JPS6328063B2 - - Google Patents

Description

[Detailed description of the invention]

OBJECTS OF THE INVENTION The present invention relates to a method for producing a β-lactam compound having formula (1) (formula below). Recently, a method for synthesizing penem and carbapenem derivatives that exhibit excellent antibacterial activity against a wide range of disease-causing bacteria, including Gram-positive and Gram-negative bacteria, has been reported (Japanese Patent Application Laid-open No. 119486-1986; J.Am.Chem.Soc., 100 ,
313 (1978)). The inventors have conducted research and development on pharmaceuticals with antibacterial effects, and have completed the present invention by discovering that the compound having formula (1) is useful as an intermediate in the synthesis of penem and carbapenem derivatives. Structure of the invention The present invention is based on the general formula The present invention relates to a method for producing a β-lactam compound having the following. In the above formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ² represents a protecting group for a hydrogen atom or a nitrogen atom, and R ³ and R ⁴ are the same or different and are a hydrogen atom, a carboxyl group, a protected group. carboxyl group, acyl group, mercapto group, alkylthio group, arylthio group, alkylsulfinyl group,
It represents an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a cyano group or a nitro group. However, this excludes the case where R ³ and R ⁴ are both hydrogen atoms. In the general formula (1), R ¹ is preferably a hydrogen atom; an aliphatic acyl group such as formyl, acetyl, propionyl, n-butyryl, and isobutyryl;
Aromatic acyl groups such as benzoyl, 2-nitrobenzoyl, 4-nitrobenzoyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl; 2,2,2-trichloroethoxycarbonyl , halogeno-lower alkoxycarbonyl groups such as 2,2,2-tribromoethoxycarbonyl; aralkyl groups such as benzyl, 2-nitrobenzyl, and 4-nitrobenzyl;
Aralkyloxycarbonyl groups such as benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl; trilower alkylsilyl groups such as trimethylsilyl, dimethyl-tert-butylsilyl; 2-
Contains an oxygen or sulfur atom in the ring with or without a lower alkoxy group as a substituent such as tetrahydrofuranyl, 2-tetrahydropyranyl, 4-methoxytetrahydropyran-4-yl, 2-tetrahydrothiopyranyl 5 to 6
Member heterocyclic group; methoxymethyl, ethoxymethyl,
Lower alkyl groups having a lower alkoxy group or aralkyloxy group as a substituent such as 1-ethoxyethyl, benzyloxymethyl; lower alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl, n-propylthiomethyl, isopropylthiomethyl or benzylthiomethyl,
It represents an aralkylthiomethyl group such as 2-nitrobenzylthiomethyl, 4-nitrobenzylthiomethyl, and R ² is a hydrogen atom; benzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2, 4,5-trimethoxybenzyl,
3,4-dimethoxybenzyl, 4-hydroxy-
Such as 3,5-di-tert-butylbenzyl, 4-methoxy-3,5-di-tert-butylbenzyl, 4-hydroxy-3,5-dimethylbenzyl, 4-methoxy-3,5-dimethylbenzyl Aralkyl group; methoxy, ethoxy, n-propoxy,
Lower alkoxy groups such as isopropoxy; aryloxy groups such as phenoxy, 4-methoxyphenoxy, 4-nitrophenoxy; aralkyloxy groups or trimethylsilyl such as benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy , a tri-lower alkylsilyl group such as dimethyl-tert-butylsilyl, or 4
- represents an aryl group such as methoxyphenyl, 4-methoxymethyloxyphenyl, 2,4-dimethoxyphenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-nitrophenyl, and R ³ and R ⁴ are the same or Differently hydrogen atom; carboxyl group; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl; 2,2,2
-Trichloroethoxycarbonyl, 2,2,2-
Halogeno lower alkoxycarbonyl groups such as tribromoethoxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl; formyl, acetyl, propionyl, n-butyryl, isobutyryl; Aliphatic acyl groups such as hydroxyacetyl, methoxyacetyl, methoxymethoxyacetyl, 2-tetrahydropyranyloxyacetyl,
Aliphatic acyl groups having an optionally protected hydroxyl group such as benzyloxyacetyl; aromatic acyl groups such as benzoyl, 4-nitrobenzoyl, and 4-brombenzoyl; phenylacetyl,
Aroliphatic acyl groups such as 4-nitrophenylacetyl; mercapto groups; lower alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio; phenylthio, 2,5-
Arylthio groups such as dimethoxyphenylthio, 4-nitrophenylthio, 4-chlorophenylthio; lower alkyl groups such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl Sulfinyl group; arylsulfinyl group such as phenylsulfinyl, 2,5-dimethoxyphenylsulfinyl, 4-nitrophenylsulfinyl, 4-chlorophenylsulfinyl; methylsulfonyl, ethylsulfinyl, Lower alkylsulfonyl groups such as n-propylsulfonyl, isopropylsulfonyl; phenylsulfonyl, 2,5-
An arylsulfonyl group such as dimethoxyphenylsulfonyl, 4-nitrophenylsulfonyl, 2-cyanophenylsulfonyl, 4-chlorophenylsulfonyl; represents a cyano group or a nitro group. In the compound having the general formula (1) obtained by the present invention, the substituents bonded to the 3- and 4-positions of the azetidinone ring and the side chain

[Formula] Various stereoisomers exist depending on the arrangement of the groups. In the general formula (1), all of these isomers and mixtures of these isomers are represented by a single formula, but the scope of the description of the present invention is not limited thereby. Compound (1) according to the present invention has the general formula (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and X represents a halogen atom such as chlorine, bromine, or iodine.) Treating a compound having the following with a base. It can be obtained by In this reaction, compound (2)
When R ¹ is a hydrogen atom, compound (1) may be produced via epoxide (2'). This reaction is achieved by treating a compound having general formula (2) with a base in the presence of a solvent. The base used is not particularly limited, but includes alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal amides such as sodium amide and potassium amide, triethylamine, pyridine, and 1,5-diazabicyclo [4.3 .0] organic bases such as nonanene-5 (DBN), 1,5-diazabicyclo[5.4.0] undecene-5 (DBU), alkyl lithiums such as n-butyllithium, tert-butyllithium, lithium diisopropylamide Alternatively, lithium amide compounds such as lithium hexamethyldisilazide are suitable. The solvent used is benzene,
Aromatic hydrocarbons such as toluene, ethers such as ethyl ether, tetrahydrofuran and dioxane, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide,
Dimethyl sulfoxide and the like are preferred. Although the reaction temperature is not particularly limited, it is usually carried out at -50 to 100°C. The reaction time varies depending on the raw material compound and the type of base used, but is usually 1 to 24 hours. After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate to the reaction mixture, washing and drying the organic solvent layer, and then distilling off the solvent. Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below. 1-(2,4-dimethoxybenzyl)-3-
(1'-Hydroxyethyl)-4,4-bisethoxycarbonylazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-Hydroxyethyl)-4-tert-butoxycarbonylazetidin-2-one, 1-(4-methoxyphenyl)-3-(1'-hydroxyethyl)-4-tert-butoxycarbonylazetidine- 2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-Hydroxyethyl)-4-phenylsulfonylazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-tert-butyldimethylsilyloxyethyl)
-4-Phenylsulfonylazetidin-2-one, 1-(4-methoxymethyloxyphenyl)-3
-(1'-hydroxyethyl)-4-(4-nitrophenyl)azetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-acetoxyethyl)-4,4-bisethoxycarbonylazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-benzoyloxyethyl)-4-carboxyazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-benzyloxyethyl)-4-ethoxycarbonyl-4-methylsulfonylazetidine-2-
1-tert-butyloxy-3-(1'-tetrahydropyranyloxyethyl)-4-formyl-4-
Phenylsulfonylazetidin-2-one, 1-(4-methoxyphenyloxy)-3-
(1'-Trichloroethyloxycarbonyloxyethyl)-4-acetyl-4-cyanoazetidin-2-one, 1-tert-butyldimethylsilyl-3-[1'-
(2-nitrobenzyloxycarbonyl)oxyethyl]-4-phenylsulfinyl-4-phenylthio-azetidin-2-one, 1-trimethylsilyl-3-(1'-dimethyl-
