JPH06104657B2 - Azetidinone derivative - Google Patents

Description

The present invention relates to novel azetidinone derivatives, more particularly formulas In the formula, R ₁ and R ₂ each represent a lower alkyl group, or R ₁ and R ₂ together represent a lower alkylene group,
Z represents a hydrogen atom or an amino protecting group, and relates to an azetidinone derivative represented by: and a method for producing the same.

The compound of the above formula (I) provided by the present invention is already known as various drugs, particularly carbapenam or carbapenem antibiotics, for example, carbapenem antibiotics having excellent antibacterial activity and being relatively stable. The following formula It is useful as an intermediate for the synthesis of antibiotics represented by.

The antibiotic of formula (A) and its manufacturing method were first developed by Sand Company of Switzerland.
Although disclosed in JP-A-59-84886, the method for producing the antibiotic of formula (A) disclosed therein requires an extremely large number of steps and complicated reaction operations, and is not an industrially suitable method. Unthinkable.

Then, the inventors of the present invention have conducted diligent research on a relatively simple production method of the antibiotic of the formula (A) with a small number of steps, and as a result, use of the novel azetidinone derivative of the formula (I) as an intermediate. By doing so, it was found that the antibiotic of formula (A) can be obtained with a relatively small number of steps and a good yield, and the present invention was completed.

In the present specification, the term "lower" has 6 or less carbon atoms in the group or compound to which this term is attached, preferably 4
Means less than or equal to

However, in the above formula (I), the “lower alkyl group” which may be represented by R ₁ and R ₂ may be linear or branched, and examples thereof include methyl, ethyl, n-propyl, Examples include isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl groups. Further, the “lower alkylene group” represented by R ₁ and R ₂ together may also have a branched chain, for example, ethylene, trimethylene, tetramethylene,
Methylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,3-dimethyltrimethylene, ethylethylene, 1,2-diethylethylene, 1,1,3,3-tetramethyl Examples thereof include triethylene and 2,2-dimethyltrimethylene. Further, examples of the “amino protecting group” which can be represented by Z include, for example, tri (lower alkyl) silyl group such as trimethylsilyl and tert-butyldimethylsilyl; aralkyl group such as benzyl; p-methoxyphenyl, o, p Substituted or unsubstituted phenyl groups such as -dimethoxyphenyl are included.

Also, the 4-position substituent The stereo configuration of may be either S or R.

Then, representative examples of the compound of formula (I) provided by the present invention are as follows: (3R, 4R) or (3R, 4S) -4- (dimethoxy) methyl-3-[( R) -1-fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone, (3R, 4R) or (3R, 4S) -1-benzyl-4- (dimethoxy) methyl-3-[(R ) -1-Fluoroethyl]
2-azetidinone, (3R, 4R) or (3R, 4S) -4- (dimethoxy) methyl-3-[(R) -1-fluoroethyl] -1-trimethylsilyl-2-azetidinone, (3R, 4R) Or (3R, 4S) -4- (diethoxy) methyl-3-[(R) -1-fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone, (3R, 4R) or (3R, 4S ) -1-Benzyl-4- (diethoxy) methyl-3-[(R) -1-fluoroethyl]
-2-azetidinone, (3R, 4R) or (3R, 4S) -4- (diethoxy) methyl-3-[(R) -1-fluoroethyl] -1-trimethylsilyl-2-azetidinone, (3R, 4R) Or (3R, 4S) -4- (ethoxymethoxy)
Methyl-3-[(R) -1-fluoroethyl] -1-
(P-methoxy) phenyl-2-azetidinone, (3R, 4R) or (3R, 4S) -1-benzyl-4- (ethoxymethoxy) methyl-3-[(R) -1-fluoroethyl] -2- Azetidinone, (3R, 4R) or (3R, 4S) -4- (ethoxymethoxy)
Methyl-3-[(R) -1-fluoroethyl] -1-trimethylsilyl-2-azetidinone, (3R, 4R) or (3R, 4S) -4- (1,3-dioxolan-2-yl) -3 -[(R) -1-fluoroethyl]-
1- (p-methoxy) phenyl-2-azetidinone, (3R, 4R) or (3R, 4S) -1-benzyl-4- (1,3
-Dioxolan-2-yl) -3-[(R) -1-fluoroethyl] -2-azetidinone, (3R, 4R) or (3R, 4R) -4- (1,3-dioxolane is -yl)- 3-[(R) -1-fluoroethyl] -1
-Tolumethylsilyl-2-azetidinone and the like.

