JPH03385B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, R ¹ is a hydrogen atom or a protecting group or substituent for an amide NH group, R ² is a hydrogen atom or a hydroxyl protecting group, R ³ is a hydrogen atom, an alkyl group, or an aryl group, R ⁴ and R ⁵ are the same or different hydrogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, alkylthio groups, arylthio groups, heterocyclic thio groups, aromatic heterocyclic thio groups, sulfinyl groups, sulfonyl groups, alkoxycarbonyl groups, It represents an alkylthiocarbonyl group, an acyloxy group, an acylthio group, an amino group, an amide group, a halogen atom, a carboxy group, a cyano group, or a nitro group. ] and its production method, as well as a general formula which is an important intermediate in the synthesis of carbapenem derivatives by hydrolyzing the compound () [In the formula, R ¹ , R ² and R ³ have the same meanings as described above, R ⁸ has the same meaning as R ⁴ or R ⁵ described above, and 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 () is a compound having the general formula ()
has Compounds having the general formula () or () or By treating with a base and then reacting, a compound having the general formula () can be obtained. R ¹ in the general formulas () and () is a hydrogen atom or a protecting group or substituent for the amide NH, such as an aryl group [phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 2,4- dimethoxyphenyl group], aralkyl group [benzyl, 4-methoxybenzyl,
3,4-dimethoxybenzyl, 2,4-dimethoxybenzyldi-(4-methoxyphenyl)methyl group, or benzhydryl group],

[Formula] Group [In the formula, R ⁹ represents a commonly used protecting group for a carboxy group. For example, an alkyl group (methyl, ethyl, propyl or tert-
butyl group), aralkyl group (benzyl, diphenylmethyl, 4-nitrobenzyl, or 2-
nitrobenzyl group, etc.), alkenyl group (allyl,
2-chloroallyl or 2-methylallyl group), a halogenated alkyl group (such as 2,2,2-trichloroethyl or 2,2,2-tribromoethyl group), or 2-(trimethylsilyl)ethyl group. ],

[Formula] Group [In the formula, R ⁹ has the same meaning as defined above. ], -
CH ₂ CO ₂ R ⁹ group [wherein R ⁹ has the same meaning as described above]. ], ether group [such as methoxy, benzyloxy group or tert-butoxy group], silyl group [such as trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl group], or halogen atom [chlorine or bromine atom]
etc. In the general formulas () and ()
R ² is a hydrogen atom or a hydroxyl group protecting group [alkyl group (methyl, ethyl, propyl, or isopropyl group, etc.), silyl group (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl or triphenylsilyl 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), alkoxycarbonyl group (benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, 2,2,
2-trichloroethoxycarbonyl, allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl, t-butoxycarbonyl, diphenylmethyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl group, etc.) or ether group (tetrahydro pyranyl, methoxymethyl, 1-ethoxyethyl or 2-(trimethylsilyl)ethoxymethyl group]. R ³ in the general formulas () and () is a hydrogen atom, an alkyl group [methyl, ethyl or propyl group, etc.] or an aryl group [phenyl, 4-methoxyphenyl or 4-methylphenyl group]. General formula (),
R ⁴ and R ⁵ in () and () are the same or different hydrogen atoms, alkyl groups [methyl, ethyl, propyl, etc.], substituted alkyl groups [-
CH ₂ CH ₂ A, −CH (CH ₃ ) CH ₂ A, CH ₂ OCOCH ₂ A
or CH ₂ OCOCH ₂ CH ₂ A {in the formula, A is a NHR ¹⁰ group (in the formula, R ¹⁰ is a hydrogen atom or a general amino protecting group (acyl group (formyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, benzoyl, etc.), alkoxycarbonyl groups (ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, benzyl) oxycarbonyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, or allyloxycarbonyl group), aralkyl group (benzyl, diphenylmethyl, or triphenylmethyl group, etc.)