tert-butylsilyloxyethyl)-4-nitro-4-methylthioazetidin-2-one, 1-(3,5-dimethyl-4-methoxybenzyl)-3-[1'-(4-nitrobenzyloxycarbonyl) oxy)ethyl]-4-nitroazetidin-2-one, 1-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-(1'-acetyloxyethyl)-4,4-bis Phenylsulfonylazetidin-2-one, 1-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-(1'-benzyloxyethyl)-4-ethoxycarbonyl-4-phenylsulfonyl Azetidin-2-one, 1-(3,5-di-tert-butyl-4'-hydroxybenzyl)-3-(1'-acetyloxyethyl)
-4-benzenesulfonylazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-Methylthiomethyloxyethyl)-4-benzenesulfonylazetidin-2-one, 1-(2-4-dimethoxybenzyl)-3-
(1'-benzyloxyethyl)-4-benzoylazetidin-2-one, 1-(2,4-dimethoxybenzyl)-3-
(1'-acetyloxyethyl)-4-benzoylazetidin-2-one. The compound having the general formula (2), which is the starting material for the production method of the present invention, can be produced, for example, by the method shown below. In the above formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described above. In other words, carboxylic acid derived from threonine
Compound (2) can be obtained by reacting (3) or a reactive derivative thereof such as acid chloride or acid bromide with amine derivative (4). When using carboxylic acid (3), a condensing agent such as dicyclocarbodiimide is used, and when using a reactive derivative thereof such as acid chloride, sodium hydride, sodium amide, sodium ethoxide, triethylamine, pyridine, DBU,
Compound (2) can be obtained by a conventional method using a base such as DBN, n-butyllithium, lithium diisopropylamide, or lithium hexamethyldisilazane. Effects of the Invention The compound (1a) obtained by the present invention can be converted into a carbapenem derivative (11) according to the formula shown below. In the above formula, R ⁵ represents a hydroxyl protecting group having the same meaning as R ¹ described above, R ⁶ represents a nitrogen atom protecting group having the same meaning as R ² described above, and R ⁷ represents methyl, ethyl, n-propyl, isopropyl, n-
Lower alkyl groups such as butyl, isobutyl,
Protecting groups for carboxyl groups such as halogeno lower alkyl groups such as 2,2,2-trichloroethyl and 2,2,2-tribromoethyl, and aralkyl groups such as benzyl, 2-nitrobenzyl and 4-nitrobenzyl. and X represents a halogen atom such as chlorine or bromine. The carboxyl group of compound (1a) is removed to form a compound
Compound (6) is obtained by removing the protecting group for the carboxy group of compound (5). When compound (6) is converted into acid chloride (7) and compound (7) is diazomethylated, diazoketone compound (8) is obtained. The alcohol compound (10) is obtained by converting the diazoketone compound (8) into a compound (9), reducing the carboxy group of the compound (9), and removing the protecting group for the nitrogen atom. This alcoholic substance is BGChristensen
(J.Am.Chem.Soc., 100 , 313 (1978))
Thienamycin exhibits excellent antibacterial activity according to
This can lead to (11). Moreover, the compound (1b) obtained by the present invention can be led to the penem derivative (20) according to the formula shown below. In the above formula, R ¹ , R ² and R ⁷ have the same meanings as described above. Hydrolysis of compound (1b) produces lactone form (12)
and carboxy form (13) are obtained. Lactone body (12)
is reacted with methylmagnesium to form a lactol compound (14), which is then reacted with trimethylsilyl chloride etc. in the presence of an alkali, and then the protecting group of the nitrogen atom is removed to obtain compound (15) (R ¹ : trimethylsilyl group, etc.) . Acetoxyazetidinone (16) is obtained by reacting compound (15) with a peracid (eg, peracetic acid, 3-chloroperbenzoic acid, etc.). On the other hand, protect the hydroxyl group of the previously obtained carboxy compound (13) to form compound (17), convert compound (17) into acid chloride, and then react this acid chloride with dimethyl cadmium to remove the protecting group on the nitrogen atom. Compound (18) (trans form of compound (15)) is then obtained. When compound (18) is reacted with peracid, acetoxyazetidinone (19) (trans isomer of compound (16)) is obtained. Cis and trans acetoxyazetidinones (16) and (19) can be converted to penem derivatives (20) according to the method of RB Woodward et al. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 1-(2,4-dimethoxybenzyl)-3-
(1'-acetoxyethyl)-4,4-bisethoxycarbonylazetidin-2-one 254 g of α-bromamide obtained in Reference Example 1 was
1.6 of benzene and additionally 76 g of diazabicyclo[5.4.0]undecene-5 (DBU).
Add 200ml of benzene solution and leave at room temperature overnight. Remove precipitated DBU and hydrobromide,
Add 2 portions of ethyl acetate to the solution, wash with 10% hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, and dry over anhydrous magnesium sulfate. After decolorizing with activated carbon, the solvent was removed to obtain 206.5 g of the desired product as an oil. IR (film) 1778, 1747cm ^-1 NMRδ (CDCl ₃ ) 1.10 (3H, t, J = 7Hz) 1.15 (3H, t, J = 7Hz) 1.37 (3H, d, J = 6Hz) 1.93 (3H, s) 3.76 (6H, s) 3.7~4.4 (5H, m) 4.44 (2H, bs) 5.20 (1H, m) 6.45 (2H, m) 7.14 (1H, d, J=9Hz) MS m/e451 (M ⁺ ) Example 2 (1'R, 3S, 4S)-tert-butyl 1-(2,4-
dimethoxy)benzyl-3-(1'-hydroxy)
Ethyl-2-azetidinone 4-carboxylate (a) Hydroxybromine compound obtained in Reference Example 2
2.2 mmol of LiN(SiMe ₃ ) ₂ was added to 446.4 mg (1.0 mmol) of 8 ml of THF solution at 0℃ under nitrogen flow.
When half (3 ml) of the TEF 6 ml solution is added and stirred for 15 minutes, the raw material completely disappears and changes to the intermediate epoxide. (Confirmed by TLC) Add the remaining 3 ml to 20°C.
Add and keep for 20 minutes. Acidify with dilute hydrochloric acid, dilute with ethyl acetate, wash with aqueous sodium bicarbonate solution and saturated brine, and dry over magnesium sulfate. The solvent was distilled off and the product was purified by silica gel chromatography to obtain 185 mg (50.6%) of the desired product. In addition, after removing the intermediate epoxide, LiN was applied to this epoxide under the same conditions.
Exactly the same result is obtained when (SiMe ₃ ) ₂ is used. NMRδ (CDCl ₃ ) 1.23 (3H, d, J=6Hz), 1.45 (9H, s),
2.83 (1H, bs, OH), 3.10 (1H, dd, J=
2.5, 4Hz), 3.79 (6H, s), 3.88 (1H, d,
J=2.5Hz), 4.11 (1H, m), 4.14, 4.61 (2H,
AB-q, J=14Hz), 6.40(1H, dd, J=
2,9Hz), 6.41 (1H, d, J=2Hz), 7.11
(1H, d, J=14Hz) IRν _nax (film): 3430, 1760, 1745, 1615, 1590
cm ^-1 MS m/e: 365 (M ⁺ ), 337, 321, 309, 265,
237, ......, 153 [α] ²⁴ _D + 20.1゜ (c2.25, CHCl ₃ ) (b) In the reaction of (a) above, add the remaining 3 ml of LiN (SiMe ₃ ) ₂ to the intermediate epoxide The THF solution was cooled to -78°C, stirred for 3 hours, and treated in the same manner as in (a) to obtain 196 mg of epoxide, 12 mg of cis-isomer, and 91 mg of desired trans-isomer. The physical constants of the cis-isomer and epoxide are listed below. cis-isomer NMRδ ( _CDCl3 ) 1.38 (3H, d, J=6Hz), 1.53 (9H, s),
2.60 (1H, bs, OH), 3.30 (1H, dd, J=
5.5, 10Hz), 3.81 (6H, s), 3.95 (1H, d,
J=5.5Hz), 4.12, 4.69(2H, AB−q, J=
14Hz), 6.43 (1H, dd, J=2, 9Hz), 6.45
(1H, d, J=2Hz), 7.12 (1H, d, J=
9Hz) IRν _nax (film): 3430, 1760, 1745, 1615, 1590
cm ^-1 MS m/e: 365 (M ⁺ ), 337, 321, 309, 153 [α] ²⁵ _D +13.1° (c0.75, CHCl ₃ ) Epoxide NMRδ (CDCl ₃ ) 1.36 (3H, d, J=6Hz), 1.44 (9H, s),
3.32 (1H, quintet, J=5Hz), 3.81 (6H,
s), 3.81 (1H, d, J=5Hz), 3.70, 4.18
(2H, AB-q, J=16Hz), 4.59 (2H, s),
6.45 (1H, dd, J=2, 9Hz), 6.47 (1H, d,
J=2Hz), 7.05 (1H, d, J=9Hz) IRν _nax (film): 1745, 1665, 1615, 1590cm ^-1 MS m/e365 (M ⁺ ) [α] ²⁴ _D +60.8° (c2. 00, CHCl ₃ ) Example 3 (3S,1′R)-3-(1′-tert-butyldimethylsilyloxy)ethyl-4,4-dicarboethoxy-1-(2,4-dimethoxy)benzyl-
2-Azetidinone Butyrylamide obtained in Reference Example 6 (261.5g,
0.43mol) of dry tetrahydrofuran (THF,
1.5) A solution of DBU (65.9 g, 0.43 mol) in dry THF (500 ml) was added to the solution at room temperature and left overnight. removing the hydrobromide salt of DBU from the reaction mixture;
After washing the hydrobromide salt with dry THF, the liquid was evaporated under reduced pressure. The oily residue was then diluted with ethyl acetate (1.3), washed sequentially with saturated copper sulfate solution, saturated sodium bicarbonate solution, and brine, and dried over magnesium sulfate. After treatment with activated carbon, the magnesium sulfate was removed and the solvent was evaporated under reduced pressure, yielding 210 g (93%) of 4,4-dicarboethoxyazetidinone compound as an oil.
