JPH039902B2 - - 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, a lower alkyl group which may have a halogen as a substituent, a lower alkyl, a halogen, a phenyl group which may have a nitro as a substituent, or a nitrogen atom in the ring) Indicates a 5- to 6-membered heterocyclic group containing 1 to 3 rings.
R ² represents an aralkyloxycarbonyl group, an allyloxycarbonyl group, a lower alkoxycarbonyl group which may have a halogen as a substituent, or an aralkyl group having 2 to 3 phenyls as a substituent. ) to novel N-substituted amidine derivatives. The compound of the present invention having the general formula () is:
It is useful as a synthetic intermediate for penem or carbapenem derivatives that have excellent antibacterial activity. Conventionally,
For example, imidoesters are used to produce amidines of thienamycin (JP-A-52-85188 or Tetrahedron Letters, Vol. 23, No. 47, 4930-
(See p. 4906, 1982, etc.) Also, for example (5R,
(5R,6S,8R)- 6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)
It is obtained by reacting -2-carbapenem-3-carboxylic acid with ethylacetimidate hydrochloride (see JP-A-58-32879). However, imidoesters are themselves unstable compounds, and the target compound obtained by reacting the imidoester is difficult to isolate and purify, resulting in a disadvantage that the target compound cannot be obtained in good yield. On the other hand, the compound of the present invention is an extremely stable compound, and can rapidly react with primary and secondary amines to obtain the target compound in good yield. In addition, its isolation and purification are easy. Furthermore, since the compound of the present invention specifically reacts with amino groups, it is possible to selectively obtain amidine derivatives even when other functional groups coexist. In the general formula () of the present invention, examples of the lower alkyl group in which R ¹ may have halogen as a substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
t-Butyl, pentyl, isopentyl, chloromethyl, dichloromethyl, trichloromethyl, 1-
Chloroethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl, 5-chloropentyl, bromomethyl, 2-bromoethyl, fluoromethyl, iodomethyl, trifluoromethyl containing chlorine, bromine, fluorine, iodine as a substituent. Examples include lower alkyl groups which may be substituted. As the phenyl group in which R ¹ may have lower alkyl, halogen, or nitro as a substituent,
For example, as lower alkyl, methyl, ethyl, n-
Propyl, n-butyl, n-pentyl, etc.; halogens include chlorine, bromine, fluorine, iodine; and phenyl groups which may have nitro as a substituent at the 2, 3 or 4 position. R ¹ contains 1 to 3 nitrogen atoms in the ring 5
Examples of the 6-membered heterocyclic group include 3-pyrrolyl, 2H-pyrrol-3-yl, 2-pyrrolin-
3-yl, 2-pyrrolidinyl, 2-imidazolyl, 1-pyrazolyl, 2-imidazolidinyl, 2
-imidazolin-4-yl, 3-pyrazoline-2
-yl, 2-virazolidinyl, 1H-1,2,3
-triazol-4-yl, 1H-1,2,4-
Triazol-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 2-piperidine, 1
-piperazinyl, 1,3,5-triazine-4-
We can give groups like il. When R ² is an aralkyloxycarbonyl group, examples thereof include benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and 1-(p-nitrophenyl)ethyloxycarbonyl. When R ² is a lower alkoxycarbonyl group which may have halogen as a substituent, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl,
Examples include isobutyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, trichloroethoxycarbonyl, and tribromoethoxycarbonyl. When R ² is an aralkyl group having 2 to 3 phenyl substituents, examples thereof include diphenylmethyl and triphenylmethyl. Next, compounds having the above general formula () will be illustrated.

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[Table] In the compound having the general formula (), R ¹ is preferably a hydrogen atom, a methyl group, an ethyl group,
Chloromethyl group, dichloromethyl group, trichloromethyl group, 1-chloroethyl group, phenyl group, 4
-nitrophenyl group, 3-nitrophenyl group, 2
-pyridyl group, 3-pyridyl group. R ² is a benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 1-(p-nitrophenyl)ethyloxycarbonyl group, allyl group, methoxycarbonyl group, ethoxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group It is. In carrying out the method of the present invention, the compound having the general formula () is (In the formula, R ¹ has the same meaning as above.)