According to the present invention, the azetidinone derivative of the formula (I) has the formula (a): In the formula, R ₃ represents a carboxyl protecting group, and a dianion derived from a compound represented by In the formula, R ₁ , R ₂ and Z have the above-mentioned meanings, and are reacted with a compound represented by In the formula, R ₁ , R ₂ and Z have the above-mentioned meaning, and can be produced by treating the compound represented by with a fluorinating agent.

In the step (a), the compound of formula (II) used as a starting material is a compound known per se, and the “carboxyl protecting group” represented by R ₃ is, for example, methyl, ethyl, propyl or isopropyl. , A lower alkyl group such as butyl, sec-butyl and hexyl; an aryl group such as benzyl, methoxybenzyl, nitrobenzyl and chlorobenzyl; a lower haloalkyl group such as 2-iodoethyl, 2,2,2-trichloroethyl; methoxymethyl,
Lower alkoxymethyl groups such as ethoxymethyl; lower alkanoyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like.

The compound of formula (II) is first derivatized with its dianion.
The structure of the dianion cannot be rigorously defined, but when an organolithium compound is used as a reagent for this dianion, the dianion has the following formula: Is understood to be indicated by.

The induction of the compound of formula (II) into the above dianion is usually
In a suitable solvent, for example, a mixed solvent of ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, tetrahydrofuran and dimethylformamide, etc., a compound of formula (II), an organic metal compound having an anion-forming ability, -100 It can be carried out by reacting at a low temperature in the range of ~ 0 ° C, preferably -78 to -20 ° C.

Examples of the “organometallic compound having anion-forming ability” that can be used here include lithium diisopropylamide,
Suitable examples include organolithium compounds such as lithium isopropylcyclohexyl amide, lithium hexamethyldisilazide, tert-butyllithium, methyllithium, and the like, and the organometallic compound is generally 1.8 per mole of the compound of formula (II). Conveniently, it is used in an amount in the range of -2.8 mol, preferably 2.0-2.3 mol.

The dianion thus formed is subsequently reacted as it is with the compound of formula (III). The reaction temperature can be generally -100 to 50 ° C, preferably -78 to 25 ° C. The amount of the compound of the formula (III) used is not critical, but generally it is 0.
It can be in the range of 8 to 2.0 mol, preferably 0.9 to 1.5 mol.

Formula (III) used as a starting material in the above reaction
The compound of In the formula, R ₁ and R ₂ have the above-described meanings, and the acetal of acrolein represented by In the formula, R ₁ and R ₂ have the above-mentioned meanings, and the compounds are represented by the formulas NH ₂ —Z, where Z has the above-mentioned meanings, and are reacted by reacting with an amine can do.

Thus, according to the above reaction, the following formula A mixture of the two epimers of The mixture of these epimers may be separated into respective epimers at this point, or the mixture may be directly used in the next reaction.

The compound of formula (IV) thus obtained is then treated with a fluorinating agent. As the fluorinating agent that can be used here,
Examples thereof include diethylaminosulfate trifluoride (DAST), hexalfluoropropene-diethylamine (Ishikawa reagent) and the like. The fluorination reaction of the compound of formula (IV) using these fluorinating agents can be carried out by a method known per se. For example, when the above DAST is used, Ching-Pong Mak et al. Heterocycles 19 , 1399 (1982), and when the Ishikawa reagent is used, Ishikawa et al., Brutein of the Chemical Society of Japan ( Bull.Chem.Soc.
Jpn.) 52 3377 (1979).

As a result, OH of S-configuration in the 3-position side chain becomes R
-Stereoselectively substituted under the configuration to give compounds of formula (I).

Thus, the compound of formula (I) thus obtained can be separated and purified by a method known per se, for example, extraction with an organic solvent, silica gel column chromatography and the like.