Obtained. [α] ²⁵ _D = +28.51° (c2.55, CHCl ₃ ) NMR (CDCl ₃ ) δ: 0.08 (6H, s), 0.88 (9H, s), 1.04 (3H, t,
J=7Hz), 1.26 (3H, t, J=7Hz), 1.32
(3H, d, J=6Hz), 3.80 (6H, s), 4.14
(2H, q, J=7Hz), 4.20 (2H, q, J=7
Hz), 4.50, 4.80 (2H, AB-q, J=14Hz),
6.40 (1H, dd, J=2, 9Hz), 6.40 (1H, d,
J=2Hz), 7.12 (1H, d, J=9Hz), 3.6~
4.4 (1H, m) Example 4 (3S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-acetoxy)ethyl-4,4-
Dicarboethoxy-2-azetidinone α-bromoamide obtained in Reference Example 11 (396 g,
DBU in a solution of 0.744 mol) of special grade benzene (2.5 mol)
A solution of (119 g, 0.744 x 1.05 = 0.781 mol) in special grade benzene (300 ml) was added at 15°C (about 5 minutes) and left overnight at room temperature. After the addition, precipitation of DBU/hydrobromide was observed while increasing the temperature to room temperature.
Next, DBU/hydrobromide was filtered through a glass filter, and the hydrobromide was washed twice with ethyl acetate. This solution was diluted once with 10% hydrochloric acid (400ml×
1), washed once with saturated aqueous sodium bicarbonate solution and once with brine, and dried over magnesium sulfate. After treatment using a slightly thicker activated carbon, the magnesium sulfate and activated carbon were removed, and the solvent was evaporated under reduced pressure at a bath temperature of 40°C. The residual oil was sufficiently dried to obtain 332 g of the desired diester of azetidinone. Yield 98.7% Thin layer chromatography: cyclohexane/ethyl acetate = 6/4R _f = 0.5 [α] ²⁴ _D = +39.5° (c, 2.03・EtOH) NMR (CDCl ₃ ) δppm: 1.15 (3H, t , J=7Hz), 1.20(3H, t, J=
7Hz), 1.94 (3H, s), 3.78 (6H, s), 3.7−
4.4 (5H, m), 4.54 (2H, bs), 4.8−5.3 (1H,
m), 6.3-6.6 (2H, m), 7.0-7.2 (1H, d, J
=9Hz) Reference example 1 N-diethylmalonyl-N-(2,4-dimethoxybenzyl)-1-bromo-2-acetoxybutyramide Diethylmalonyl-2,4-dimethoxyamine
A solution of 132 g (0.54 mol) of erythro-β-acetoxy-α-brombutyryl chloride in 200 ml of THF is added to a solution of 160 g (0.49 mol) of THF 1.4 at room temperature. Add 55g of triethylamine to this mixed solution.
(0.54 mol) in 200 ml of THF is gradually added while stirring under water cooling (approximately 15°C). Triethylamine hydrochloride precipitates immediately. Leave to stand at room temperature overnight to remove triethylamine hydrochloride, and remove the solution under reduced pressure.
Concentrate to 800ml at a bath temperature of 40℃ or less. 1.5 for this
of ethyl acetate, washed twice with 10% hydrochloric acid, aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The solvent was removed under reduced pressure to obtain 254 g of the desired product. IR (film) 1747, 1670, 1613, 1590 cm ^-1 NMR δ (CDCl ₃ ) 1.14 (6H, t, J = 7Hz), 1.40 (3H, d, J =
6Hz), 2.03 (3H, s), 3.72 (3H, s), 3.76
(3H, s), 3.7-4.3 (2H+1H, m), 4.60 (2H,
bs), 4.88 (1H, s), 5.31 (1H, m), 6.32~
6.55 (2H, m), 7.18 (1H, d, J = 11Hz) Reference example 2 (2S,3R)-N-tert-butoxycarbonylmethyl-N-(2,4-dimethoxy)benzyl-
2-bromo-3-hydroxybutyrylamide (2S,3R)-2-bromo-3-hydroxybutyric acid, 1.83 g (10 mmol) and tert-butoxycarbonylmethyl-(2,4-dimethoxy)benzylamine 2.81 g (10 mmol) ) was dissolved in 30 ml of THF, and 2.06 g (10 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) was added at room temperature.
Stir for 15 minutes. Remove the precipitated DCC・H ₂ O,
The liquid was concentrated and purified by silica gel column chromatography (hexane-ethyl acetate 2:1 elution) to obtain 3.85 g (yield: 86%) of the desired product. IRν _nax (film) 3430, 1740, 1640, 1615, 1590cm
^-1 NMRδ (CDCl ₃ ) 1.28 (3H, d, J=6Hz), 1.45 (9H, s),
3.81 (6H, s), 3.9~5.0 (6H, m), 6.35~6.6
(2H, m), 7.05 (1H, d, J = 8.5Hz) MS m/e447 (M ⁺ , ⁸¹ Br) 445 (M ⁺ , ⁷⁹ Br),
366, 348, 293, 281,……. Reference example 3 (2R,3R)-2-bromo-3-hydroxybutyric acid 1.25M sulfuric acid (4.3 ) was added to this solution, and then sodium nitrite (228 g, 2.07 x 1.6
= 3.31 mol) of crystals were gradually added. The ice bath was removed, the temperature was raised to 15°C, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was saturated with sodium chloride, extracted four times with ethyl ether, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure at a bath temperature of 40°C or less.
