JPS604812B2 - Production method of β-lactam - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing 8-lactam.

More specifically, the present invention relates to a method for producing an 8-lactam by reacting a ketene silylacetal with a Schiff base in the presence of a halogenated titanium compound. The 8-lactam produced by the method of the present invention has the general formula [wherein,
R1, R2 and R9 are hydrogen, an alkyl group or an aryl group, R7 and R8 are hydrogen, an alkyl group, an aryl group, an alkoxy group, an alkyl or arylthio group or an amino group, and RI and R2, R7 and R8 or R7
and R9 are carbon chains (a heteroatom may be included in the chain).

) are also included. ] This is a compound represented by The 8-lactam represented by the above general formula (1) has recently been found to be useful as an antibiotic in itself [see Tokusei No. 51-29476], and is also the main skeleton of benicillin and cephalosporin, and is important as a medicine. It is a basic substance. Conventionally, there are the following methods for producing 3-lactam.

Method for cyclizing '-8-amino acid ester using Grignard reagent [R. Breckpot. , B sail. S ratio. Chem. Bel bag s. 32,412 (1923:E
．． Testa, et al. , Ahn. Chem. ,63
9, 157 (1961)].

'. } Method for reacting ketene with Schiff base [J. S
Neudinger, Value n, Chem,, 356 51 (
1907): J. C. Sheehan, et al. ，
J. Amer. Chem. S.M. ,73,1204(1
951)). Shiichi In the presence of zinc, Schiff base and Q
- Method of reacting with promocarboxylic acid ester [F.
Dardoize, et al. , B mountain 1. SC℃. C
Him. See FMnCe, 3841 (1972)].

However, since the method involves side reactions, the yield is generally low; In the method ', the types of ketene substituents used are limited and lack generality. Furthermore, the first method has the drawback that the reaction yield is greatly affected by the types of substituents of the Q-bromocarboxylic acid ester and the Schiff base, and the yield is significantly lower for products other than penzylidene aniline derivatives. It lacks. The present inventors have completed the present invention as a result of repeated studies on the method for producing 8-lactam in order to eliminate such drawbacks of the conventional method.

According to the method of the present invention, various 3-lactams can be produced in high yields without producing by-products. The ketene silyl acetal used as a raw material in the method of the present invention has the general formula RI
R2C=C(OR3)OSiR4R5R6 (b) [In the formula, R1 and R2 are hydrogen, an alkyl group or an aryl group, R3 is an alkyl group or an aryl group, and R4
, R5 and R6 are an alkyl group or an aryl group, and R
I and R2, RI and R3, or R2 and R3 are carbon chains (a heteroatom may be included in the chain).

) are also included. ] is a compound that can be represented by The ketene silylacetal of the general formula (0) can be used, for example, in the ester hydrosilylation reaction [1.
Ojima, et al. ,). Nometal.
Chem. , 111.43 (see (1976)), or the reaction of ester, lithium diisopropylamide with chlorosilane [C.
) can be synthesized in high yield. The general formula (D)
Examples of compounds included in this include 0-methyl-○-trimethylsilyldimethylketene acetal, 0-methyl-○-trimethylsilylmethylketene acetal, 0-methyl-○-trimethylsilylbentamethylene ketene acetal, 0-methyl-○-trimethylsilyl phenol ketene acetal, etc. can be mentioned. The other starting material, Schiff's base, has the general formula [where R7 and R
8 is hydrogen, an alkyl group, an aryl group, an alkoxy group, an alkyl or arylthio group, or an amino group, and R
9 is hydrogen, an alkyl group, or an aryl group, and R7 and R
8 or R7 and R9 are carbon chains (a heteroatom may be included in the chain).

) are also included. ] This is a compound represented by The Schiff base included in this formula (0) is a compound that can be easily produced, for example, by a dehydration reaction between ammonia or a substituted dihydroamine and a carbonyl compound. The present invention requires the presence of a halogenated titanium compound.

Examples of halogenated titanium compounds include titanium tetrachloride, titanium tetrabromide, and chlorotitanium triisopropoxide and dichlorotitanium diisopropoxide in which halogen is substituted with an alkoxy group; Considering this, titanium tetrachloride is the most desirable. It is sufficient to use the halogenated titanium compound in an amount equivalent to that of the ketene silyl acetal. Further, in carrying out the present invention, it is preferable to use a solvent, and for example, inert solvents such as methylene chloride, chloroform, carbon tetrachloride, ether, benzene, hexane, etc. can be used. The reaction is -78qC
- 3-lactam can be produced in high yield by mixing at room temperature and hydrolyzing after completion of the reaction. Incidentally, since the ketene silyl acetal used in the present invention is generally easily hydrolyzed, it is desirable to carry out the reaction under anhydrous conditions. Furthermore, in carrying out the present invention, in the reaction between ketene silylacetal and Schiff's base, a mono- and 8-amino acid ester derivative is passed through the intermediate, so if a thick intermediate is formed, cyclization is not possible. It is preferred to treat the reaction mixture with a base such as potassium tert-butoxide, sodium hydroxide, lithium diisopropylamide, etc. to promote the reaction.

Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 TIC141. Bamboo (0.01
Pour a solution of 10 moles of methylene chloride, cool it on an ice-water level, and add 2.38 moles of penzylidene methylamine (0 mole) to this solution.
．． A solution of 0.02 mol) of methylene chloride was gradually added dropwise while stirring.

After the dropwise addition was completed, the case was removed, the temperature was returned to room temperature, and 0-methyl-○-trimethylsilyldimethylketene acetal 1.
A solution of 74 mmol (0.01 mol) of methylene chloride was added dropwise. After stirring for 6 hours, the reaction mixture was poured into ice water for 100 minutes. After separating the organic layer, the aqueous layer was extracted twice with 100 g of methylene chloride, and the extracts were combined with the organic layer and dried over magnesium sulfate. After that, the solvent was distilled off and further distilled under reduced pressure to obtain a boiling point of 96oo/0.6 Yanagi Hg.
1.36 ml of 1,3,3-trimethyl-4-phenyl-2-azetidinone (yield 72%) was obtained. Example 2 A solution of 5.43 g (0.03 mol) of penzylidene aniline in 60 ml of methylene chloride was cooled in an ice-water bath and added with TI.
C14 methylene chloride solution (IM) 30 [(0.03
I dripped it while worshiping the mole).

After the completion of dripping, after continuing to worship for 1q minutes, ○-methyl-○
-trimethylsilyldimethylketene acetal 5.22
(0.003 mol) was added dropwise. Next, except for ice water level,
After being concentrated at room temperature for 6 hours, the reaction mixture was poured onto 200 ml of ice water. Post-treatment was carried out in the same manner as in Example 1, and the melting point was 1.
N-phenyl-2,2-dimethyl-3-phenyl-8-alanine methyl ester having 22-12-0 was obtained. Yield: 6.70 yen (yield: 79%). The substituted B-alanine methyl ester obtained was then cyclized in the presence of lithium diisopropylamide to give the corresponding 8-lactam.
That is, a THF-bentane solution prepared from diisopropylamine and n-butyllithium or tium diisopropylamide (0.01 mol) was cooled on an ice-water level, and the previously obtained substituted P - A solution of 2.83 mol (0.01 mol) of alanine methyl ester in 15 THF was gradually added dropwise. After dropping, remove the ice water bath and incubate at room temperature for 4 hours.
After dilution, the reaction mixture was treated with ice water for 100 min, and the product was isolated in the same manner as in Example 1.
3,3-dimethyl-1,4-diphenyl-2-azetinone having a temperature of 0-151°C was obtained. Yield: 2.28 min (yield: 91%), total yield: 72%. Examples 3 to 6 The results shown in Table 1 below were obtained in the same manner as in Example 1 or 2.

In Examples 5 and 6, one intermediate, 3-amino/acid ester, was isolated and treated with lithium diisopropylamide to induce the corresponding 8-lactam. length of the ship

Claims (1)

[Scope of Claims] 1. A method for producing a β-lactam, which comprises reacting a ketene silylacetal with a Schiff base in the presence of a halogenated titanium compound. 2. A process according to claim 1, which comprises treating the reaction mixture of ketene silylacetal and Schiff's base with a base. 3 Ketensilyl acetal has the general formula R^1R^2C=C(OR^3)OSiR^4R^5R
It is a compound represented by ^6, and the Schiff base has the general formula ▲
There are mathematical formulas, chemical formulas, tables, etc. The method according to claim 1 or 2, which is a compound represented by ▼ [in the formula,
R^1, R^2 and R^9 are hydrogen, an alkyl group or an aryl group, R^3 is an alkyl group or an aryl group, and R^4, R^5 and R^6 are an alkyl group or an aryl group. group, R^7 and R^8 are hydrogen, an alkyl group, an aryl group, an alkoxy group, an alkyl or arylthio group, or an amino group, and R^1 and R^2, R^1 and R
^3, R^2 and R^3, R^7 and R^8 or R^7
and R^9 also include those connected by a carbon chain (the chain may contain a heteroatom). ]. 4. The method according to claim 1, 2 or 3, wherein the titanium halide is titanium tetrachloride. 5. A method according to claim 1, 2, 3 or 4, which comprises carrying out the reaction under anhydrous conditions.