It is. ), -NR ¹¹ R ¹² group {wherein R ¹¹ and R ¹² are
Same or different hydrogen atoms, alkyl groups (such as methyl, ethyl, propyl, or isopropyl groups), acyl groups (such as acetyl,
propionyl, isobutyryl, or benzoyl group), a sulfonyl group (for example, methylsulfonyl, ethylsulfonyl, or phenylsulfonyl group), or an amino group-protecting group (same meaning as the amino-protecting group in R ¹⁰ ). . ),

[Formula] group (wherein R ¹³ is a hydrogen atom, an alkyl group (e.g., methyl, ethyl, or propyl group, etc.) or an aryl group (e.g.,
phenyl, p-methoxyphenyl or p-aminophenyl group). R ¹⁴ is a hydrogen atom,
an alkyl group (for example, methyl, ethyl, or propyl group), an amino group-protecting group (having the same meaning as the amino group-protecting group in R ¹⁰ ), a phenyl group, or R ¹³ and R ¹⁴ together to form a ring (for example, R ³ and R ¹⁴ are -(CH ₂ ) ₃ - or -(CH ₂ ) ₄ - groups, etc.). ),

[Formula] group ((in the formula, R ¹⁵ , R ¹⁶ and R ¹⁷ are the same or different hydrogen atoms, alkyl groups (for example, methyl, ethyl, or propyl groups),
A protecting group for an amino group (same meaning as the protecting group for an amino group in R ¹⁰ ), a group in which R ¹⁶ and R ¹⁷ come together to form a ring (for example, a group in which R ¹⁶ and R ¹⁷ are -
(CH ₂ ) ₄ −, −(CH ₂ ) ₅ −, or −(CH ₂ ) ₆ − groups), or groups in which R ¹⁵ and R ¹⁶ are taken together to form a ring (for example, R ¹⁵ and R ¹⁶ is −(CH ₂ ) ₂ −, −
(CH ₂ ) ₃ - or -(CH ₂ ) ₄ - group, etc.), alkoxy groups [methoxy, ethoxy, propoxy, tert-butoxy, methoxymethyloxy, methylthiomethoxy, 2-tetrahydropyranyloxy, or −OCH ₂ OCOR ¹⁸ groups (in the formula R ¹⁸
is a hydrogen atom, methyl, ethyl, propyl, tert
-butyl, phenyl or benzyl group)], alkylthio group [methylthio, methoxymethylthio, methylthiomethylthio, -SCH ₂ CH ₂ A group (in the formula, A has the same meaning as the above-mentioned substituent A), -
SCH ₂ OCOR ¹⁸ groups (in the formula, R ¹⁸ has the same meaning as R ¹⁸ described above), -SCH ₂ SCOR ¹⁸ groups (in the formula, R ¹⁸ is
Shows the same meaning as R ¹⁸ above. )], arylthio group [phenylthio or 4-methoxyphenylthio group], heterocyclic thio group [pyrrolidinylthio, tetrahydrofuranylthio, thiazolidinylthio or 2-oxohexahydropyrimidinylthio group, whose nitrogen atom is May have the following substituents

[Formula] Group (In the formula, R ¹⁹ has the same meaning as R ¹³ described above, and R ²⁰ has the same meaning as R ¹⁴ described above.)

[Formula] Group (In the formula, R ¹⁵ , R ¹⁶ and R ¹⁷ have the same meanings as described above.)