After thorough drying using a vacuum pump, 286 g (75%) of a yellow oily bromide compound was obtained. NMR ( _CDCl3 ) δ: 1.45 (3H, d, J=6Hz), 4.0-4.5 (2H, m),
7.3 (2H, s, OH, COOH) Reference example 4 (2R,3R)-2-bromo-3-tert-butyldimethylsilyloxybutyric acid The 3-hydroxy compound obtained in Reference example 3 (91.5 g, 0.5 mol) Mix tert-butyldimethylsilyl chloride (166 g, 0.5 x 2.2 = 1.1 mol) in dry dimethylformamide (300 ml) solution,
Triethylamine (109 g, 0.5×
2.15=1.08mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (2.2), saturated copper sulfate solution, water,
Each was washed with saline and dried over magnesium sulfate. Next, remove the magnesium sulfate,
The solvent is evaporated under reduced pressure, and then the dimethylformamide is distilled off by thorough evaporation under reduced pressure at a bath temperature of 60 to 65°C.
g (quantitative) obtained. NMR (CDCl ₃ ) δ: 0.10 (6H, s), 0.98 (9H, s), 1.36 (3H, d,
J=6Hz), 3.9-4.5 (2H, m) Reference Example 5 (2R,3R)-2-Bromo-3-tert-butyldimethylsilyloxybutyryl chloride Carboxylic acid obtained in Reference Example 4 (158g,
Oxalyl chloride (174.6 g, 0.53×
2.6=1.38 mol), a small amount (1 drop with a pipette) of dimethylformamide was added and the mixture was refluxed for 3 hours. After cooling the reaction mixture, the target acid chloride compound was evaporated under reduced pressure at a bath temperature of 30°C.
g (81%) was obtained. NMR (CDCl ₃ ) δ: 0.1 (6H, s), 0.86 (9H, s), 1.38 (3H, d,
J=6Hz), 4.1-4.6 (2H, m) Reference example 6 (2R,3R)-2-bromo-3-tert-butyldimethylsilyloxy-N-(2,4-dimethoxy)benzyl-N-diethylmalonyl Butyramide diethyl N-2,4-dimethoxybenzylaminomalonate (115.6g, 0.36mol) in dry THF
Bromobutyryl chloride (112.1 g,
A solution of 0.36 mol) in dry THF (100 ml) was mixed at once. Next, triethylamine (35.9 g, 0.36 mol) was added to dry THF (100 ml) while maintaining the reaction temperature at 15°C.
solution was added. After stirring the reaction mixture at room temperature for 1.5 hours, the hydrochloride was removed, the hydrochloride was washed with dry THF, and the solvent was evaporated under reduced pressure at a bath temperature of 40°C or less. This oily residue was diluted with ethyl acetate (1.3), diluted hydrochloric acid (<10%), saturated sodium bicarbonate,
Each was washed with saline solution and dried with magnesium sulfate. The magnesium sulfate was removed and the solvent was evaporated under reduced pressure at a bath temperature of 40° C. or less to obtain 220 g of the target butyrylamide compound as a black oil. Melting point 89-90℃ (ethanol) [α] ²⁵ _D = -17.7゜ (c1.0, CHCl ₃ ) NMR (CDCl ₃ ) δ: 0.1 (6H, s), 0.9 (9H, s, tBu (CH ₃ ) _2- ),
1.06 (3H, t, J=7Hz, CH ₃ CH ₂ −), 1.25
(3H, t, J=7Hz), 1.34 (3H, d, J=6
Hz), 3.78 (3H, s), 3.80 (3H, s), 3.9−4.5
(1H, m), 4.20 (2H, q, J=7Hz), 4.22
(2H, q, J=7Hz), 4.69 (2H, s), 5.62
(1H, s), 6.38 (1H, dd, J=2, 9Hz),
6.38 (1H, d, J = 2Hz), 7.22 (1H, d, J =
9Hz) Reference example 7 (2R,3R)-2-bromo-N-(2,4-dimethoxybenzyl-N-diethylmalonyl-3-
Hydroxybutyrylamide Silyl compound obtained in Reference Example 6 (3.18g,
To a solution of 5.26 mmol) in ethanol (200 ml) was added 10% hydrochloric acid (80 ml) under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residual oil was subjected to rapid chromatography on silica gel (135 g), eluting with cyclohexane-ethyl acetate (6-4). As a result, 1.4g of the desired hydroxy compound
(54%) obtained. IRν _nax (film): 3500, 1750, 1660, 1620, 1590cm
^-1 NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7Hz), 1.22 (3H, t, J =
7Hz), 1.40 (3H, d, J = 6Hz), 3.78 (3H,
s), 3.8-4.6 (1H, m), 3.82 (3H, s), 4.07
(2H, q, J=7Hz), 4.10 (2H, q, J=7
Hz), 4.40 (1H, d, J=4Hz), 4.24, 4.85
(2H, ABq, J=16Hz), 4.62 (1H, s), 6.40
(1H, dd, J = 2, 9Hz), 6.40 (1H, d, J
= 2 Hz), 7.12 (1H, d, J = 9 Hz) Reference example 8 (2R, 3R)-2-bromo-3-hydroxybutyric acid (2R, 3R)-threonine (300 g, 2.52 mol)
and potassium bromide (1050 g, 2.52 x 3.5 = 8.82 mol) under ice-cooling.
) was added. Crystals of sodium sulfite (278 g, 2.52 x 1.6 = 4.03 moles) were added to this ice-cold solution over 90 minutes. During that time, the temperature rose from 0°C to 14°C, and NO ₂ gas was generated intensely. The ice bath was removed, the temperature was raised to 15°C, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was saturated with common salt (2 Kg) (NO ₂ gas generation) and extracted four times with ethyl ether (1.2
4) It was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure at a bath temperature of 40°C or less. When thoroughly dried with a vacuum pump, the yellow oily bromide becomes 350
g was obtained. Yield 84.1%. Reference Example 9 (2R,3R)-2-bromo-3-acetoxybutyric acid Bromide obtained in Reference Example 8 (350 g, 1.91
Acetyl chloride (345 g, 1.91 x 2.3 = 4.39 mol) was mixed with dry methylene chloride (1) (mol), and pyridine (325 g, 1.91 x
2.15 = 4.11 mol) of dry methylene chloride (1) solution was added dropwise (temperature, 5-12°C, dropwise addition time 50 minutes),
The mixture was stirred for 1 hour each on ice and at room temperature. The reaction mixture was washed (1 x 1) with dilute hydrochloric acid (concentrated hydrochloric acid/water = 1/2), washed with water (500 ml x 1), and dried over magnesium sulfate. Next, methylene chloride was evaporated under reduced pressure at a bath temperature of 40° C. or lower, and then 1.5 liters of a 1/1 mixture of THF/water was added and stirred at room temperature for 4 hours. From reaction solution to bath temperature
THF was evaporated under reduced pressure at 30°C, and the aqueous layer was saturated with sodium chloride (300 g), extracted three times with ethyl ether (500 ml x 3), washed once with brine, and dried over sodium sulfate. strained with sodium sulfate;
After the solvent was evaporated under reduced pressure at a bath temperature of 30°C, chloroform was added and acetic acid was azeotropically removed (500ml x 3) and thoroughly dried to obtain 406.5g of the desired product. NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 6Hz), 2.06 (3H, s),
4.35 (1H, d, J = 7Hz), 5.25 (1H, q, d,
J = 6, 7Hz), 8.36 (1H, s) [α] ²⁴ _D = +9.54° (c1.87・EtOH) Reference example 10 (2R, 3R)-2-bromo-3-acetoxybutyryl chloride Reference Carboxylic acid obtained in Example 9 (445 g, 1.98
865 g of thionyl chloride (1.98 x 3.67 = 7.27 mol) is added to a solution of 2 to 3
The mixture was added dropwise at a speed of 1 minute, and then refluxed for 8 hours. A ratio of methylene chloride/thionyl chloride = 3/1 was an appropriate temperature for the reaction to proceed. Moreover, more than an equivalent amount of thionyl chloride was required. Next, the solvent, hydrogen chloride, thionyl chloride, etc. were evaporated from the reaction mixture using a water jet vacuum pump, and after almost evaporation, benzene was added and azeotroped twice. This product was sufficiently dried using a vacuum pump to obtain 427 g of the target acid chloride. Yield 88.7%. NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 6Hz), 2.07 (3H, s),
4.60 (1H, d, J=8Hz), 5.26 (1H, q, d,
J=6,8Hz). Reference example 11 (2R,3R)-N-(2,4-dimethoxybenzyl)-N-diethylmalonyl-2-bromo-3
-acetoxybutyrylamide diethyl N-2,4-dimethoxybenzylaminomalonate (266 g, 0.867 x 0.944 = 0.818 mol)
A dry THF solution of acetoxybromobutyryl chloride (211 g, 0.867 mol) obtained in Reference Example 10 was added all at once to a dry THF (2.3) solution of the above while cooling to 15°C. The temperature at this time rose to 28℃. A dry THF solution of triethylamine (87.7 g, 0.867 mol) was then added dropwise over 40 minutes while maintaining the reaction temperature at 13-15°C. Triethylamine hydrochloride precipitated with the addition, and there was almost no rise in temperature. Further, triethylamine and butyryl chloride were added in an equimolar amount, and care was taken not to add too much triethylamine. After the reaction mixture was left at room temperature overnight (3
The hydrochloride was filtered through a glass filter, washed with dry THF 2 to 3 times with gentle suction, and then the solvent was evaporated under reduced pressure at a bath temperature of 40° C. or less. Concentrate to approximately 1.3, dilute with ethyl acetate (2.4), and add dilute hydrochloric acid (<10
%) twice (250 ml x 2), twice with an aqueous sodium bicarbonate solution, and once with brine, and dried over sodium sulfate. The sodium sulfate was removed and the solvent was evaporated under reduced pressure at a bath temperature of 40° C. or lower to obtain 431 g of the desired product. Yield 93.5%. *100ml of concentrated hydrochloric acid
+400ml of water. Reference example 12 1-(2,4-dimethoxybenzyl)-3-
(1'-acetoxyethyl)-4-ethoxycarbonyl-4-carboxyazetidin-2-one 206 g of diethyl ester obtained in Example 1
(0.456 mol) in 250 ml of pyridine. Add 500 ml of 1N sodium hydroxide and stir under ice cooling.