A compound having the formula R ² -X ¹ () (wherein R ² has the same meaning as described above).
X ¹ represents an azide group. ) or in the presence of a base to react with a compound having the formula R ² -X ² () (wherein R ² has the same meaning as defined above).
X ² represents a halogen atom. ) can be obtained by reacting with a compound having That is, when using a compound having the above general formula (), the presence of a base is not required, but when using a compound having the above general formula (), the reaction is carried out in the presence of a base.
Here, X ² represents a halogen atom such as chlorine or bromine. Examples of the salts of the compound having the general formula () include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, and oxalic acid. I can give it to you. Further, the compound having the general formula () is used in an equimolar amount relative to the compound having the general formula (), and the amount of the compound having the general formula () is at least equimolar, preferably about 1.5 Double molar amounts are used. The reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in this reaction; for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; nitriles such as acetonitrile; N,N-dimethylformamide, N , N-dimethylacetamide, amides such as hexamethylphosphoramide; ether,
Ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, n-
Alcohols such as propanol; Esters such as methyl acetate, ethyl acetate, and ethyl formate; Ketones such as acetone and methyl ethyl ketone; Sulfoxides such as dimethyl sulfoxide; Nitroalkanes such as nitromethane and nitroethane; Alternatively, a mixed solvent of these organic solvents or a mixed solvent of these organic solvents and water can be mentioned. Further, the reaction between the compound having the general formula () and the compound having the general formula () is carried out in the presence of a base. The base used is not particularly limited as long as it does not affect the reaction, and examples include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, dimethylaniline, 2,4-lutidine, and diazabicyclononene. organic base;
Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate; sodium hydride, lithium hydrand Alkali metal hydroxide; sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide, lithium methoxide, and lithium ethoxide are preferably used. The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to conduct the reaction at a relatively low temperature, usually from room temperature to about -70°C, preferably from room temperature to -15°C. The reaction time varies mainly depending on the reaction temperature, the type of raw material compound, etc., but is from several tens of minutes to several tens of hours. After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the target compound precipitated from the reaction mixture can be collected as is, or the reaction mixture can be extracted with an organic solvent that is immiscible with water, the extract can be washed with water, dried, and then the solvent can be distilled off. You can get it. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography. The object compound () of the present invention obtained by the above production method is important as a synthetic intermediate for penem or carbapenem derivatives having excellent antibacterial activity as described above. For example, penem and carbapenem derivatives with extremely excellent antibacterial activity can be obtained by the method shown in the following formula. In the above formula, R ¹ and R ² have the same meanings as described above. R ³ represents a hydrogen atom or a substituent.
Y represents a nucleophilic leaving group such as halogen, alkylsulfonyloxy, trihalogenoalkylsulfonyloxy, or arylsulfonyloxy. R ⁴ represents an acyl group or an amidino group. R ⁵ represents a hydrogen atom or an alkali metal atom. R ⁶ represents a carboxyl group protecting group. R ⁷ represents a hydroxyl protecting group. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples. In addition, the nuclear magnetic resonance spectrum of the example was measured at 60 MHz, and the infrared absorption spectrum was measured with Nujol. Example 1 N-(p-nitrobenzyloxycarbonyl)
Formamidine 12.1 g (0.15 mol) of formamidine hydrochloride was dissolved in a mixed solvent of 100 ml of water and 20 ml of tetrahydrofuran, and then cooled to -5°C. In the lysate,
With vigorous stirring, a solution of 21.5 g (0.1 mol) of p-nitrobenzyloxycarbonyl chloride in 50 ml of tetrahydrofuran and 20%
Add 50 ml of sodium hydroxide aqueous solution to an internal temperature of -5 to -10.