or a nitrogen atom-protecting group (same definition as the amino group-protecting group ^R10 described above)], an aromatic heterocyclic thio group [pyridylthio, thienylthio, or furylthio group],

[Formula] Group [In the formula, R ¹⁸ has the same meaning as defined above. ], -SO ₂ R ¹⁸ group [wherein R ¹⁸ has the same meaning as described above. ], -CO ₂ R ¹⁸ group [wherein R ¹⁸ has the same meaning as described above. ], -
COSR ¹⁸ groups [In the formula, R ¹⁸ has the same meaning as described above. ], -SCOR ¹⁸ groups [wherein R ¹⁸ has the same meaning as described above. ], -NHR ²¹ groups [in the formula,
RN ²¹ has the same meaning as the above-mentioned R ¹⁸ or the same meaning as the above-mentioned amino group protecting group R ¹⁰ . ], -
NHCOR ¹⁸ groups [wherein R ¹⁸ has the same meaning as described above]. ], a halogen atom [fluorine, chlorine, bromine or iodine atom], a carboxy group, a cyano group or a nitro group. R ⁶ in the general formula () is an alkyl group [methyl, ethyl, propyl, isopropyl or butyl group]. ], alkoxy group [methoxy, ethoxy,
propoxy, isopropoxy or butoxy group]
Aryl group [phenyl, 4-methoxyphenyl or 4-methylphenyl group], aryloxy group [phenoxy, 4-methoxyphenoxy or 4
-methylphenoxy group] or an amino group [dimethylamino, diethylamino, or dipropylamino group]. ^R7 in the general formula () is an alkyl group [methyl, ethyl, propyl, isopropyl or butyl group] or an aryl group [phenyl, 4-methoxyphenyl or 4-methylphenyl group]. Horner- obtained by treating a compound having the general formula () or a compound having () with a base
A compound having general formula () can be obtained by reacting an Emmons or Wittig reagent with a compound having general formula (). 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 chlorine [triethylamine, pyridine, 4-dimethylaminopyridine] , 1,5-diazabicyclo[4.3.0]non-5-ene or 1,
4-diazabicyclo[2,2,2]octane] or a lithium compound [butyllithium, tert-butyllithium, lithium diisopropylamide or di(trimethylsilyl)lithiumamide]. Solvents used in this reaction include aromatic hydrocarbons [benzene, toluene or xylene], ethers [diethyl ether, tetrahydrofuran or dioxane], amides [dimethylformamide or dimethylacetamide] or dimethyl sulfoxide. The reaction temperature is -78° to 120°C. The reaction time varies depending on the raw material compound, type of base used, and reaction temperature, but is 10 minutes or more.
It is 24 hours. The compound having the general formula () obtained here can be isolated according to a conventional method. Table 1 shows examples of compounds having the general formula ().

【table】

【table】

[Table] The abbreviations in the table are THP: tetrahydropyranyl PNZ: 4-nitrobenzyloxycarbonyl PNB: 4-nitrobenzyl. All compounds in the table are new compounds. Regarding the stereochemistry of the compound (), various isomers can be considered, and the general formula () represents one of the stereoisomers or a mixture thereof. A compound having the general formula () can be obtained by hydrolyzing the compound having the general formula (). In the general formula (), R ¹ , R ² and R ³ have the same meanings as above, and R ⁸ is R ⁴ or R 3 above.
The same meaning as R ⁵ is given, and Y represents an oxygen or sulfur atom.
This hydrolysis reaction is promoted by acid or base catalysts. 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, pyridine,
-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0.]non-5-ene or 1,4-diazabicyclo[2.2.2]octane. The solvents used in the reaction are alcohols [methanol, ethanol, propanol or butanol], acetone, ethers [diethyl ether,
A mixed solvent of water and amide [dimethylformamide or dimethylacetamide], dimethyl sulfoxide, halogenated hydrocarbon [methylene chloride, chloroform or carbon tetrachloride], or aromatic hydrocarbon [benzene, toluene or xylene], etc. . At this time, an interphase catalyst such as an ammonium salt can be used if necessary. Reaction temperature is -78℃~
The temperature is 150℃. Reaction time is 10 minutes to 24 hours.
After completion of the reaction, the compound () can be isolated according to a conventional method. Note that the compound having the general formula () which is the starting material of the present invention has the general formula [In the formula, R ¹ , R ² and R ³ have the same meanings as described above. ] or by oxidizing a compound having the general formula [In the formula, R ¹ and R ² have the same meanings as described above, and Z represents a chlorine atom or an alkoxy group. ] can be obtained by reduction or Grignard reaction. The compound having the general formula () obtained by the present invention is an important intermediate leading to carbapenem derivatives having strong antibacterial activity such as thienamycin.
In other words, the compound (
46265, JP-A-59-51286 or JP-A-60-16764
(No. Publication), carbapenem derivatives can be derived.