This mixture is left at 0°C overnight. Add 300 ml of sodium bicarbonate solution to this reaction mixture, wash twice with 1 portion of ethyl acetate,
To recover unreacted raw materials, the ethyl acetate layer was
After washing with % hydrochloric acid and saturated saline, drying with anhydrous magnesium sulfate, decolorizing with activated carbon, and removing the solvent, 82 g of raw material is recovered. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried over anhydrous magnesium sulfate.
After removing the solvent, 120 g of oily target material is obtained. IRν _nax (film) 1750 (broad) cm ^-1 NMRδ (CDCl ₃ ) 0.93 (3H, t, J = 7Hz), 1.33 (3H, d, J =
6Hz), 1.89 (3H, s), 3.66 (3H, s), 3.76
(3H, s), 3.6-4.1 (3H, m), 4.28, 4.57
(2H, AB-q, J=15Hz), 5.08 (1H,
quintet, J=6Hz), 6.36 (1H, s), 6.35
(1H, d, J=2Hz), 6.43 (1H, dd, J=2,
9Hz), 7.19 (1H, d, J = 9Hz), 7.67 (1H,
bs) MS m/e423 (M ⁺ ), 379 (M ⁺ , -CO ₂ ) Reference example 13 1-(2,4-dimethoxybenzyl)-3-
(1'-acetoxyethyl)-4-ethoxycarbonylazetidin-2-one 0.1 ml of pyridine was added to 756 mg of the carboxylic acid obtained in Reference Example 12, and the mixture was heated at 140°C for 30 minutes. Add ethyl acetate, wash with 10% hydrochloric acid, sodium bicarbonate solution, and saline solution.
Dry with anhydrous magnesium sulfate. Removal of ethyl acetate leaves an oil. Two types of isomers are separated from this oil by thin layer silica gel chromatography. When separated with benzene-ethyl acetate (3:1), the cis-isomer has a higher R _f value (0.39).
308 mg, R _f value, smaller (0.28) trans-isomer
Get 168mg. Write down the physical constants for each. cis-isomer: NMRδ ( _CDCl3 ) 1.20 (3H, t, J=7Hz), 1.33 (3H, d, J=
6.5Hz), 1.90 (3H, s), 3.42 (1H, dd, J=
6, 11Hz), 3.73 (3H, s), 3.77 (3H, s),
3.97 (1H, d, J = 6Hz), 4.08 (2H, q, J =
7Hz), 4.08, 4.56 (2H, AB-q, J=15Hz),
5.13 (1H, qd, J=6.5, 11Hz), 6.42 (1H, dd,
J = 2, 9Hz), 6.43 (1H, d, J = 2Hz),
7.10 (11H, d, J = 9Hz) IR (film) ν _nax 1768, 1748, 1615, 1590 cm ^-1 MS m/e379 (M ⁺ ) trans-isomer: NMRδ (CDCl ₃ ) 1.23 (3H, t, J =7Hz), 1.28(3H, d, J=
6.5Hz), 1.88 (3H, s), 3.21 (1H, dd, J=
2.5, 6.5Hz), 3.79 (6H, s), 3.87 (1H, d, J
= 2.5Hz), 4.14, 4.65 (2H, AB-q, J = 15
Hz), 4.21 (2H, q, J=7Hz), 5.20 (1H,
quintet, J=6.5Hz), 6.44(1H, dd, J=3,
9Hz), 6.47 (1H, d, J=3Hz), 7.15 (1H,
d, J = 9Hz) IR (film) ν _nax 1765, 1740, 1615, 1590cm ^-1 MS m/e = 379 (M ⁺ ) Reference example 14 trans-1-(2,4-dimethoxybenzyl)
-3-(1'-acetoxyethyl)-4-carboxyazetidin-2-one obtained as described in Reference Example 13,
Dissolve 229 mg of trans-isomer in 3 ml of pyridine.
Add 6 ml of 0.1N sodium hydroxide dropwise at 0°C.
Stir for 1 hour and leave at 0°C overnight. Add ethyl acetate and extract the acidic part with aqueous sodium bicarbonate. 71 mg of starting material is recovered from the neutral portion. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. Wash with saturated saline and dry with anhydrous magnesium sulfate. 160 excluding solvent
mg of target product is obtained. NMRδ (CDCl ₃ ) 1.29 (3H, d, J=6.5Hz), 1.85 (3H, s),
3.39 (1H, dd, J=2, 6.5Hz), 3.78 (6H,
s), 3.98 (1H, d, J=2Hz), 4.16, 4.68
(2H, AB-q, J=15Hz), 5.25 (1H,
quintet, J=6.5Hz), 6.47(1H, dd, J=2,
9Hz), 6.51 (1H, d, J=2Hz), 7.20 (1H,
d, J=9Hz), 10.45 (1H, bs) IR (film) ν _nax 3500-2400, 1740 (broad) cm ^-1 Reference example 15 trans-1-(2,4-dimethoxybenzyl)
-3-(1'-acetoxyethyl)-4-(1-oxo-2-diazoethyl)azetidin-2-one 160 mg of the carboxylic acid obtained in Reference Example 14 was added to THF4
ml, add 0.15 ml of oxalyl chloride, and reflux for 1 hour. The solvent was removed under reduced pressure, and the remaining oil was dissolved in 4 ml of THF and added dropwise to an ice-cooled ethereal solution of excess diazomethane with stirring. After dropping, stir at room temperature for 30 minutes and remove the solvent under reduced pressure to obtain an oil. Purify by thin layer chromatography (benzene-ethyl acetate = 2-
Expand in 1. ) and the desired diazoketone is 114
Obtained as mg crystals. Melting point 69.5-71℃ NMR δ (CDCl ₃ ) 1.25 (3H, d, J = 6.5Hz), 1.87 (3H, s),
3.17 (1H, dd, J=2.5, 6.5Hz), 3.76 (6H,
s), 4.06, 4.56 (2H, AB-q, J=15Hz),
5.13 (1H, quintet, J = 6.5Hz), 5.35 (1H,
s), 6.4-6.6 (2H, m), 7.15 (1H, d, J=
9Hz) Elemental analysis value C ₁₈ H ₂₁ O ₆ N ₃ Calculated value: C, 57.59; H, 5.64; N, 11.20 Actual value: C, 57.61; H, 5.62; N, 11.22 Reference example 16 Trans-1-( 2,4-dimethoxybenzyl)
-3-(1'-acetoxyethyl)-4-carboxymethylazetidin-2-one 82 mg of the diazoketone obtained in Reference Example 15 was dissolved in 3 ml of dioxane and 3 ml of water in a Pyrex test tube, and heated to 75 ml with a high-pressure mercury lamp (450 W). Irradiate with light for 1 minute under water cooling. Add ethyl acetate and extract the acidic part with baking soda. The aqueous layer is acidified with hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent, 82 mg of crystals are obtained. Melting point 109.5-110.5℃ (recrystallized from ethyl acetate) IRν _nax (Nujol) 1735, 1704, 1615, 1587 cm ^-1 NMRδ (CDCl ₃ ) 1.32 (3H, d, J = 6.5Hz), 2.46 (1H, dd, J
= 8.5, 16Hz), 2.81 (1H, dd, J = 4.5, 16Hz),
3.06 (1H, dd, J=1.5, 8Hz), 3.71 (1H,
ddd, J=1.5, 4.5, 8.5Hz), 3.82 (3H, s),
3.84 (3H, s), 4.10, 4.52 (2H, AB-q, J
= 15Hz), 5.16 (1H, dq, J = 8, 6.5Hz), 6.46
(1H, dd, J = 25, 9Hz), 6.47 (1H, d, J
= 2.5Hz), 7.17 (1H, d, J = 9Hz) Elemental analysis value C ₁₈ H ₂₃ O ₇ N Calculated value: C, 59.18; H, 6.33; N, 3.83 Actual value: C, 59.11; H, 6.29 ;N, 3.96 Reference example 17 (3R,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-acetoxyethyl)-4-
Carboethoxy-4-carboxy-2-azetidinone Diester obtained in Example 4 (331.2g,
An ice-cold 1N aqueous sodium hydroxide solution (749 ml, 0.734 x 1.02 = 0.749 mol) was added to a solution of 0.73 mol) in pyridine (375 ml) under ice cooling (below 6°C). The addition temperature at this time is kept at 4-6℃ for 1 hour.
