3S-C3a (s*), 4β(E, S*)]
]- and (3S-(3(1(S*), 4β(Z, S*)l
)- and (33-[3α(S*).

4β(Z,R*)]]-1-(2,4-dimethoxybendi/')-3-(1-t-f thyldimethylsilyloxyethyl)-4-(2-tetrahydropyranyloxy-
2-Phenylthiovinyl)-2-azetidinone mixture.

Under a nitrogen stream, noethyl (l-phenylthio-1-tetrahydropyranyloxy)methyl phosphonate (2
08■+0.58mmot) of tetrahydrofuran (
5mg) butyl lithium (l, 6 wards, 0.8
Add mfr at -40°C.

After 10 minutes, a 5 ml solution of aldehyde (1) in 5 ml of tetrahydrofuran was added, and the temperature was slowly raised to room temperature. Diluted with ethyl acetate, washed with water and saline, MgS
Dry with O4. After concentrating under reduced pressure, the remaining oil was separated and purified using silica gel thin layer chromatography (developed with cyclohexane:ethyl acetate = 2:1), resulting in Rf = 0.
．． 483 to 31m9 Rf = 0.2 = 50 to 41■ target objects each as a 1:1 mixture of diastereomers? 4J Rare. Yield 48%.

Physical constant IR spectrum of town = 0°25 ν”c, 'In-': 1752,16
15°ax 59O NMR spectrum (CDCt3) δpPm: 0.02
(6H, s), 0.83 (9H, s), 1.12 (1,
5H, d, J=6Hz), 1.15 (1,5)1,
d, J=61(z), 1.47(6H,m),
2.86 (IH, m), 3.4-3.8 (2) i+6H
Qδ3.75 includes 6H5@)], 4.0-5.5
(6H, m), 6.2-6.5 (2H, rn), 7.0
-7.3 (5H+ LH, m.

5H28 is included in δ718).

MS spectrum km/e: 557 (M”-Bu
t), 530.474.422,...

Example 4 [38-[3α(S*), 4β]] -1-(2,
4-dimethoxybenzyl) -3-(1' tert-
butyldimethylsilyloxyethyl)-4-phenylthiocarzanylmethyl-2-azetidinone Isomer (4) with Rf=0.48 obtained in Example 3 28
ml (0,046 mmol) f, acetic acid-THF-
Dissolve in 1 tnt of water (4:2:1) and stir at room temperature for 4 hours. Direct thin layer chromatography (cyclohexane.

17 mg (7 mg) of thioester in ethyl acetate = 2:1)
1) was obtained.

Similarly, compound (5) was obtained from (4) with R = 0.25 in a yield of 64%.

NMR spectrum (CDCt3) δppm = (1,0
2 (6H, s), 0.80 (9H, s), 1.16 (3
H, d, J=6Hz), 2.72 (IH, dd,
J=8, 15Hz), 3.08 (IH.

dd, J=5, 15Hz), 2.96(IH,
dd, J=3.4Hz), 3.83 (6H, a), 3.
85-4.25 (2H, m), 4.32 (2H, bs)
, 6.43 (IH.

dd, J=2, 9Hz), 6.43(IH, d
, J=2Hz), 7.12 (IH, d, J=9Hz),
7.38 (5H, s), IR
': 1750 r 1700, 1612°ax 1588.

MS spectrum m/e: 472 (M+But),
152...

Example 5゜(38-(3α(S*), 4β:] :] -1-
(2,4-dimethoxybenzyl)-3-(1-t-butyldimethylsilyloxyethyl)-4-vinyl-2-azetidinone (1) (6) Hexane solution of butyllithium (0,31d.

05 mmol)'f: dry ethyl ether (2 ml)
Triphenylmethylphosphonium bromide (0.1791%, 0.5 mmol) was gradually added thereto, and the mixture was stirred at room temperature for 3 hours.

This reaction mixture was added with aldehyde compound (1) (0
, 1355', 033 mmol) in dry ethyl ether (1-) was added and refluxed for 3 hours.

The reaction mixture was cooled with water, diluted with ethyl acetate, insoluble matter was removed by filtration, washed with a carbonate solution, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the residual oil was subjected to a rabid chromatography using silica dal (1:l) to remove cyclohexane.
Elution with ethyl acetate (8:2) gave the desired vinyl compound (6) at 0.04'1-(35%) as a colorless oil.

IR spectrum VLiqcm-1:1750.1615
．． 151011aX NMR spectrum (cDct,) δppm: U, (
+4 (6H.

g, Dlmethyl), 0.82 (9H, g
, tert -Eutyl ) 1.17 (3H, d
, J=6.5Hm, CM, ), 2.80 (IH.

dd, J=5Hz, 2Hz, 3-H), 3
．． 7-4.3 (2H, m.

