JPH0572894B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing β-amino esters and β-aminothioesters. β-amino esters and β-aminothioesters can be easily converted into β-lactams, and the present invention particularly provides β-amino esters and β-lactams that are effective as raw materials for the synthesis of β-lactam antibiotics.
-This invention relates to a method for producing aminothioester. [Prior Art and Problems] β-Aminoesters and β-aminothioesters have been synthesized by various methods.
Typical synthesis examples thereof are shown below. A method in which Schiff's base acts on an ester in the presence of lithium diisopropylamine. [GIGeorg, Tetrahedron Lett., 26 , 3903
(1985); T. Nakai, Chem. Lett., 1985 , 652;
G. Cainelli, Tetrahedron Lett., 26 , 937
(1985)] A method in which Schiff base acts on ketene silylacetal in the presence of titanium tetrachloride. [I.Ojima, Tetrahedron Lett., 21 , 2081
(1980); J.-E. Dubois, Tetrahedron Lett.
26, 1523 (1985)] A method of reacting a thioester with a Schiff base in the presence of 9-borabicyclo[3.3.1]nonan-9-yl-triflate and diisopropylethylamine. [M. Shibasaki, Tetrahedron Lett., 26 , 1523
(1985)] All of the above conventional methods are applicable only to a limited number of Schiff bases. The Schiff bases applied in the examples are Schiff bases derived from aromatic aldehydes and cinnamaldehydes, that is, the substituent R ¹ shown in the following general formula (1) is limited to phenyl groups and cinnamyl groups. In the examples R ¹ is limited to phenyl and isopropyl groups. As ^is clear from these facts, β-amino esters and β-
There are few synthetic methods for aminothioesters. In particular, when the α-position carbon of the Schiff base is methylene (-CH ₂ -) as shown in the general formula (2) below, it is difficult to synthesize the corresponding β-amino ester and β-aminothioester, and the only By the method in the example, from the Schiff base shown in general formula (2), the corresponding β
-It is possible to synthesize aminothioesters, but the yield is low. [Formula] [Formula] Furthermore, these methods use strong bases (examples), bases (examples), and strong acids (examples), and the reaction conditions are not necessarily mild. That is, according to conventional methods, various side reactions occur in reactions with Schiff bases having complex functional groups. [Means for Solving the Problems] As a result of intensive research in order to solve the above-mentioned problems, the present inventors found that under mild conditions, that is, near neutral conditions, the substituent represented by the above general formula (1) We have found a method by which the corresponding β-amino esters and β-aminothioesters can be synthesized from any Schiff base in which R ¹ is an aromatic or aliphatic hydrocarbon group, and furthermore, the products β-amino esters or β- With respect to the relative configuration of the α and β positions of aminothioester, it has become possible to selectively obtain one diastereomer, and the present invention has been completed. That is, the present invention provides β-amino esters and β-amino esters, which are characterized by reacting a Schiff base with a ketene in the presence of a divalent tin alcoholate or a divalent tin thiolate and, if necessary, a Lewis acid.
This relates to a method for producing aminothioester. The divalent tin alcoholate or divalent tin thiolate used in the present invention has the formula Sn(X ² R ⁵ )
Examples include those shown in ₂ . Here, X ² represents a sulfur element or an oxygen element, and R ⁵ represents an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms), an allyl group, an aryl group (preferably a phenyl group), or a pyridyl group; It may have a substituent. Methods for synthesizing divalent tin alcoholate or divalent tin thiolate include a method in which alcohol or thiol is reacted with bismethylcyclopentadienyltin (), and a method in which alcohol is reacted with tin chloride () in the presence of triethylamine [JSMorrison , J.Inorg.Nucl.Chem., 29 ,
393 (1967)], but is not particularly limited. Examples of ketenes used in the present invention include those represented by the following general formula. [Chemical formula] In the formula, R ⁶ and R ⁷ may be the same or different,
H, halogen, alkyl group (preferably 1 carbon number
~6 alkyl group), an aryl group (preferably a phenyl group), or [Formula] (where R ⁸ , R ⁹ , and R ¹⁰ may be the same or different, and R ⁶
or the same alkyl group or aryl group as R ⁷ ), such as ketene, alkyl ketene, aryl ketene, dialkyl ketene, alkylaryl ketene, halo ketene, dihaloketene, trialkylsilyl ketene, dialkylarylsilyl ketene, diaryl Examples include alkylsilylketene, triarylsilylketene, and the like. The Schiff base used in the present invention has the above general formula (1).