It took me 40 minutes to add it. After the addition, the mixture was stirred on ice for 30 minutes and left overnight at 0°C (refrigerator). Add more than half of the pyridine from the reaction mixture to a bath temperature of 40°C.
After evaporating under reduced pressure with
Pyridine as a raw material was removed by washing. The aqueous layer was made acidic (PH-1) with concentrated hydrochloric acid (approximately 250 ml), saturated with sodium chloride (700 g), extracted with ethyl acetate three times (750 ml x 3), washed with brine,
Dry with magnesium sulfate. The magnesium sulfate was separated and the liquid was evaporated under reduced pressure at a bath temperature of 60°C to obtain 197.5 g of a mixture of the desired product as a viscous oil and a small amount of lactonized carboxylic acid. Yield 62.4%. Thin layer chromatography: n-butanol/acetic acid/water = 4/1/1, R _f = 0.7 [α] ²⁵ _D = +37.3° (c2.136・EtOH) IR (CHCl ₃ ) cm ^-1 : 1710, 1770 NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 8Hz), 1.38 (3H, d, J =
6Hz), 1.95 (3H, s), 3.66 (3H, s), 3.76
(3H, s), 3.6-4.1 (2H+1H, m), 4.28,
4.58 (2H, ABq, J=15Hz), 4.8−5.3 (1H,
m), 6.3-6.6 (2H, m), 7.12 (1H, d, J=
9Hz), 8.60 (1H) Reference example 18 (3S,4R,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-acetoxyethyl)-4-
Ethoxycarbonyl-2-azetidinone.
(3S,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-acetoxyethyl)-4-
Ethoxycarbonyl-2-azetidinone.
(1S,4R,5S)-2,6-dioxo-4-methyl-(2,4-dimethoxybenzyl)-3-oxa-7-azabicyclo[3.2.0]heptane-1
-Carboxylic acid Acetoxycarboxylic acid (183.5 g) containing a small amount of lactone carboxylic acid obtained in Reference Example 17 was dissolved in 2,4,6-collidine (740 ml) dried with sodium hydroxide by heating to 70°C. , at an internal temperature of 160℃
The mixture was stirred for 45 minutes (45 minutes after the internal temperature rose to 160°C). First, the generation of carbon dioxide gas was confirmed. In addition, the low boiling point portion (approximately 20 ml) was removed using a dehydration tube. This low boiling point component was ethyl acetate, water, etc. After cooling to 100℃, add Collidine to bath temperature 70-80℃.
Ethyl acetate to concentrate, evaporated with a vacuum pump at 2.5
diluted with diluted hydrochloric acid twice (400ml x
2) Wash to remove collidine, and then add 1 ml of saline solution.
The acidic portion was removed by washing twice with a saturated aqueous sodium bicarbonate solution, followed by washing with brine and drying with magnesium sulfate. After treatment with activated carbon, the magnesium sulfate was removed and the solvent was evaporated under reduced pressure to obtain 135.5 g of an oily ester, which is a mixture of cis and trans isomers. yield
82.5%. In addition, the acidic part was adjusted to pH 2 with concentrated hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate three times, washed once with brine, dried, and the solvent was distilled off to form lactonized carboxylic acid crystals. 25.9g was obtained.
Recrystallization was performed with ethyl acetate/n-hexane to obtain pure crystals. Melting point 179-180℃ [α] ²³ _D = -77.9° (c2.00・THF) NMR (DMF-d ₇ ) δ: 1.45 (3H, d, J = 7Hz), 3.80 (6H, s),
4.12 (1H, d, J = 2.5Hz), 4.45 (2H, s,
CH ₂ ), 4.92 (1H, q・d, J=7Hz, 2.5Hz),
6.42 (1H, dd, J=8, 2.5Hz), 6.50 (1H, d,
J=2.5Hz), 7.13 (1H, d, J=8Hz), 8.0
(1H, bs) Elemental analysis value C ₁₆ H ₁₇ NO ₇ Calculated value: C, 57.31; H, 5.11; N, 4.18% Actual value: C, 57.49; H, 5.22; N, 4.18% IR (Nujol) cm ^-1 : 1745, 1785 Reference example 19 (3S, 4R, 1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-hydroxyethyl)-2
-Azetidinone-4-carboxylic acid Ethyl ester (282.9 g, 0.746 mol), which is a mixture of cis and trans obtained in Reference Example 18, was dissolved in pyridine, and 1N sodium hydroxide (1567 ml) was added to this solution at 10 to 20°C. , 0.746×2.1=1.567 moles)
Added in 40 minutes. After standing overnight at room temperature, the reaction solution was concentrated to two thirds (3 hours) at a bath temperature of 40° C. or below, and pyridine was distilled off. Dilute this with saturated sodium bicarbonate solution (2) and add ethyl acetate three times (1 x 2, 0.5 x 1)
The neutral part (raw material) and pyridine were removed by washing. Next, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid (500 ml), saturated with sodium chloride, and extracted with ethyl acetate three times (1×
3) After washing with saline once, drying with magnesium sulfate, and evaporating the solvent under reduced pressure, a viscous oily carboxylic acid, which is a mixture of cis and trans, was obtained. 243.5g. On the other hand, the neutral part of the ethyl acetate washing solution is 10% hydrochloric acid water,
It was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After separating the magnesium sulfate and evaporating the solvent under reduced pressure,
5.14g of cis-ester was recovered. Reference example 20 (3S,4R,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-hydroxyethyl)-2
-Azetidinone-4-carboxylic acid The cis-ethyl ester (5.14 g, 0.0136 mol) recovered in Reference Example 19 was dissolved in pyridine (15 ml), and 1N-sodium hydroxide (28.6 ml,
0.0136×2.1=0.0286 mol) was added. Thereafter, it was left at room temperature overnight. Concentrate the reaction solution to two-thirds (bath temperature 40°C or less),
A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to this, and the mixture was washed three times with ethyl acetate to remove the neutral part. Next, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, saturated with sodium chloride, extracted three times with ethyl acetate, washed with brine,
Dry with magnesium sulfate. The magnesium sulfate was separated and the solvent was evaporated under reduced pressure to obtain 1.26 g of the desired viscous oily cis-carboxylic acid.
Yield, 30.1%. Reference example 21 (1R, 4R, 5S)-2,6-dioxo-7-
(2,4-dimethoxybenzyl)-3-oxa-
7-Azabicyclo[3.2.0]heptane (3S,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-hydroxyethyl)-2
-Azetidinone-4-carboxylic acid To a solution of the mixture of cis and trans carboxylic acids (243.5 g) obtained in Reference Example 19 in dry THF (4) was added concentrated hydrochloric acid (2 ml) and left overnight at room temperature. The THF was evaporated under reduced pressure at a bath temperature of 40-45℃, the residual oil was diluted with ethyl acetate, washed three times (1 x 3) with saturated aqueous sodium bicarbonate solution and once with brine, and then extracted with magnesium sulfate. It was dried. The magnesium sulfate was separated and the solvent was evaporated under reduced pressure to obtain 90.0 g of the desired lactone. In order to convert the unreacted cis isomer into a lactone, the following experiment was conducted in a similar manner. The sodium bicarbonate solution (washing solution) was made acidic (PH-2) with concentrated hydrochloric acid (approximately 300 g), saturated with sodium chloride, and diluted twice with ethyl acetate (1 x 1, 750 g).
ml×1), washed with brine, dried, and the solvent was evaporated under reduced pressure. Dry the residual oil in THF (2
), concentrated hydrochloric acid (1 ml) was added, and the mixture was left at room temperature for one day. Next, THF was evaporated under reduced pressure, the residual oil was dissolved in ethyl acetate (1.5), and this was diluted with saturated aqueous sodium bicarbonate solution three times and brine once.