4-H, CH3CJI-), 3.78 (6H2s, o
cH5), 4.05.

4.44 (2H, ABq, J=15Hz, CH2
), 4.93-6.07 (3H1m, CH-CH2),
6.25-6.52, 7.00-7.30 (3H, m
, Phenyl) Example 6 [38-[3α(S*),4β(E)))- and [3
s-(S*), 4β(Z)]) -1-(2,4-
dimethoxybenzyl) -3-(1-tert-butyldimethylsilyloxyethyl)-4-(2-phenylthiovinyl)-2-azetidinone diethyl phenylthiomethyl 7-osphonate (0,
13F, 0.5 mmol) in dry tetrahydrofuran (
2-) Add butyl lithium (0,311n) to the solution under water cooling.
t, 0.5 mmol) was added.

Next, aldehyde compound (1) (0,135?, 0.3
A solution of dry tetrahydrone (1-) (3 mmol) was added under water cooling, and the mixture was stirred at the same temperature for 2 hours. After the tetrahydrofuran in the reaction mixture was distilled off under reduced pressure, it was diluted with ethyl acetate, washed with aqueous sodium chloride, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the remaining oil was subjected to rapid chromatography using silica gel (20?) using cyclohexane:ethyl acetate (2:1).
Dissolved in AIIF and obtained 8 vinyl sulfide compounds (7)
is (1,066? (39%), 2 bodies (8) is 0.111
2V (7%), obtained as a colorless oil.

8 bodies (7) IR spectrum ν"'Qcm': 1760.16N
+, 1510ax NMR spectrum (cut, )δppm: o,
o4(6)1+grDlmethyl),
0.81 (9H, s, tart-1utyl
), 1, 16 (3H, d , J = 6 Hz, CH
s), 2.78 (IH.

dd, J=5H2,2,5Hz,3H), 3.76(
6H,s.

0CR3), 4.09.4.40 (2H, ABq, J=
15Hz.

C■I2), 5.55 (IH, dd, J=9Hz, 1
5Hz.

vinyl-H), 6.29 (IH, d, J = 151 (
y,.

vinyl-H), 6.25-7.30 (3H, m
, Phenyl), analysis division value: C, 65,45; H, 7,65; N, 2.7
3: S, 6.24 Measured value: C, 65, 37; H, 7,
88; N, 2.71; S, 6.292 bodies (8) IR spectrum 1750.165 in L'qcrrL-
0.151ONIVIR spectrum (cDcz3) δp
prn: 0.04 (6H, s.

Dimethyl), 0.82 (9H, s, t
ert-Eutyl), 1-16 (3H, d, J
=6 Hz 1CL(s), 2.78(LH.

m, 3-H), 3.70 (6H, a, 0cHs)
, 4.06.4.33 (2t(, ABq , J=14H
z, CH2), 4.48(1)1. dd.

J==10Hz, 2Hz, 4-H bar 5.44 (
JH, ad, J=10i(z, 10Hz, vkny
l-H), 6.12 (IH, d, J=10 Hz +
vinyl-H), 6.10-7.30 (3H, m.

Phenyl), 7.15 (5H, s, Phe
nyl) Example 7゜[:3S-(3α(S*), 4β(E)]:l- and [3S-[3α(8*), 4β(Z)])-t=(
2,4-Simeto#'/H:/)ru)-3-(1-
t-butyltzmethylsilyloxyethyl)-4-(2-
Mixture of chloro-2-phenylthiovinyl)-2-azetidinone diethyl (1-chloro-1-phenylthio)
A solution of methyl phosphonate (0,195p, 0.66 mmol) in dry tetrahydro7rane (3mj)
Butyl lithium (0.41 ml, 0.66
mmol) was added. Next, an aldehyde compound (ln(
0.135P, 0.33 mmol) in dry tetrahydrofuran (1-) W1. The mixture was added under cooling with t-water and stirred at the same temperature for 2 hours. After the tetrahydrofuran in the reaction mixture was distilled off under reduced pressure, the mixture was diluted with ethyl acetate and chlorinated.) The mixture was washed with IJ cum water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residual oil was subjected to rapid chromatography using silica dal (221) and eluted with cyclohexane:ethyl acetate (8:2). As a result, a 1:1 mixture of olefin compounds E and 2 was obtained as a 0.08V-(44%) colorless oil.