The following can be mentioned. In the formula, R ¹ , R ²
may be the same or different, and may represent an alkyl group, an aryl group, an allyl group, etc., and may have a functional group. Specific examples include 3-phenylpropyl group, furyl group, cinnamyl group, phenyl group, isopropyl group, and those having functional groups such as ketone, ester, halogen, and alkoxy group in these substituents. Some Schiff bases require the addition of Lewis acids such as Sn(OTf) ₂ (Tf represents a trifluoromethanesulfonyl group) and SnX ¹ (X ¹ represents a halogen). However, the present invention does not limit the presence or absence or type of Lewis acid. The reaction formula of the present invention is shown by the following formula. [Chemical structure] [Chemical structure] The present invention uses tetrahydrofuran as a reaction solvent,
Either polar or non-polar solvents may be used, such as methylene chloride, diethyl ether, toluene, hexane, acetonitrile, dimethyl sulfoxide, and the like. In general, β-amino(thio)esters can be obtained in good yields when using non-coordinating solvents such as methylene chloride, and with good stereoselectivity when using coordinating solvents such as tetrahydrofuran. . The reaction temperature is -100 to -23℃, and the ketene (A), alcoholate or thiolate (B) used,
The molar ratio of Schiff base (C) and Lewis acid (D) is (A)/
(B)/(C)/(D)=2.0~1.0/1.0/2.0~0.5/0~1.0,
Preferably (A)/(B)/(C)/(D)=1.2/1.0/0.75~
It is 0.5/0 to 1.0. These reaction solvents, reaction temperatures, molar ratios, etc. are appropriately selected depending on the compound used and the target β-amino(thio)ester. β-amino ester and β obtained according to the present invention
-Aminothioesters can be easily converted into β-lactams. For example, β-aminothioester is converted to β-lactam in good yield in acetonitrile in the presence of mercuric trifluoroacetate. From this, the β-amino(thio)ester obtained in the present invention is considered to be an important synthetic intermediate for β-lactam compounds. In particular, in the present invention, β-amino(thio)esters can be synthesized in good yields from Schiff's base obtained from aliphatic aldehydes, so various functional groups, such as R ^{1 =}
By providing CH ₂ CH ₂ OCH ₂ Ph, it is also possible to synthesize intermediates of β-lactam antibiotics all at once. [Image Omitted] Anti-isomer obtained preferentially [Effects of the invention] The method for producing β-amino esters and β-aminothioesters of the present invention has the following effects. 1. Synthesis is now possible under mild conditions (neutral conditions). 2 The corresponding β-hydroxy(thio)esters can also be obtained in high yields from Schiff bases obtained from aliphatic aldehydes. Regarding the relative configuration of α and β positions of 3 β-hydroxy(thio)ester, it has become possible to preferentially obtain one diastereomer. [Example] Next, the present invention will be explained in more detail with reference to Examples. In the examples, Me represents a methyl group, Ph represents a phenyl group, Et represents an ethyl group, tBu represents a tert-butyl group, and Bn represents a benzyl group. Example 1 (Production of β-benzylamino-α-methylthioester) The reaction formula of this example is represented by the following formula. [C] [C] Bismethylcyclopentadienyltin () 150 mg according to the method of HGParrison et al.
(0.54 mmol) in tetrahydrofuran (2 ml) at room temperature.
Add 122 μ (1.08 mmol), stir for 30 minutes,
A solution of tin t-butyl thiolate in tetrahydrofuran was prepared. CC in this solution at −78 °C.
The method of McCarney et al. (J.Chem.soc., Perkin1,
1.2 ml (0.65 mmol) of a tetrahydrofuran solution of methyl ketene obtained by
-Benzylbenzylideneamine 80 mg (0.41 mmol)
A tetrahydrofuran solution (1 ml) was added and stirred for 90 minutes. After the reaction was stopped by adding phosphate buffer (PH7), chloroform extraction was performed.