After washing each time, drying, and evaporating the solvent, an additional 34.9 g of lactone was obtained. In the same way, repeat the same operation two more times.
11.0g and 5.5g were obtained, giving a total of 141.4g. Yield: 61.7%, melting point: 87-89°C (ethyl ether) In addition, 65.6 g of trans carboxylic acid was recovered. [α] ²³ _D = −65.9° (c2.00・ethanol) NMR (CDCl ₃ ) δ: 1.38 (3H, d, J = 6Hz), 3.43 (1H, dd, J =
4.2Hz), 3.80 (3H, s), 3.83 (3H, s), 4.05
(1H, d, J = 4Hz), 4.08, 4.63 (2H, AB−
q, J = 15Hz), 4.93 (1H, qd, J = 6, 2
Hz), 6.40 (1H, dd, J=9, 2Hz), 6.42 (1H,
d, J=2Hz), 7.15 (1H, d, J=9Hz) Reference example 22 (3S,4R,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-hydroxyethyl) -4
-Acetyl-2-azetidinone Lactone obtained in Reference Example 21 (133.6g, 0.459
A dry THF (1.68 mol) solution was cooled to -60°C, and methylmagnesium bromide (918 ml, 0.459 x 2 = 0.918 mol:
Methylmagnesium bromide……approx. 1mol/
1 tetrahydrofuran) in dry THF (420ml)
Add the diluted solution at -60℃ to -45℃ (about 12 minutes),
The mixture was stirred at 60°C for 30 minutes. At this point, it was confirmed by thin layer chromatography that no raw materials remained. Next, at the same temperature, 10% hydrochloric acid (500 ml) (calculated amount: 317 ml) was added, diluted with ethyl acetate (7), the aqueous layer was separated, and the organic layer was diluted with saturated sodium bicarbonate water once (300 ml x 1 ), washed once with brine (300 ml), and dried over magnesium sulfate. After treatment with activated carbon, the solvent was filtered and evaporated under reduced pressure to obtain 138 g of the target product (a 3:1 equilibrium mixture of hemiacetal and keto forms). Yield 97.9%. Thin layer chromatography: benzene/ethyl acetate = 2/1, R _f = 0.15. Reference example 23 (3S,4R,1'R)-1-(2,4-dimethoxybenzyl)-3-(1'-tert-butyldimethylsilyloxyethyl)-4-acetyl-2-azetidinone In reference example 22 Obtained alcohol (keto alcohol/hemiketal = 1/3) (138 g, 0.449 mol)
tert-butyldimethylsilyl chloride (135.4 ml) in dry dimethyl formaldehyde (450 ml)
g, 0.449×2=0.898 mol) was added and dissolved. Next, dimethylaminopyridine (110g, 0.449
x2=0.898 mol) was added and stirred at room temperature for 2 days. When dimethylaminopyridine was added, it was not completely dissolved, but stirring was continued. Further, the dimethyl formaldehyde used at this time was dried with a molecular sieve (4A). After 2 days, the reaction mixture containing the precipitate of dimethylaminopyridine hydrochloride was diluted with ethyl acetate (4), twice with 5% aqueous copper sulfate solution (600 ml x 2), once with water (500 ml x 1), Twice with saturated sodium bicarbonate aqueous solution (500ml x 2) and once with saline (500ml)
x1), each was washed and dried with magnesium sulfate. After removing the magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 230 g of an oily residue. When this residue was subjected to silica gel rapid chromatography using silica gel (1.4 kg) and eluted with a mixed solvent of benzene/ethyl acetate = 9/1, the target cis acetoxysilyl compound was obtained at 167.3 kg.
g was obtained. Yield 88.4%. Thin layer chromatography: Benzene/ethyl acetate = 9/1 R _f = 0.35 [α] ²⁵ _D = -20.7° (c1.96・EtOH) NMR (CDCl ₃ ) δ: 0.05 (6H, s), 0.86 ( 9H, s), 1.25 (3H, d,
J=7Hz), 2.20 (3H, s), 3.32 (1H, d・d,
J=7, 6Hz), 3.74 (3H, s), 3.78 (3H,
s), 3.92 (1H, d, J=6Hz), 4.10, 4.63
(2H, AB-q, J=14Hz), 4.20 (1H, q・
d, J=7, 6Hz), 6.40 (1H, d・d, J=
9, 2.5Hz), 6.40 (1H, d, J = 2.5Hz), 7.06
(1H, d, J=9Hz) Reference example 24 (3S, 4R, 1′R)-3-(1-tert-butyldimethylsilyloxyethyl)-4-acetyl-2
-Azetidinone A solution of the cis-acetoxydimethoxybenzyl derivative (64.3 g, 0.153 mol) obtained in Reference Example 23 in acetonitrile (special grade) (2.2), water (2.2), dipotassium phosphate (120 g), potassium persulfate (360 g),
g) was added, and the mixture was heated and stirred at 65°C with a mantle heater in an argon atmosphere. After rising to 65℃
The reaction solution was checked by thin layer chromatography three times at 35, 45, and 60 minutes, and after 60 minutes, it was confirmed that the raw materials had disappeared, and the reaction solution was cooled. Next, the acetonitrile was almost evaporated under reduced pressure at a bath temperature of 40 to 45°C, and the remaining aqueous layer was extracted with ethyl acetate three times (1, 500 ml, 500 ml), and then extracted with saturated aqueous sodium bicarbonate solution.
It was washed once with saline and dried over magnesium sulfate. After removing the magnesium sulfate, the solvent was evaporated under reduced pressure, and the residual oil (54.6 g) was subjected to rapid chromatography using silica gel (800 g) to obtain a solvent system of benzene/ethyl acetate = 7/3. When eluted with
30.8g was obtained. Yield 74.4%. Thin layer chromatography; benzene/ethyl acetate = 7/3, R _f = 0.4 (vanadate detection (blue)) NMR (CDCl ₃ ) δ: 0.06 (6H, s), 0.86 (9H, s), 1.30 ( 3H, d,
J=6Hz), 2.32 (3H, s), 3.52 (1H, d, d,
d, J = 7, 6, 2Hz), 4.23 (1H, d, J =
6Hz), 4.28 (1H, q・d, J=6, 7Hz),
6.63 (1H, bs) Reference example 25 (3R,4S,1′R)-3-(1′-tert-butyldimethylsilyloxyethyl)-4-acetoxy-
2-Azetidinone cis-acetyl compound obtained in Reference Example 24 (84.1g,
m-chloroperbenzoic acid (280 g) was dissolved in a solution of 0.139 mol) in chloroform (special grade 1.7), and the mixture was left standing for 89 hours (3.7 days) with the light removed. in between
The progress of the reaction was checked by NMR and the results were as follows. (Changes over time were measured using an NMR tube.

[Table] Chloroform was evaporated from the reaction mixture under reduced pressure at a bath temperature of 40°C, and the residue was diluted with ethyl acetate (3). Next, 3 times with 10% sodium bisulfite aqueous solution (500 ml x 3) and 7 times with saturated sodium bicarbonate solution (700 ml x 3).