It was added at the same time while being maintained at ℃. The dropwise addition was completed in 30 minutes to 1 hour. After the dropwise addition was completed, the mixture was further stirred at the same temperature for 1 hour, and the precipitated crystals were collected by filtration. The filtered crystals were washed with water and dried to obtain 20.5 g of the title compound. Melting point 147-149℃ Nuclear magnetic resonance spectrum (DMSO- _d6 ) δ:
ppm 5.25 (2H, s) 7.50, 8.30 (4H, A ₂ B ₂ , J = 9.0Hz) 8.48 (1H, s) Infrared absorption spectrum ν _nax cm ^-1 : 3410, 1708, 1660, 1580, 1503, 1332,
1270, 1160 Example 2 N-(benzyloxycarbonyl)formamidine Formamidine hydrochloride 12.1g (0.15 mol) and benzyloxycarbonyl chloride 17.1g
(0.1 mol) was carried out in the same manner as in Example 1 to obtain 13.0 g of the title compound. Melting point 120-122.5℃ Nuclear magnetic resonance spectrum (DMSO- _d6 ) δ:
ppm 5.05 (2H, s) 7.25 (5H, s) 8.04 (1H, s) Infrared absorption spectrum νmaxcm ^-1 : 3280, 1660, 1580, 1320, 1250, 1140 Example 3 N-(allyloxycarbonyl)formamidine Form Using 25 g (0.3 mol) of amidine hydrochloride and 25 g (0.2 mol) of allyl chloroformate,
It was carried out in the same manner as in Example 1. After the reaction was completed, 250 ml of ethyl acetate was added to the reaction mixture for extraction. The aqueous layer was further extracted with 250 ml of ethyl acetate. The extract was washed with 200 ml of 10% saline and dried over magnesium sulfate. After filtering off magnesium sulfate from the extract and then concentrating it under reduced pressure, the title compound was obtained.
22.5g was obtained. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 4.43-4.62 (2H, m) 5.10-5.39 (3H, m) 5.60-6.25 (1H, m) Infrared absorption spectrum νmaxcm ^-1 : 3260, 1700, 1642, 1245 Implemented Example 4 N-(isobutyloxycarbonyl)formamidine Formamidine hydrochloride 12.1 g (0.15 mol) and isobutyloxycarbonyl chloride 13.7
When the procedure was carried out in the same manner as in Example 3 using 0.1 mol), 9.5 g of the title compound was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 0.93 (6H, d, J = 7.0Hz) 1.96 (1H, m) 3.88 (2H, d) 8.42 (1H, s) Infrared absorption spectrum νmaxcm ^-1 : 3300, 1695 , 1660, 1415, 1320, 1250, 1160 Example 5 N-(p-nitrobenzyloxycarbonyl)
Acetamidine The same procedure as in Example 1 was carried out using 142 g (1.5 mol) of acetamidine hydrochloride and 215.5 g (1 mol) of p-nitrobenzyloxycarbonyl chloride to obtain 225 g of the title compound. Melting point 143-145℃ Nuclear magnetic resonance spectrum (DMSO- _d6 ) δ:
ppm 2.05 (3H, s) 5.20 (2H, s) 7.49, 8.16 (4H, A ₂ B ₂ , J = 9.0Hz) Infrared absorption spectrum νmaxcm ^-1 : 3360, 1665, 1600, 1520, 1345, 1260, 1140 Implemented Example 6 N-(benzyloxycarbonyl)acetamidine Acetamidine hydrochloride 71g (0.75 mol) and benzyloxycarbonyl chloride 85g
(0.5 mol) was carried out in the same manner as in Example 1 to obtain 86.4 g of the title compound as white crystals. Melting point 91℃ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 1.95 (3H, s) 5.05 (2H, s) 7.21 (5H, s) Infrared absorption spectrum νmaxcm ^-1 : 3330, 1660, 1520, 1260, 1140 Examples 7 N-(allyloxycarbonyl)acetamidine Using 30 g (0.3 mol) of acetamidine hydrochloride and 25 g (0.2 mol) of allyl chloroformate,
When carried out in the same manner as in Example 3, 24.4 g of the title compound was obtained. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 2.10 (3H, s) 4.57 (2H, dd, J=2.5, 6.0Hz) 5.10-5.45 (2H, m) 5.70-6.30 (1H, m) 8.48 ( 2H, s) Infrared absorption spectrum νmaxcm ^-1 : 3320, 1660, 1630, 1540, 1255, 1142 Example 8 N-(t-butyloxycarbonyl)acetamidine Acetamidine hydrochloride 1.9 g (0.02 mol) and t- Butyloxycarbonyl azide 2.7g