The compound of formula (I) of the present invention produced as described above can be converted into the antibiotic of formula (A) by a method known per se, for example, through the following reaction steps: Reagents _{a) Pb (OCOCH 3) 4} b) H 2 C = C [OSi (CH _{3) 3] -C (N 2) -COO-R} 4, ZnI 2 c) Rh 2 (OCOCH 3) 4 Footnote 1) The hydrolysis of the compound of formula (I) can be carried out, for example, by reacting with a hydrochloric acid aqueous solution in an acetic acid-water solvent, or in a tetrahydrofuran-water mixed solvent, a hydrochloric acid aqueous solution or p-
It can be carried out by hydrolysis with a usual means in the presence of an acid, such as by reacting with toluenesulfonic acid.

2) The 1-position amino-protecting group of the compound of formula (VII) is a suitable deaminating protecting group reaction depending on the kind of the amino-protecting group [for example, an acid when Z'is a tri (lower alkyl) silyl group]. Hydrolysis, hydrogenolysis when Z'is an aralkyl group, and oxidative elimination when Z'is a p-methoxyphenyl or o, p-dimethoxyphenyl group] and a group of formula (VIII ). In addition,
When Z'is a trimethylsilyl group, it may be subjected to the next step without being deprotected.

Document 1) Day self-defense Heart (DjHart) et al., Tetrahedron Letters (Tetrahedron Letters) 26, 5493 ( 198
5) 2) P. self-defense leader (PjReider) et al., Tetrahedron Letters (Tetrahedron Letters) 23, 2293
(1982) 3) W. Flitsch et al., Tetrahedron Letters 23 , 2297 (198)
2) 4) D. G. Melillo and others, Tetrahedron Letters 21 , 2783 (19)
80) The antibiotic of formula (A) produced as described above has a wide range and excellent antibacterial activity, is stable against renal dehydropeptidase, and is extremely useful as an antibacterial agent. Therefore, the compound represented by the formula (I) of the present invention is useful as a synthetic intermediate.

The present invention will be further described with reference to examples.

Example 1: (3R, 4S)-and (3R, 4R) -4- (diethoxy) methyl-3-[(S) -1-hydroxyethyl]-
1- (p-methoxy) phenyl-2-azetidinone (1
Production of a, 1b) N-isopropylcyclohexylamine 0.691 ml (4.2 mm
ol) in anhydrous tetrahydrofuran (4 ml) was cooled to -45 ° C and 2.62 ml of 1.6M n-Bu Li hexane solution (4.
2 mmol) was added dropwise, and the reaction solution was stirred at -45 ° C for 1 hour.

A tetrahydrofuran solution (1.5 m) of 236 mg (2.0 mmol) of (S) -β-hydroxybutyric acid methyl ester was added to the reaction solution.
l) was slowly added dropwise. After stirring at -45 ° C for 2 hours,
N-anisyl- (2,2-diethoxyethyl) imine 522 mg
(2.2 mmol) N, N-dimethylformamide solution (5 ml)
Was slowly added dropwise over about 15 minutes.

After the dropping was completed, the reaction solution was gradually heated from -45 ° C to room temperature and stirred overnight.

The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution and then ethyl acetate were added, and the mixture was stirred for a while. After liquid separation, the aqueous layer was extracted again with ethyl acetate, and the organic layers were combined and washed successively with a cold 0.5N hydrochloric acid aqueous solution, saturated sodium bicarbonate water, and saturated saline.

After drying over sodium sulfate, the residue obtained by distilling off the solvent was adsorbed on a silica gel (25 g) column, and benzene / ethyl acetate (10/1), (5/1), (3/1), (1 / 1)
It was eluted stepwise at. UV on Rf 0.39 and 0.29 on TLC using benzene / ethyl acetate (2/1) as eluent
The group having absorption and the group having UV absorption only at Rf 0.29 were collected and concentrated under reduced pressure to obtain a mixture of compounds 1a and 1b ( 1
a : 1b- 1: 4) 51.8 mg (8.0%) and compound 1a 271.8 mg (4
2.0%) each as a colorless syrup.