One method is shown in Figure 1, in which a compound (R ¹ : hydrogen atom) having the general formula () is reacted with acid chloride () to form a compound (), which is then reacted with triethyl phosphite. A carbapenem derivative is obtained. R ⁹ in the general formula () represents the above-mentioned protecting group for the carboxy group, and R ² , R ³ , R ⁸ and R ⁹ in the general formulas () and () have the same meanings as described above. The present invention will be specifically illustrated by giving examples below. Example 1 [3S-[3α-(S ^* ), 4β]]-1-(2,4-dimethoxybenzyl)-3-(1-t-butyldimethylsilyloxyethyl)-4-(2,2- Bisphenylthiovinyl)-2-azetidinone Under a nitrogen stream, butyl lithium (0.75 ml of a 1.6 M hexane solution) was added to a solution of diethyl di(phenylthio)methyl phosphonate (442 mg, 1.2 mmol) in tetrahydrofuran (10 ml) under ice cooling, and after stirring for 5 minutes, the aldehyde was dissolved. (407.4mg, 1.0mmol)
A solution of 100% in tetrahydrofuran (5 ml) was added dropwise.
After 30 minutes, warm to room temperature and stir for an additional 30 minutes. Dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate, and brine, and dry with MgSO ₄ . The solvent was distilled off under reduced pressure, and the remaining oil was subjected to silica gel TLC.
Purification was performed to obtain 511 mg (82%) of the desired product as a sticky oil. NMR spectrum (CDCl ₃ ) δppm: 0.04 (6H,
s), 0.84 (9H, s), 1.15 (3H, d, J=
6Hz), 2.80 (1H, dd, J=2,3Hz),
3.79 (6H, s), 4.22 (1H, dq, J=3,6
Hz), 4.23 (2H, s), 4.85 (1H, dd, J=
2, 9.5Hz), 5.77 (1H, d, J = 9.5Hz),
6.27-6.50 (2H, m), 7.03-7.25 (11H,
m). Elemental analysis value Actual value: C, 64.67; H, 7.35; N, 2.20; S,
10.04 Theoretical value: C, 65.66; H, 6.97; N, 2.25; S,
10.31% Reference example 1 [3S-[3α(S ^* ), 4α]]-1-(2,4-dimethoxybenzyl)-3-(1-hydroxyethyl)-
4-(phenylthiocarbonylmethyl)-2-azetidinone Vinyl sulfide (2) 100 mg CF ₃ COOH−H ₂ O
(2:1) 3 ml solution is stirred at room temperature for 2 hours.
Dilute with ethyl acetate, wash with sodium bicarbonate solution and brine, and dry with MgSO ₄ . The solvent is removed under reduced pressure to obtain crude crystals. Purification by silica gel chromatography yielded 24 mg (36%) of the desired product (3) and 7 mg of vinyl sulfide which had undergone only desilylation.
IR spectrum of compound (3) ν ^Nujol _nax cm ^-1 : 3310, 1777,
1745, 1633, 1618, 1588 NMR (CDCl ₃ ) spectrum δppm: 1.30 (3H,
d, J=6Hz), 2.12(1H, dd, J=8,
10Hz, _C3 - H ), 2.53 (1H, dd, J=6.5,
17Hz), 2.98 (1H, dd, J=6.5, 17Hz),
3.77 (1H, dt, J=8, 6.5Hz, _C4 -H),
3.78 (3H, s), 3.80 (3H, s), 4.1−4.8
(3H, m), 6.0-6.5 (2H, m), 7.0-7.3
(6H, m), MS spectrum m/e: 415 (M ⁺ ), 306,
260, 234,…. Example 2 [3S-[3α(S ^* ), 4β(E,S ^* )]]- and [3S-[
3α
(S ^* ), 4β(E,R ^* )]]-, and [3S-[3α(S ^* )
,
4β (Z, S ^* )]] - and [3S - [3α (S ^* ), 4β (Z,
R ^* )]-1-(2,4-dimethoxybenzyl)-3
-(1-t-butyldimethylsilyloxyethyl)
-4-(2-tetrahydropyranyloxy-2-
Mixture of phenylthiovinyl)-2-azetidinones. Under a nitrogen stream, diethyl (1-phenylthio-1
-tetrahydropyranyloxy)methylphosphonate (208 mg, 0.58 mmol) in tetrahydrofuran (5 ml) in butyl lithium (1.6 M, 0.8
ml) at -40°C. After 10 minutes, aldehyde (1)
Add 5 ml of tetrahydrofuran solution of Example 100,
Slowly heat up to room temperature. Dilute with ethyl acetate, wash with water, brine, and dry with _MgSO4 .