(0.02 mol) was dissolved in a mixed solvent of 20 ml of ethyl acetate and 20 ml of water, and then stirred at room temperature for 1 hour. After the reaction was completed, the ethyl acetate layer was separated from the reaction mixture, dried, and concentrated to obtain 2.5 g of the title compound. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 1.47 (9H, s) 2.35 (3H, s) 5.05 (1H, s) 8.42 (1H, s) Example 9 N-(p-nitrobenzyloxycarbonyl)
Propioamidine Propioamidine hydrochloride 10.9g (0.1mol)
Example 1 using 14.4 g (0.067 mol) of
When carried out in the same manner as above, 16.4 g of the title compound was obtained. Melting point 84-85℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 1.22 (3H, t, J = 7.0Hz) 2.03 (2H, q, J = 7.0Hz) 3.77-5.66 (2H, broad) 5.18 (2H, s) 7.13 (2H, d, J = 8.0Hz) 8.12 (2H, d, J = 8.0Hz) Infrared absorption spectrum νmaxcm ^-1 : 3420, 3300, 1650, 1605, 1530, 1350, 1270 Example 10 N-( Benzyloxycarbonyl) propioamidine Propioamidine hydrochloride 21.1g (0.19 mol)
and benzyloxycarbonyl chloride 22.8
When the procedure was carried out in the same manner as in Example 1 using 0.13 mol), 26.5 g of the title compound was obtained. Melting point 82-83℃ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 1.17 (3H, t, J = 7.0Hz) 2.28 (2H, q, J = 7.0Hz) 5.08 (2H, s) 7.28 (5H, s) 7.83-9.53 (2H, broad) Infrared absorption spectrum νmaxcm ^-1 : 3300, 1660, 1608, 1565, 1380, 1270 Example 11 N-(allyloxycarbonyl)propioamidine Propioamidine hydrochloride 21.1g (0.19 mol )
When carried out in the same manner as in Example 3 using 16.1 g (0.13 mol) of allyl chloroformate, the title compound was obtained.
20.4g was obtained. Melting point 49.5-51℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 1.22 (3H, t, J = 7.0Hz) 2.01 (2H, q, J = 7.0Hz) 4.55 (2H, dd, J = 2, 6Hz) 5.00~5.50 (2H, m) 5.63~6.30 (1H, m) 6.27~7.63 (2H, broad) Infrared absorption spectrum νmaxcm ^-1 : 3360, 3080, 1670, 1630, 1550, 1530,
1465, 1150 Example 12 N-(ethoxycarbonyl)propioamidine Propioamidine hydrochloride 21.1g (0.19 mol)
and ethoxycarbonyl chloride 14.5g
(0.13 mol) was carried out in the same manner as in Example 3 to obtain 16.3 g of the title compound. Melting point 62-64℃ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 1.22 (3H, t, J = 7.0Hz) 1.28 (3H, t, J = 7.0Hz) 2.00 (2H, q, J = 7.0Hz) 3.78 (2H, q, J = 7.0Hz) 5.18-7.67 (2H, broad) Infrared absorption spectrum νmaxcm ^-1 : 3300, 1660, 1370, 1270, 1045 Example 13 N-(p-nitrobenzyloxycarbonyl)-
α-Chloroacetamidine α-chloroacetamidine hydrochloride 19.4g
(0.15 mol) and p-nitrobenzyloxycarbonyl chloride 21.6 g (0.1 mol),
When carried out in the same manner as in Example 1, 25.5 g of the title compound was obtained. Melting point 97-99℃ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 4.21 (2H, s) 5.10 (2H, s) 7.49, 8.16 (4H, A ₂ B ₂ , J = 9.0Hz) Infrared absorption spectrum νmaxcm ^-1 : 3380, 3275, 1650, 1615, 1520, 1345 Example 14 N-(benzyloxycarbonyl)-α-chloroacetamidine α-chloroacetamidine hydrochloride 9.6 g
(0.074 mol) and benzyloxycarbonyl chloride 8.5 g (0.05 mol) Example 1
When carried out in the same manner as above, 10.2 g of the title compound was obtained as white crystals. Melting point 93℃ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 4.15 (2H, s) 5.16 (2H, s) 7.28 (5H, s) Infrared absorption spectrum νmaxcm ^-1 : 3415, 3285, 1675, 1605, 1275, 1245 Example 15 N-(allyloxycarbonyl)-α-chloroacetamidine α-chloroacetamidine hydrochloride 20g
(0.155 mol) and allyl chloroformate 12.1 g (0.1