7: Acidify the washing solution with concentrated hydrochloric acid until no white precipitate of benzoic acid appears), then wash once with saline (500 ml x
1) Washed and dried with magnesium sulfate. Ten%
When cleaning with sodium bisulfite, it generated heat, so it was cooled. After removing the magnesium sulfate and evaporating the solvent under reduced pressure at a bath temperature of 45 to 50°C, the cis-acetoxy form of the oil was sufficiently removed using a vacuum pump to obtain 85.1 g of the desired product. Yield 95.6%. A portion of this oil was recrystallized from n-hexane. When the crystals precipitated by standing at 0°C were cooled, needle-shaped crystals with a melting point of 52-53°C were obtained. Thin layer chromatography: benzene/ethyl acetate = 7/3
R _f =0.7 (vanadate detection). [α] ²³ _D = −119.1° (c2.00, EtOH) NMR (CDCl ₃ ) δ: 0.12 (6H, s), 0.88 (9H, s), 1.37 (3H, d,
J=6Hz), 2.14 (3H, s), 3.35 (1H, d, d,
d, J=9, 5, 2Hz), 4.35 (1H, q・d,
J = 6, 9Hz), 5.84 (1H, d, J = 5Hz),
6.90 (1H, bs) Reference example 26 (3S,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-tert-butyldimethylsilyloxyethyl)-2-azeazinon-4 -Carboxylic acid 1.5 g of trans-oxyacid obtained in Reference Example 21
(4.85 mmol) was dissolved in 6 ml of DMF, and 2.20 g (3.0 eq, 14.6 m
mol) and dimethylaminopyridine 1.75g (3.0eq,
14.6 mmol) and continued stirring at room temperature overnight.
Add ethyl acetate, wash twice with 5% aqueous copper sulfate solution and once with saturated saline, and dry over magnesium sulfate. Ethyl acetate is removed under reduced pressure to obtain the desired silyl oil. This oil was used as it was in the next reaction. Reference example 27 (3S,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-tert-butyldimethylsilyloxyethyl)-2-acetidinone-4-carboxylic acid Reference example 26 Dissolve the oil obtained in 20 ml of THF, add 1.0 ml of oxalyl chloride, and stir at room temperature for 2 hours. The solvent is removed under reduced pressure and the mixture is sufficiently dried using a pump to obtain the desired acid chloride as an oil. This product was used as it was in the next reaction. Reference example 28 (3S,4S,1′R)-1-(2,4-dimethoxybenzyl)-3-(1′-tert-butyldimethylsilyloxyethyl)-4-acetyl-2-azetidinone In reference example 27 20 ml of the resulting acid chloride
Dimethyl cadmium obtained by dissolving this solution in THF and adding 1.37 g of cadmium chloride (7.5 mmol) to a 1 mol THF solution of 15 mmol methylmagnesium bromide under ice cooling and stirring at room temperature for 1 hour.
Add to 7.5 mmol THF solution under ice cooling. 1.5 at room temperature
After stirring for ~2 hours, cool on ice, add 10% aqueous copper sulfate solution to destroy excess dimethyl cadmium, and extract with ethyl acetate. Wash with baking soda solution and saturated salt solution,
Dry with magnesium sulfate. After decolorizing with activated carbon, the ethyl acetate was removed under reduced pressure to obtain 1.358 g as a crude oil. When this product is purified by preparative TLC, 831 mg of the target product in trans form is obtained.
The yield is 45% from the trans-hydroxycarboxylic acid, which is the raw material for Reference Example 26. NMRδ (CDCl ₃ ): 0.04 (6H, s), 0.80 (9H, s), 1.20 (3H, d,
J = 6Hz), 2.05 (3H, s), 2.95 (1H, dd, J
=2.5, 4Hz), 3.73 (3H, s), 3.78 (3H, s),
4.00 (1H, d, J = 2.5Hz), 4.21 (1H, qd, J
= 6, 4Hz), 4.20, 4.54 (2H, AB-q, J =
15Hz), 6.39 (1H, dd, J=2, 9Hz), 6.39
(1H, d, J=2Hz), 7.11 (1H, d, J=9
Hz) MS・m/e421 (M ⁺ ), 364 (M ⁺ −C ₄ H ₉ ) IR (film) 1760, 1718, 1616, 1590 cm ^-1 Reference example 29 (3S, 4S, 1′R) −1− (2,4-dimethoxybenzyl)-3-(1'-tert-butyldimethylsilyloxyethyl)-4-acetyl-2-azetidinone Copper iodide (477 mg) was dissolved in dry ether (5 ml) under ice-cooling in a nitrogen stream. ). Add methyllithium (3.5 ml (1.6 mol ether solution)) to this and
Cool to -78°C after 10 minutes. Add ether/ether of the acid chloride (221 mg) obtained in Reference Example 28 to this solution.
A THF (4/1, 2.5 ml) solution was added dropwise, and after 15 minutes methanol (1 ml) was added. Ethyl acetate is added to the reaction mixture, washed with water and brine in that order, dried over magnesium sulfate, and the solvent is distilled off to obtain an oily substance.
This was purified by silica gel thin layer chromatography (cyclohexane/ethyl acetate = 3/1) to obtain 187 mg of the title compound. Reference example 30 (3S,4S,1′R)-3-(1′-tert-butyldimethylsilyloxyethyl)-4-acetyl-2
-Azetidinone 792 mg of the 2,4-dimethoxybenzyl compound obtained in Reference Example 28 or 29 was added to 30 ml of acetonitrile and 30 ml of water.
ml, further add 1.6 g of K ₂ HPO ₄ and 4.8 g of K ₂ S ₂ O ₈ and continue stirring at 70° C. in an argon stream for 1 hour. Concentrate the solvent to half under reduced pressure and extract with ethyl acetate. Wash with sodium bicarbonate and saline and dry with magnesium sulfate. Removal of the ethyl acetate under reduced pressure leaves an oily substance. When this product is purified by column chromatography (silica gel), 416 mg (yield: 82%) of the target product is obtained. If left untreated, it will crystallize. Melting point 72-73°C (n-hexane) NMRδ ( _CDCl3 ): 0.11 (6H, s), 0.91 (9H, s), 1.30 (3H, d,
J=6Hz), 2.26 (3H, s), 3.10 (1H, m),
4.1−4.5 (2H, m), 6.55 (1H, bs) Reference example 31 (3R, 4R, 1'R) -3-(1'-tert-butyldimethylsilyloxyethyl)-4-acetoxy-
2-Azetidinone 320 mg of trans-acetyl compound obtained from Reference Example 30
was dissolved in 5 ml of chloroform, 1.0 g of m-chloroperbenzoic acid was added, and the mixture was left at room temperature in the dark for two days. Add ethyl acetate and wash 5 to 6 times with 10% Na ₂ SO ₃ to completely remove perbenzoic acid and benzoic acid. Wash with salt water and dry with magnesium sulfate. When ethyl acetate is removed under reduced pressure, the desired trans acetoxy form is obtained.
Obtained as 285 mg crystals. Melting point 101-103℃ (n-hexane) [α] ²⁵ _D +47.9゜ (c1.0, CHCl ₃ ) IRν _nax (Nujol) 3200, 1785, 1745cm ^-1 MS・m/e230 (M ⁺ −C _{4 H9} ), 188, 144...... NMRδ ( _COCl3 ): 0.07 (6H, s), 0.85 (9H, s), 1.24 (3H, d,
J = 6.5Hz), 2.12 (3H, s), 3.22 (1H, dd, J
= 1.3Hz), 4.24 (1H, q・d, J = 6.5, 3Hz),
5.89 (1H, d, J = 1Hz) Reference example 32 3-(1'-acetoxyethyl)-1-(2,4-
Dimethoxybenzyl)-4-(2-hydroxyethyl)-2-azetidinone The carboxylic acid (10 mmol) obtained in Reference Example 16 and methyl chloroformate (960 mg) were dissolved in tetrahydrofuran (THF, 20 ml), and in a nitrogen stream,
Cool to −20 °C, pyridine (780 mg) in THF (10
ml) and keep at this temperature for 10 minutes, quickly straining the reaction mixture. The solution was added to a solution of sodium boron hydride (750 mg) in water-THF (20 ml/20 ml).
Add dropwise at 15℃. Keep the solution at this temperature for 15 minutes. Add dilute hydrochloric acid to the reaction solution to make it acidic and extract with ethyl acetate. Wash the extract in the order of sodium bicarbonate solution and saline solution,
After drying (MgSO ₄ ) and purification by silica gel chromatography, the title compound is obtained. IR spectrum ( _CHCl3 ) cm ^-1 : 1750

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ² represents a protecting group for a hydrogen atom or a nitrogen atom, and R ³ and R ⁴ are the same or different and are hydrogen atoms, carboxyl groups, protected carboxyl group, acyl group, mercapto group, alkylthio group,
It represents an arylthio group, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a cyano group or a nitro group, and X represents a halogen atom. However R ³ and R ⁴
except when both are hydrogen atoms. ) is treated with a base to form the general formula (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.) A method for producing a β-lactam compound having the following formula.