It was concentrated under reduced pressure, and the remaining oil was subjected to silica gel thin layer chromatography (cyclohexane:ethyl acetate=
After separation and purification (developed at a ratio of 2:1), R _f =
31 mg at 0.483 and 41 mg at R _f =0.250 were obtained as a 1:1 mixture of diastereomers. Yield 48%. Physical constant IR spectrum of R _f = 0.25 ν ^Liq _nax cm ^-1 : 1752, 1615,
1590 NMR spectrum ( _CDCl3 ) δppm: 0.02 (6H,
s), 0.83 (9H, s), 1.12 (1.5H, d, J
= 6Hz), 1.15 (1.5H, d, J = 6Hz),
1.47 (6H, m), 2.86 (1H, m), 3.4−3.8
(2H+6H, m (6H, s included in δ3.75)],
4.0−5.5 (6H, m), 6.2−6.5 (2H, m),
7.0-7.3 (5H+1H, m, 5H, s included in δ7.18). MS spectrum m/e: 557 (M ^{+ -But} ),
530, 474, 422,…. Reference example 2 [3S-[3α(S ^* ), 4β]]-1-(2,4-dimethoxybenzyl)-3-(1-tert-butyldimethylsilyloxyethyl)-4-phenylthiocarbonylmethyl- 2-azetidinone 28 mg of isomer (4) with R _f =0.48 obtained in Example 3
(0.046 mmol) in acetic acid-THF-water (4:2:1)
Dissolve in 1 ml and stir at room temperature for 4 hours. 17 mg (71%) of thioester was obtained by thin layer chromatography (cyclohexane: ethyl acetate = 2:1).
I got it. Similarly, compound (5) was obtained from (4) with R _f =0.25 in a yield of 64%. NMR spectrum (CDCl ₃ ) δppm: 0.02 (6H,
s), 0.80 (9H, s), 1.16 (3H, d, J=
6Hz), 2.72 (1H, dd, J=8, 15Hz),
3.08 (1H, dd, J=5, 15Hz), ) 2.96 (1H,
dd, J=3,4Hz), 3.83 (6H, s), 3.85
−4.25 (2H, m), 4.32 (2H, bs), 6.43
(1H, dd, J = 2,9Hz), 6.43 (1H, d,
J=2Hz), 7.12 (1H, d, J=9Hz),
7.38 (5H, s), IR spectrum ν ^Liq _nax cm ^-1 : 1750, 1700,
1612, 1588. MS spectrum m/e: 472 (M ^{+ -But} ),
152,…. Example 3 [3S-[3α(S ^* ), 4β]]-1-(2,4-dimethoxybenzyl)-3-(1-t-butyldimethylsilyloxyethyl)-4-vinyl-2-azetidinone Butyllithium in hexane (0.31ml, 0.5
To this was slowly added triphenylmethylphosphonium bromide (0.179 g, 0.5 mmol) and stirred at room temperature for 3 hours. Add aldehyde compound (1) to this reaction mixture under ice cooling.
(0.135 g, 0.33 mmol) in dry ethyl ether (1 ml) was added and refluxed for 3 hours. The reaction mixture was cooled with ice, diluted with ethyl acetate, insoluble materials were removed by filtration, washed with sodium hydrogen carbonate solution, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the residual oil was subjected to rapid chromatography using silica gel (13 g) to obtain cyclohexane-ethyl acetate (8:
2) to elute the desired vinyl compound (6).