mol) was carried out in the same manner as in Example 3 to obtain 15.1 g of the title compound. Melting point 45-47℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 4.15 (2H, s) 4.57 (2H, dd, J=2.5, 6.0Hz) 5.10-5.47 (2H, m) 5.70-6.25 (1H , m) 8.35 (2H, s) Infrared absorption spectrum νmaxcm ^-1 : 3310, 1675, 1620, 1255, 1115 Example 16 N-(p-nitrobenzyloxycarbonyl)
Benzamidine 28.6 g of the title compound was obtained by carrying out the same procedure as in Example 1 using 21.7 g (0.14 mol) of benzamidine hydrochloride and 21.5 g (0.1 mol) of p-nitrobenzyloxycarbonyl chloride. Melting point 140-140.5℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 5.25 (2H, s) 7.25-8.27 (11H, m) Infrared absorption spectrum νmaxcm ^-1 : 3440, 3295, 1655, 1596, 1520, 1355, 1260 Example 17 N-(benzyloxycarbonyl)benzamidine 21.7 g (0.14 mol) of benzamidine hydrochloride and 17.1 g of benzyloxycarbonyl chloride
(0.1 mol) was carried out in the same manner as in Example 1 to obtain 23.0 g of the title compound. Melting point 108.5-109℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 5.17 (2H, s) 7.17-8.15 (12H, m) Infrared absorption spectrum νmaxcm ^-1 : 3435, 3290, 1655, 1600, 1575, 1265 Examples 18 N-(allyloxycarbonyl)benzamidine When carried out in the same manner as in Example 3 using 21.7 g (0.14 mol) of benzamidine hydrochloride and 12.1 g (0.1 mol) of allyl chloroformate, the title compound 20.1 was obtained.
g was obtained. Melting point 58-62℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 4.55 (2H, dd, J=2.5, 6.0Hz) 5.05-5.45 (2H, m) 5.65-6.30 (1H, m) 7.25-7.80 (5H, m) Infrared absorption spectrum νmaxcm ^-1 : 3320, 3200, 1655, 1605, 1505, 1260 Example 19 N-(ethoxycarbonyl)benzamidine Benzamidine hydrochloride 21.7g (0.14 mol) and ethoxycarbonyl chloride 10.9g ( 0.1
When the procedure was carried out in the same manner as in Example 3 using mol), 17.6 g of the title compound was obtained. Melting point 64-65℃ Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 1.26 (3H, t, J = 6.0Hz) 3.96 (2H, AB-q, J = 6.0Hz) 4.22 (2H, AB-q, J = 6.0Hz) 7.22 to 7.85 (5H, m) Infrared absorption spectrum νmaxcm ^-1 : 3320, 1660, 1605, 1515, 1260, 1120 Example 20 N-(benzyloxycarbonyl)-p-nitrobenzamidine p-nitrobenzamidine Hydrochloride 12.7g
(0.063 mol) in 100 ml of dichloromethane and 20 ml of water
After dissolving in ml of mixed solvent, it was cooled to -10. Add 13 ml of 20% aqueous sodium hydroxide solution and 8.5 g (0.05 g) of benzyloxycarbonyl chloride to the solution.
mol) was added dropwise, and the mixture was stirred for 1 hour. After the reaction is complete, separate the dichloromethane layer from the reaction mixture,
After washing with water and drying, the dichloromethane layer was distilled off to obtain 15.1 g of the title compound. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: ppm 5.20 (2H, s) 7.41 (9H, m) 8.27 (2H, m) 8.63 (1H, m) Infrared absorption spectrum νmaxcm ^-1 : 3460, 3430, 1655, 1608, 1530, 1350, 1250 Example 21 N-(benzyloxycarbonyl)pyridyl-
2-amidine pyridyl-2-amidine hydrochloride 10.24g (0.065
Example 20 was repeated using 8.5 g (0.05 mol) of benzyloxycarbonyl chloride and 13.3 g of the title compound were obtained. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm 5.19 (2H, s) 7.21-7.50 (5H, m) 7.65-7.90 (1H, m) 8.36-8.60 (3H, broad) Infrared absorption spectrum νmaxcm ^-1 : 3440, 3320, 1658, 1625, 1258 Reference example 1 3R-hydroxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine 3R-hydroxypyrrolidine hydrochloride (12.3g)
and N-(p-nitrobenzyloxycarbonyl)acetamidine (23.7 g) in ethanol (30 g).
ml) and methylene chloride (100 ml), and stirred at 40-42°C for 2 hours.