Physicochemical properties of mixture 1a ▲ [α] ²⁴ _D ▼ -36.8 ° (C 1.02, CH ₂ Cl ₂ ). ¹ H NMR (CDCl ₃ ) δ 1.17 (3H, t, J = 7.5Hz, OCH ₂ CH ₃ ) 1.33 (3H, t, J = 7.5Hz, OCH ₂ CH ₃ ) 1.47 (3H, d, J = 6.8Hz , CH ₃ CH (OH) −) 2.55 (1H, b, OH) 3.34 (1H, dd, J = 2.4and6.0Hz, H-3) 3.35-3.95 (4H, m, 2 × OCH ₂ CH ₃ ) 3.85 (3H, S, OMe) 4.06 (1H, dd, J = 2.4and4.5Hz, H-4) 4.0-4.4 (1H, m, CH 3 CH (OH) -) 4.75 (1H, d, J = 4.5Hz , -CH (OE ₊ ) ₂ ), 6.95 (2H, d, J = 9Hz, phenyl), 7.52 (2H, d, J = 9Hz, phenyl).

Physicochemical properties of compound 1b ▲ [α] ²³ _D ▼ + 73.4 ° (C 0.7, CH ₂ Cl ₂ ) ¹ H NMR (CDCl ₃ ) δ 1.16 (6H, t, J = 7.5Hz, 2 × OCH ₂ CH ₃ ) 1.22 (3H, d, J = 6.8Hz, CH ₃ CH (OH) −), 3.2 (1H, b, OH), 3.3-4.0 (5H, m, H-3and2 × OCH ₂ CH ₃ ) 3.84 (3H, S, OMe) 4.26 (1H, t, J = 6.0Hz, H-4), 4.2-4.6 ( _{1H, m, CH 3 CH (} OH) -) 5.12 (1H, d, J = 6.0Hz, -CH (OE +) 2), 6.92 (2H, d, J = 9.5Hz, phenyl), 7.55 (2H, d, J = 9.5 Hz, phenyl).

Example 2: (3R, 4R) -4- (diethoxy) methyl-3-
[(R) -1-Fluoroethyl] -1- (p
-Methoxy) phenyl-2-azetidinone (2)
Manufacturing Diethylaminosulfatrifluoride 114 μl (0.9
A solution of 34 mmol) in methylene chloride (1.5 ml) was cooled to -70 ° C and (3R, 4S) -4- (diethoxy) methyl-3-[(S) -1-hydroxyethyl] -1- (with stirring. p-
Methoxy) phenyl-2-azetidinone ( 1a ) 151mg
A solution of (0.467 mmol) in methylene chloride (2.0 ml) was slowly added dropwise. The reaction solution was stirred overnight while gradually raising the temperature from -70 ° C to room temperature.

The reaction mixture was poured into cold saturated sodium bicarbonate water, and then methylene chloride was added to separate the layers. Extract the aqueous layer again with methylene chloride,
The organic layers were combined, washed with saturated brine, and dried over sodium sulfate.

The syrup obtained by distilling off the solvent is silica gel (13 g)
Column chromatography, and eluted stepwise with benzene / ethyl acetate (20/1), (10/1). Of the eluate, the fractions with UV absorption at Rf 0.40 on TLC with benzene / ethyl acetate (7/1) as the developing system were collected and concentrated under reduced pressure to obtain 92 mg (61%) of the title compound as a colorless syrup. It was

▲ [α] ²² _D ▼ -56.6 ° (C 0.92, CH ₂ Cl ₂ ) ¹ H NMR (CDCl ₃ ) δ 1.14 (3H, t, J = 7.5Hz, OCH ₂ CH ₃ ), 1.20 (3H, t, J = 7.5Hz, OCH ₂ CH ₃ ) 1.48 (3H, dd, J = 6.5) and24.5Hz, CH ₃ CHF−) 3.26-4.00 (5H, m, H−3and2 × OCH ₂ CH ₃ ), 3.83 (3H, S, OMe) 4.25 (1H, dd, J = 2.1and3.3Hz, H− 4), 4.80 (1H, d , J = 3.3Hz, CH (OE +) 2), 4.65-5.60 (1H, m, CH 3 CHF-), 6.92 (2H, d, J = 9Hz, phenyl), 7.52 (2H, d, J = 9Hz, phenyl).