Obtained 0.047 g (35%) as a colorless oil. IR spectrum ν ^Liq _nax cm ^-1 : 1750, 1615, 1510 NMR spectrum (CDCl ₃ ) δppm: 0.04 (6H,
s, Dimethyl), 0.82 (9H, s, tert-
Butyl) 1.17 (3H, d, J=6.5Hz, CH ₃ ),
2.80 (1H, dd, J=5Hz, 2Hz, 3-H),
3.7-4.3 (2H, m, 4-H, CH3CH- ₎ ,
3.78 (6H, s, OCH ₃ ), 4.05, 4.44 (2H,
ABq, J=15Hz, CH ₂ ), 4.93-6.07 (3H,
m, CH= _CH2 ), 6.25-6.52, 7.00-7.30
(3H, m, Phenyl) Example 4 [3S-[3α(S ^* ), 4β(E)]]- and [3S-(S ^*
),
4β(Z)]-1-(2,4-dimethoxybenzyl)
-3-(1-tert-butyldimethylsilyloxyethyl)-4-(2-phenylthiovinyl)-2-
Azetidinone To a solution of diethyl phenylthiomethyl phosphonate (0.13 g, 0.5 mmol) in dry tetrahydrofuran (2 ml) was added butyllithium (0.31 ml, 0.5 mmol) under ice cooling. Next, a solution of aldehyde compound (1) (0.135 g, 0.33 mmol) in dry tetrahydrofuran (1 ml) was added under ice 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, the mixture 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 residual oil was subjected to rapid chromatography using silica gel (20 g) and eluted with cyclohexane:ethyl acetate (2:1). 7) is 0.066g (39%), Z-form (8)
0.012 g (7%) was obtained as a colorless oil. E-form (7) IR spectrum ν ^Liq _nax cm ^-1 : 1760, 1610, 1510 NMR spectrum (CDCl ₃ ) δppm: 0.04 (6H,
s, Dimethyl), 0.81 (9H, s, tert-
Butyl), 1.16 (3H, d, J=6Hz, CH ₃ ),
2.78 (1H, dd, J=5Hz, 2.5Hz, 3H),
3.76 (6H, s, OCH ₃ ), 4.09, 4.40 (2H,
ABq, J=15Hz, CH ₂ ), 5.55 (1H, dd,
J = 9Hz, 15Hz, vinyl-H), 6.29 (1H,
d, J=15Hz, vinyl-H), 6.25-7.30
(3H, m, Phenyl), 7.25 (5H, s,
Phenyl) MS spectrum m/e: 513 (M ⁺ ), 456 (M -
57) Analysis Calculated value: C, 65.45; H, 7.65; N, 2.73; S,
6.24 Measured value: C, 65.37; H, 7.88; N, 2.71; S,
6.29 Z-form (8) IR spectrum ν ^Liq _nax cm ^-1 : 1750, 1650, 1510 NMR spectrum (CDCl ₃ ) δppm: 0.04 (6H,
s, Dimethyl), 0.82 (9H, s, tert-
Butyl), 1.16 (3H, d, J=6Hz, CH ₃ ),
2.78 (1H, m, 3-H), 3.70 (6H, s,
OCH ₃ ), 4.06, 4.33 (2H, ABq, J=14
Hz, CH ₂ ), 4.48 (1H, dd, J = 10Hz, 2
Hz, 4-H), 5.44 (1H, dd, J=10Hz,,
10Hz, vinyl-H), 6.12 (1H, d, J=10
Hz, vinyl-H), 6.10-7.30 (3H, m,
Phenyl), 7.15 (5H, s, Phenyl) Example 5 [3S-[3α(S ^* ), 4β(E)]]- and [3S-[3α(S ^*)
),
4β(Z)]-1-(2,4-dimethoxybenzyl)
-3-(1-t-butyldimethylsilyloxyethyl)-4-(2-chloro-2-phenylthiovinyl)-2-azetidinone mixture Diethyl (1-chloro-1-phenylthio)methyl phosphonate (0.195 g, 0.66 mmol)
Butyllithium (0.41 ml, 0.66 mmol) was added to a solution of dry tetrahydrofuran (3 ml) under ice cooling. Next, aldehyde compound (1) (0.135g,
0.33 mmol) of dry tetrahydrofuran (1
ml) solution was added under ice 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, the mixture 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 residual oil was subjected to rapid chromatography using silica gel (22 g) to obtain cyclohexane:ethyl acetate (8:
2). As a result, olefin compound E
0.08 g (44%) of a 1:1 mixture of and Z was obtained as a colorless oil. IR spectrum ν ^Liq _nax cm ^-1 : 1760, 1610,
1510, 835 NMR spectrum (CDCl ₃ ) δppm: 0.04 (6H,