After the reaction is completed, the reaction mixture is washed with 5% aqueous sodium bicarbonate solution (50 ml) and 10% brine (50 ml), and then dried over magnesium sulfate. The solvent was distilled off from the reaction mixture under reduced pressure to obtain the target compound (29.2 g). Nuclear magnetic resonance spectrum (DMSO- _d6 ) δ:
ppm: 2.24 (3H, s) 2.7-3.5 (5H, m) 3.5-4.2 (2H, m) 4.7-5.1 (1H, m) 5.3 (2H, s) 7.6, 8.2 (4H, A ₂ B ₂ , J =9Hz) Reference example 2 3R-methanesulfonyloxy-1-(N-p-
Nitrobenzyloxycarbonylacetimidoyl)pyrrolidine 3R-Hydroxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine (32.2g) was dissolved in methylene chloride (500ml).
Add methanesulfonyl chloride (9.3 ml) and then triethylamine (16.7 ml) under ice-cooling. After stirring for 30 minutes under ice cooling, water was added,
After extraction with methylene chloride, washing with water, and drying, the solvent was distilled off under reduced pressure to obtain the target compound (36 g). Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm: 2.31 (3H, s) 2.0-2.6 (2H, m) 3.05 (3H, s) 3.4-4.0 (4H, m) 5.17 (2H, s) 7.55, 8.15 ( 4H, _A2B2 , J=9Hz) Reference example 3 3S-acetylthio _- 1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine Sodium hydride (55% oil dispersion) in anhydrous dimethylformamide (300ml) , 7.35 g) Next, add 12.5 ml of thioacetic acid and stir for 10 minutes under ice cooling. Add 3R-methanesulfonyloxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine (40 g) and stir at 65°C for 3 hours. cool the reaction mixture;
Add water and extract with ethyl acetate. After washing the ethyl acetate extract with water and drying, the solvent was distilled off under reduced pressure and the residue was fractionated and purified by silica gel column chromatography. The target compound (30 g) was obtained from the fraction eluted with benzene:ethyl acetate = 2:1. Obtained. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm: 1.8-2.2 (2H, m) 2.30 (3H, s) 2.35 (3H, s) 3.2-4.2 (5H, m) 5.16 (2H, s) 7.5, 8.1 ( 4H, _A2B2 , J=9Hz) Reference example 4 3S-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine 3S _- acetylthio-1-(N-p-nitrobenzyloxycarbonylaceto Dissolve imidoyl) pyrrolidine (30 g) in methanol (1) and -10
Cool to ℃. Add dropwise a methanol solution of sodium methoxide prepared from sodium (1.8 g) and stir for 30 minutes. Add 4.92 ml of acetic acid, and evaporate the solvent under reduced pressure to about half the volume. Saturated brine was added to the concentrated solution, extracted with ethyl acetate, washed with saturated brine, dried, the solvent was distilled off under reduced pressure, and the residue was fractionated and purified using silica gel column chromatography to yield benzene:ethyl acetate= The target compound (20 g) was obtained from the 5:1 distillate fraction. Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: ppm: 1.7-2.7 (3H, m) 2.33 (3H, s) 3.2-4.1 (5H, m) 5.22 (2H, s) 7.54, 8.17 (4H, A ₂ B ₂ , J=8.5Hz) Reference example 5 (5R, 6S, 8R)-6-(1-hydroxyethyl)-2-[(3S)-N-p-nitrobenzyloxycarbonylacetimidoylpyrrolidine-
3-ylthio]-2-carbapenem-3-carboxylic acid p-nitrobenzyl ester (5R,6S,8R)-6-(1-Hydroxyethyl)-2-oxocarbapenem-3-carboxylic acid p-nitrobenzyl ester (1.5 g) in acetonitrile aqueous solution (70 ml) under ice-cooled nitrogen stream, diisopropylethylamine. (0.82ml) and diphenylphosphoryl chloride (0.96ml). After stirring at the same temperature for 30 minutes, diisopropylethylamine (0.82 ml) was added to 3S-mercapto-1-(N-p-