Example 3: (3R, 4S) -3-[(R) -1-fluoroethyl] -4-formyl-1- (p-methoxy)
Production of phenyl-2-azetidinone ( 3 ) (3R, 4S) -4- (diethoxy) methyl-3 [(R)-
92 mg (0.28 mmol) of 1-fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone ( 2 ) was added to acetic acid (1.6
ml) and water (0.4 ml), 1N aqueous hydrochloric acid solution (0.6 ml) was added, and the mixture was heated and stirred at 55-60 ° C for 10 hr.

The reaction solution was diluted with ethyl acetate, and saturated sodium bicarbonate water was added while stirring at 0 ° C. to neutralize. After liquid separation, the aqueous layer was re-extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over sodium sulfate.

The syrup obtained by distilling off the solvent was adsorbed on a column of silica gel (5 g) and developed with benzene / ethyl acetate (4/1). Of the eluate, the fractions having UV absorption at Rf0.21 on TLC with benzene / ethyl acetate (2/1) as the development system were collected and concentrated under reduced pressure to obtain 64.0 mg (90%) of the title compound as a colorless syrup. It was

▲ 〔α〕 ²¹ _D ▼ -134.2 ° (C 1.175, CHCl ₃ ¹ H NMR (CDCl ₃ ) δ 1.50 (3H, dd, J = 6.0and24.0Hz, CH ₃ CF−), 3.42 (1H, ddd, J = 6.0and22.5Hz, H-3) 3.78 (3H, S, OMe) 4.50 (1H, t, J = 3.0Hz, H-4) 5.07 (1H, dquint, J = 6.0and48.5Hz, CH ₃ CHF
-) 6.88 (2H, d, J = 9Hz, phenyl), 7.28 (2H, d, J = 9Hz, phenyl), 9.83 (1H, d, J = 3.0Hz, -CHO).

Example 4: (3R, 4S) -4-carboxy-3-[(R)-
Preparation of 1-fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone ( 4 ) (3R, 4S) -3-[(R) -1-fluoroethyl] -4
-Formyl-1- (p-methoxy) phenyl-2-azetidinone ( 3 ) 112 mg (0.446 mmol) was dissolved in acetone (3 ml) and stirred at 0 ° C with 0.19 ml of diyon's reagent (0.
(49 mmol) was added dropwise, and the reaction solution was stirred at 0 ° C. for 2 hours.

2-Propanol (0.2 ml) was added to the reaction solution, the mixture was stirred for 10 minutes, and then the reaction solution was poured into ethyl acetate. This was washed successively with water and saturated saline. Next, the acidic component was extracted from this organic layer with cold dilute heavy sodium water, and after liquid separation, the aqueous layer was extracted with ethyl acetate twice with a 1N aqueous hydrochloric acid solution to adjust the pH to 2-3.

The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain 76 mg of the title compound as an amorphous solid (yield 64%).

▲ [α] ²³ _D ▼ -79.4 ° (C 0.97, MeOH) ¹ H NMR (acetone-d ₆ ) δ 1.55 (3H, dd, J = 6.5and24.3Hz, CH ₃ CF−), 3.73 (1H, ddd, J = 6.0, 5.3and25.5Hz, H−
3), 3.87 (3H, S, OMe), 4.75 (1H, d, J = 3.0Hz, H-4), 5.25 (1H, dqd, J = 5.3, 6.5and49.0Hz, CH ₃ CHF
-) 7.03 (2H, d, J = 9Hz, phenyl), 7.52 (2H, d, J = 9Hz, phenyl), 7.6-8.0 (1H, b, COOH).

Claims (2)

[Claims] 1. A formula In the formula, R ₁ and R ₂ each represent a lower alkyl group,
Alternatively, R ₁ and R ₂ together represent a lower alkylene group, and Z represents a hydrogen atom or an amino protecting group. 2. Formula (a) In the formula, R ₃ represents a carboxyl protecting group, and a dianion derived from a compound represented by In the formula, R ₁ and R ₂ each represent a lower alkyl group,
Alternatively, R ₁ and R ₂ together represent a lower alkylene group, Z represents a hydrogen atom or an amino protecting group, and the compound represented by In the formula, R ₁ , R ₂ and Z have the above meanings, and the compound represented by the formula is treated with a fluorinating agent. In the formula, R ₁ , R ₂ and Z have the above-mentioned meanings.