s, Dimethyl (cis and trans)), 0.82 (9H, s,
tert-Butyl (cis and trans)) 1.15 (1.5H, d,
J=6.5Hz, _CH3 (cis or trans), 1.18
(1.5H, d, J = 6.5Hz, CH ₃ (cis or
trans)) 2.84 (1H, m, 3H, (cis and
trans)) 3.77 (6H, s, OCH ₃ (cis and
trans)), 3.9 to 4.35 (3H, m, CH ₂ , CH ₃
CH− (cis and trans)), 4.50 (0.5H, dd, J
=10Hz, 2Hz, 4-H (cis and trans)), 4.72
(0.5H, dd, J = 10Hz, 2Hz, 4-H (cis
or trans)), 4.72 (0.5H, dd, J=10Hz,
2Hz, 4-H (cis or trans)), 5.77
(0.5H, d, J=10Hz, vinyl-H (cis or
trans)), 5.96 (0.5H, d, J=10Hz,
vinyl-H (cis or trans), 6.25-7.30
(3H, m, phenyl (cis and trans)), 7.15 ~
7.30 (5H, m, phenyl (cis and trans) MS spectrum m/e: 548 (M ⁺ ), 4.91 (M-
57) Analysis Calculated value: C, 61.34; H, 6.99; N, 2.56; S,
5.85 Cl, 6.47 Measured value: C, 61.24; H, 7.26; N, 2.55; S,
6.18 Cl, 5.37 Example 6 [3S-[3α(S ^* ), 4β(E)]]- and [3S-[3α
(S ^* ),4β(Z)]]-1-(2,4-dimethoxybenzyl)-3-(1-tert-butyldimethylsilyloxyethyl)-4-(2-cyano-2-methoxyvinyl)- 2-azetidinone Diethyl (1-cyano-1-methoxy)methyl phosphonate 310 mg (1.5 mmol) under nitrogen stream
A solution of lithium hexamethyldisilazide (1.5 mmol) in tetrahydrofuran (2 ml) was added to a solution of lithium hexamethyldisilazide (1.5 mmol) in tetrahydrofuran (5 ml) at -78°C. Ten
After a few minutes, a solution of 407.4 mg (1.0 mmol) of aldehyde (1) in tetrahydrofuran (5 ml) was added at -78°C.
After 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, wash the organic layer with aqueous sodium bicarbonate and brine, and dry over Na ₂ SO ₄ . The solvent is distilled off, and the remaining oil is separated by silica gel thin layer chromatography. When developed with ethyl acetate: cyclohexane = 1:1, R _f ] 0.780 and 177 mg.
(38.4%) of one isomer of (11), R _f =0.440
284 mg (61.6%) of the other isomer of (11) was quantitatively obtained by combining both isomers. Physical constant IR spectrum of isomer with R _f = 0.780 ν ^Liq _nax cm ^-1 : 2220 (W), 1753,
1642, 1614, 1590 MS spectrum m/e: 460 (M ⁺ ), 445, 403 (M ⁺ -tBu) NMR spectrum (CDCl ₃ ) δppm: 0.03 (3H,
s), 0.05 (3H, s), 0.83 (9H, s), 1.12
(3H, d, J = 6Hz), 2.78 (1H, dd, J
=2.4Hz, _C3 -H), 3.64(3H,s),
3.86 (6H, s), 4.07 (1H, m), 4.19 (2H,
bs), 4.40 (1H, dd, J=2,9Hz, C ₄ −
H), 5.19 (1H, d, J=9Hz), 6.32 (1H,
d, J=2Hz), 6.32(1H, dd, J=2,
9Hz), 7.01 (1H, d, J = 9Hz) Physical constants of the isomer with R _f = 0.440 IR spectrum ν ^Liq _nax cm ^-1 : 2290 (w), 1752,
1638, 1614, 1590 MS spectrum m/e: 460 (M ⁺ ), 445, 403
(M ⁺ +tBu) NMR spectrum (CDCl ₃ ) δppm: 0.04 (3H,
s), 0.06 (3H, s), 0.85 (9H, s), 1.17
(3H, d, J = 6Hz), 2.80 (1H, dd, J
=2,4Hz), 3.38 (3H, s), 3.73 (3H,
s), 3.78 (3H, s), 4.11 (1H, m, C ₃ −
H), 4.21 (2H, bs), 4.38 (1H, dd, J=
2.10Hz, _C4 -H), 5.08 (1H, d, J=10
Hz), 6.32 (1H, d, J=2Hz), 6.32 (1H,
dd, J = 2,9Hz), 7.04 (1H, d, J =
9Hz) Reference example 3 [3S-[3α(S ^* ),4β]]-methyl[1-(2,4
-dimethoxybenzyl)-3-(1-hydroxyethyl)-2-azetidinone]-4-yldithioacetate (13) and [3S-[3α(S ^* ),4β]]-1-