IR spectrum ν"qcm-': 1760, 1610
．． 1510°ax 35 NMR, C vector (CDC6,) δpprn 20.
04 (6H.

s, Dlmethyl (cis and transa))
, 0.82 (9H, s.

tert-Butyl (els and trans)), 1
．． 15 (1,5H.

d + J = 6.5 Hz + CHs (ole or trans), 1.18 (1,5H, d, J = 6
．． 5Hz, CH4 (cig or trana))
2.84 (IH, m, 3B, (css and trans)
), 3.77 (6H+s +OCH, (cis and tr
ans)), 3.9-4.35 (3H, m, CH
2*CH3C1-(eta and trans)), 4.
50 (0,5H, dd, J=10Hz, 2Hz,
4-H (cis or trans)), 4.72 (
0.5H, dd, J=10Hz * 2Hz 14
-H (cia or tra, H8)), 5,77 (0,5
H, d, J=10Hz, vlnyl-H(ci
s or trans )),' 5.96 (0,5H,
d, J=10Hz.

vinyl-H (cis or trans), 625
~730 (3H + m + phenyl (cis and trans)), 715 ~ 7.30 (5H + m
+ phanyl (cis (!: trans)
Mi spectrum m/e: 548 (Mj), 491 (
λ'l-57) Analysis calculation value: C, 61,34: H, 6,99; N, 2.5
6; S, 5.85CL, 6.47 Measured value: C, 61, 24; H, 7°26; N, 2
．． 55:S, 6.18CL, 5.37 Example 8 [:3S-(:3α(S*), 4β(E)]]- and [3S-(3α(S*), 4β(Z):II )-1
-(2,4-/l toxyhenzyl) -3-(1-te
rt-butyldimethylsilyloxyethyl)-4-(2
-cyano-2-methoxyvinyl)-2-azetidinone under nitrogen stream, diethyl (1-cyano-1-methoxy)
Methyl phosphonate 310■ (1.5 mmot)
A solution of lithium hexamethyldisilazide (1,5 mmot) in tetrahydrofuran (2d) was added to a solution of lithium hexamethyldisilazide (1,5 mmot) in tetrahydrofuran (5rnt) at -78°C. 10 minutes Aldehyde (1) 407.4 Tng (1, Ommot
) in tetrahydrofuran (5-) was added at -78°C, and 10 minutes after the dropwise addition, the temperature was slowly raised to room temperature, and stirring was continued for an additional hour. Neutralize excess base with acetic acid, dilute with ethyl acetate, and wash the organic layer with aqueous sodium bicarbonate, brine, and dry over Na2S04. The solution a was distilled off, and the remaining oil was separated by silica del thin layer chromatography. When developed with ethyl acetate dichlorohexane = 1:1, R = 0.780 and α of 177■ (38.4%)
One isomer of η, 284 to (61
, 6%) was obtained quantitatively by combining the two isomers.

Physical constants of isomers with Rf = 0.780 IR scale v”q) 11: 2220 (W),
+753+ax 161.2.1614.1590 M5 spectrum m/e: 460 (M+), 445,4
03(M+-tBu) NMR spectrum (CDC25) δppm: 0.03
(3H.

II), 0.05 (3H, s), 0.83 (9H, s)
, 1.12 (3H, d, J = 6Hz), 2.
78 (IIL dd.

J” 2 + 4 Hz + Cs −H), 3.6
4 (3H, a), 3.86 (6H, s), 4.07 (I
H, m), 419 (2H, b8), 4.40 (IH, d
d, J = 2, 9Hz.

C4-H), 5.19 (IH, d, J=9Hz
), 632 (IH, d, J=2Hz), C32 (
IH, dd, J=2.9Hz), 7.01 (IH,
d, J=9Hz) Physical constant 1 of the isomer with Rf=0.440, R spectrum V"qCrrL-': 2.290
(w), 1752°1638.1614.1590 M5 base m/e: 460 (M+), 445°4
03 (M++tBu) NMR spectrum (CDC45) δppm: 0.04
(3H, s), 0.06 (3H, s), 0.85 (9H
, s), 1.17 (3H.

d, J=6Hz), 2.80(IH, dd, J=2,4
I4z), 3.38 (3H, s), 3.73 (3H, s
), 3.78 (3H.

S), 4.11 (I H1m, Cs-H), 4.2
1 (2H, b@), 438 (IHldd, J=2.1
0H2, C4-H), 5.08 (IH, d, J=10H
z), 6.32 (, LH, d.