Add nitrobenzyloxycarbonylacetimidoyl)pyrrolidine (1.5 g) and stir for an additional hour. The reaction solution was diluted with ethyl acetate, washed successively with saturated brine, 5% aqueous sodium chloride, and saturated brine, and dried over magnesium sulfate. A small amount of ethyl acetate was added to the residue after distilling off the solvent, and the precipitated crystals were collected to obtain the target compound (1.6 g). When the mother liquor was fractionated and purified using a silica gel Rover column, the target compound (0.3 g) was further obtained from the ethyl acetate elution fraction. Nuclear magnetic resonance spectrum ( _CDCl3 ) δppm: 1.35 (3H, d, J = 6.0Hz) 1.8-2.9 (3H, m) 2.28 (3H, s) 3.1-4.6 (10H, m) 5.21 (2H, s) 5.32 , 5.50 (2H, AB-q, J = 14Hz) 7.64, 8.21 (4H, A ₂ B ₂ , J = 9Hz) 7.76, 8.21 (4H, A ₂ B ₂ , J = 9Hz) Reference example 6 (5R, 6S ,8R)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-(1-
hydroxyethyl)-2-carbapenem-3-
carboxylic acid (5R,6S,8R)-6-(1-hydroxyethyl)-2-[(3S)-N-p-nitrobenzyloxycarbonylacetimidoylpyrrolidine-3-
[ylthio]-2-carbapenem-3-carboxylic acid p-nitrobenzyl ester (1.9 g) was dissolved in tetrahydrofuran (200 ml), and morpholinopropanesulfonic acid buffer (PH = 7.0, 200 ml) and
Add 10% palladium-carbon catalyst (1.52 g),
After hydrogenation for an hour, the catalyst was removed and tetrahydrofuran was distilled off under reduced pressure. The precipitated insoluble matter is removed again and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography using Diaion HP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.).
The target compound (0.73 g) was obtained from the fraction eluted with % acetone water. The obtained compound was subjected to high performance liquid chromatography (Waters Microbondapak C ₁₈ , tetrahydrofuran:water = 1:10).
A further purified target compound was obtained. Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 298 (8960) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1760, 1675 Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.29 (3H, d, J = 6.5 Hz) 1.8~2.7 (2H, m) 2.29 (3H, s) 3.23 (2H, d-like, J=9.5Hz) 3.44 (1H, dd, J=3.0, 6.0Hz) 3.3~4.4 (7H, m) The antibacterial activity of the obtained target compound is shown in the table below.

【table】

Claims (1)

[Claims] 1 formula (In the formula, R ¹ is a hydrogen atom, a lower alkyl group which may have a halogen as a substituent, a lower alkyl, a halogen, a phenyl group which may have a nitro as a substituent, or a nitrogen atom in the ring) It represents a 5- to 6-membered saturated or unsaturated heterocyclic group containing 1 to 3 rings. R ² is an aralkyloxycarbonyl group, an allyloxycarbonyl group, or a lower alkoxycarbonyl group which may have a halogen as a substituent. or an aralkyl group having 2 to 3 phenyl as a substituent. 2 formulas (In the formula, R ¹ is a hydrogen atom, a lower alkyl group which may have a halogen as a substituent, a lower alkyl, a halogen, a phenyl group which may have a nitro as a substituent, or a nitrogen atom in the ring) represents a 5- to 6-membered saturated or unsaturated heterocyclic group containing ¹ to ^{3 rings} . ,
It represents an allyloxycarbonyl group, a lower alkoxycarbonyl group which may have a halogen as a substituent, or an aralkyl group having 2 to 3 phenyl as a substituent. X ¹ represents an azide group. ) or react with a compound having
Alternatively, it is characterized by reacting with a compound having the formula R ² −X ² (wherein R ² represents the same meaning as described above and X ² represents a halogen atom) in the presence of a base. formula to A method for producing an N-substituted amidine derivative having the formula (wherein R ¹ and R ² have the same meanings as defined above).