(2,4-dimethoxybenzyl)-3-(1-hydroxyethyl)-4-(2-methylthio-2-azetoxymethylthiovinyl)-2-azetidinone (14) To a solution of 48 mg of acetoxymethyl compound (12) in methyl alcohol (2.5 ml) was added 1 ml of 20% hydrochloric acid, and the mixture was 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 gel thin layer chromatography (developing solvent: cyclohexane-ethyl acetate 1:9) to obtain 15 mg of dithioester compound (13) and the starting material desilylated compound (14). ) was obtained. Physical constants of dithioester compound (13) NMR spectrum (CDCl ₃ ) δppm: 1.12 (3H,
d, J = 6.5Hz, CH ₃ ), 2.59 (3H, s,
SCH ₃ ) 2.8~3.5 (3H, m, 3-H,
CH ₂ CS), 3.78 (3H, s, OMe), 3.81
(3H, s, OMe), 3.7~4.2 (2H, m, 4
−H, CH ₃ CH (OH)), 4.10, 4.51 (2H,
AB-q, J=14Hz, _NCH2 ), 6.3-7.2
(3H, m, phenyl) IR spectrum ν ^CHCL _3nax cm ^-1 : 3420, 1720,
1620, 1500 MS spectrum m/e: 369 (M ⁺ ) Physical constants of desilylated compound (14) NMR spectrum (CDCl ₃ ) δppm: 1.24 (3H,
d, J=6Hz, CH ₃ ), 1.99 (3H, s,
COCH ₃ ), 2.12 (3H, s, SCH ₃ ), 2.76−
2.95 (1H, m, 3H), 3.76 (6H, s,
OMe), 4.23 (2H, s, NCH ₂ ), 5.18 (2H,
s, SCH ₂ ), 5.48 (1H, d, J = 9.5Hz,
vinyl-H), 6.2-7.1 (3H, m, phenyl) MS spectrum m/e: 441 (M ⁺ )

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a protecting group or substituent for an amide NH group, R ² is a hydrogen atom or a hydroxyl protecting group, R ³ is a hydrogen atom, an alkyl group, or an aryl group, R ⁴ and R ⁵ are the same or different hydrogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, alkylthio groups, arylthio groups, heterocyclic thio groups, aromatic heterocyclic thio groups, sulfinyl groups, sulfonyl groups, alkoxycarbonyl groups, It represents an alkylthiocarbonyl group, an acyloxy group, an 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, R ¹ represents a hydrogen atom or a protecting group or substituent for an amide NH group, R ² represents a hydrogen atom or a substituent for a hydroxyl group, and R ³ represents a hydrogen atom, an alkyl group, or an aryl group. ] For compounds with the general formula [In the formula, R ⁴ and R ⁵ are the same or different hydrogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, alkylthio groups, arylthio groups, heterocyclic thio groups, aromatic heterocyclic thio groups, sulfinyl groups,
R ⁶ is a sulfonyl group, alkoxycarbonyl group, alkylthiocarbonyl group, acyloxy group, acylthio group, amino group, amide group, halogen atom, carboxy group, cyano group or nitro group,
It represents an alkyl group, an alkoxy group, an aryl group, an aryloxy group, or an amino group. ] Or general formula [In the formula, R ⁴ and R ⁵ have the same meanings as described above, R ⁷ represents an alkyl group or an aryl group,
X represents a halogen atom. General formula () characterized by reacting with Horner-Emmons reagent or Wittig reagent obtained by treating ] with a base. [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. ] A method for producing a compound having the following.