J=2Hz), 6.32(IH, dd, J=2.9Hz
), 7.04 (IH, d, J=9Hz) Example 9゜[38-[:3α(S*), 4β]]-methyl[:
1-(2,4-dimethoxybenzyl)-3-(1-hydroxyethyl)-2-azetidinone]-4-yldithioacetate q3 and (3s-[3α(8t, 4β)]
-1-(2,4-dimethoxybenzyl)-3-(1-hydroxyethyl)-4-(2-methylthio-2-azetoxymethylthiovinyl)-2-azetidinone a4 Acetoxymethyl compound (b) 48Tn9 methyl alcohol To the (2,5g) solution, 20% hydrochloric acid 1- was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica del thin layer chromatography (developing solvent: dichlorohexane-ethyl acetate 1:9) to obtain the dithioester compound (t), 151n9,
and 4 mg of the starting material desilylated compound α◆ were obtained.

Physical constant N1-〆] of dithioester compound C11:
Sesuiktor (CDC23) 6211m 21.12
(3H.

d, J = 6.5 Hz, OH5), 2.59 (3
11, s, SC horse) 28-3.5 (3H2m, 3-
H1CH2C8), 378 (3H, s, OMe)
, 3.81 (3H,s, OMe), 3.7-4.2 (
2H, m, 4-H, C horse CH(OH)), 410
゜4.51 (2H, AB-q, J=-14Hz, NCH
2), 6.3-7.2 (3H, m, pher+y
l) IR spectrum CHCt3 box-': 3420
, 1720°ax 1620.1500 MS spectrum rrV′e: 369 (M”) Physical constants of desilylated compound q4 NMR spectrum pv (CDCL,) δppm: 1.
24 (3H.

d, J=6H3,OH5), 1.99 (3H,s,
C0CHs), 2, 12 (3H, s, 5CHs
), 2.76-2.95 (IH.

m, 3H), 3.76 (6H, s, OMe), 4.23
(2H* m, NCH2), 5.18 (2H, s
, 5CH2) 15.48 (IH, d, J=9.
5Hz, vlnyl-H), 62-7.1 (3H
, m, pheny+) MS spectrum m/e:
'441 (M”) Patent applicant: Sankyo Co., Ltd. Agent: Shoji Kashiyama, patent attorney

Claims (3)

[Claims] (1) General formula [In the formula, R1 is a hydrogen atom or a protecting group or substituent for an amide NH group, R2 is a hydrogen atom or a protecting group for a hydroxyl group, H5 is a hydrogen atom, an alkyl group, or an aryl group, H4 and R5 is the same or different hydrogen atom,
Alkyl group, substituted alkyl group, alkoxy group, alkylthio group, arylthio group, heterocyclic thio group, aromatic heterocyclic thio group, sulfinyl group, sulfonyl group, alkoxycarbinyl group, alkylthiocarvinyl group, acyloxy group, acylthio group , an amino group, an amide group, a halogen atom, a carboxy group, a cyano group, or a nitro group. ]. (2) General formula [In the formula, R1 is a hydrogen atom or a protecting group for an amide NH group or a substituent + R2 is a substituent for a hydroxyl group spanning a hydrogen atom 15 is a hydrogen atom, an alkyl group, or an aryl group show. ] to a compound having the general formula % formula % () - [wherein R4 and R5 are the same or different hydrogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, alkylthio groups, arylthio groups, heterocyclic thio groups, aromatic Heterocyclic thio group, sulfinyl group, sulfonyl group, alkoxylgenyl group, alkylthiocarbonyl group, acyloxy group, acylthio group, amine group, amide group, halogen atom, carboxy group, cyan group or nitro group *
R6 represents an alkyl group, an alkoxy group, an aryl group, an aryloxy group or an amine group. ] Or the general formula [wherein R4 and R5 have the same meanings as above]
R7 is an alkyl group or an aryl group. X represents a halogen atom. [In the formula, R1
, R2, R', R' and R5 have the same meanings as described above. ] A method for producing a compound having the following. (3) Protecting group or substituent in the general formula + R2 is a hydrogen atom or a hydroxyl group protecting group R3 is a hydrogen atom, an alkyl group or an aryl group R4 and R5 are the same or different hydrogen atom, alkyl group, Substituted alkyl group, alkoxy group, alkylthio group, arylthio group, heterocyclic thio group, aromatic heterocyclic thio group, sulfinyl group, sulfonyl group, alkoxycarbonyl group, alkylthiocarbonyl group, acyloxy group, acylthio group, amine group, amide group , a halodane atom, a carboxy group, a cyan group or a nitro group. ] is hydrolyzed to form a compound having the general formula (V) [wherein R'* R2 and R3 have the same meanings as defined above, R8 has the same meaning as defined above as R4 or R5, and Y is A manufacturing method that leads to a compound having an oxygen or sulfur atom.