The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By separating and purifying this using preparative thin layer chromatography, the corresponding β-aminothioesters (a) and (b) were separated to a total of 41% {(a):(b)=
72:28}. The production ratio of diastereomers (a) and (b) was determined from the proton integral ratio of the tBu group in ¹ H-NMR. In addition, the relative configuration was converted to β-lactam by the following method and determined from the coupling constants at the 3 and 4 positions of ¹ H-NMR {J _3,4 (Hz): (c), 2.1; (d),
5.3}. That is, β-aminothioester (a), (b) (57
Add mercury trifluoroacetate (143 mg, 0.34 mmol) as a solid to a solution of mercury trifluoroacetate (143 mg, 0.34 mmol) in acetonitrile (10 ml) and stir at room temperature for 12 hours. Hydrogen sulfide gas is passed through the reaction solution to stop the reaction, and the precipitate is removed by filtration. The filtrate was once concentrated under reduced pressure and then extracted from ethyl acetate/sodium hydrogen carbonate. The extract was dried and concentrated according to a conventional method, and then separated and purified using preparative thin layer chromatography to obtain the corresponding β-lactams (c) and (d) in a combined yield of 80%. (The reaction formula is expressed by the following formula). [Chemical formula] [Chemical formula] The analytical values of the obtained compound are as follows. ¹ H-NMR (CDCl ₃ ), δ (ppm) Compound (a) 0.85 (d, 3H), 1.50 (s, 9H), 1.83 (bs, 1H),
2.67 (dq, 1H), 3.45−3.90 (m, 3H) Compound (b) 1.23 (d, 3H), 1.40 (s, 9H), 1.83 (bs, 1H),
2.75 (dq, 1H), 3.47−4.05 (m, 3H) IR (neat) cm ^-1 Compound (a) 1680 1460 964 Compound (b) 1665 1447 950 Examples 2 to 4 Except for changing the reaction solvent, An experiment similar to Example 1 was conducted. The results are shown in Table 1. [Table] Examples 5-6 Example 1 except that Lewis acid was added to the reaction solvent
conducted a similar experiment. The results are shown in Table 2. [Table] Example 7 [Chemical] [Chemical] Bismethylcyclopentadienyltin ()
150 mg (0.54 mmol) of tetrahydrofuran (2
ml) solution at room temperature was added 122μ (1.08 mmol) of 2-methyl-2-propanethiol and stirred for 30 minutes to prepare a tetrahydrofuran solution of divalent tin t-butylthiolate. To this solution was added 1.2 ml (0.65 mmol) of a tetrahydrofuran solution of methyl ketene obtained by the method described in Example 1 and N-
Diphenylmethylbenzylideneamine 111mg
(0.41 mmol) in tetrahydrofuran (1 ml) and 203 mg (0.49 mmol) of divalent tin trifluoromethanesulfonate were added at -78°C and stirred for 12 hours. After adding phosphate buffer (PH7) to stop the reaction, chloroform extraction was performed. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By separating and purifying this using preparative thin layer chromatography, a total of 89% of the corresponding β-aminothioesters (a') and (b') {(a'):
(b′)=96:4} was obtained. The relative configuration was determined by the method described in Example 1.
-converted to lactam and determined from the coupling constants at the 3rd and 4th positions of ¹ H-NMR {J _3,4 (Hz): (a′),
2.2; (b′), 6.0}. The analytical values of these products are as follows. ¹ H-NMR (CDCl ₃ ), δ (ppm) Mixture of compound (a') and compound (b') 1.17 (d, 3H), 1.53 (s, 9H), 4.46 (s, 1H)
...Equivalent to compound (a') 1.23 (d, 3H), 1.27 (s, 9H), 4.57 (s,
1H) ...Equivalent to compound (b') 2.2 (bs, 1H), 2.35−3.1 (m, 1H), 3.57−
3.93 (m, 1H), 7.00-7.50 (m, 15H)
...IR (neat) cm ^-1 common to compound (a') and compound (b') Mixture of compound (a') and compound (b') 1680, 1453, 960 Examples 8 to 14 Ketenes, Schiff base The same experiment as in Example 7 was conducted except that the molar ratio, Lewis acid, and Lewis acid were changed as shown in Table 3. The results are shown in Table 3. In addition, to determine the relative configuration, except for Example 12, convert to β-lactam as shown in Example 1, and calculate its ¹ H-NMR coupling constant {J _3,4
(Hz)}. Example 12 was carried out by the method shown in the following formula. [Formula] [Formula] [Formula] [Formula] That is, the anti-isomer (a″) was converted to β-lactam (c″) by the method shown in Example 1. (c″)
60 mg (0.16 mmol) was dissolved in liquid ammonia (5 ml) and 20 mg of sodium metal was added under reflux conditions.
(0.87 mmol) and stir for 10 minutes. Add an excess amount of ammonium chloride as a solid to the reaction solution,
The reaction was stopped. After distilling off ammonia at room temperature, ethyl acetate was added to extract organic components from the residue. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified using preparative thin layer chromatography to obtain 84% alcohol (e).
% yield. The relative configuration of (e) was found to be trans from the ¹ H-NMR data described in the literature (D.
Favara, Tetrahedron Lett., 23 , 3105 (1982)).
In addition, (b″) was converted to alcohol (f) using the same procedure, and by comparing it with ¹ H-NMR data described in the literature, it was found to be the cis form (Amedeo Omodei-Sale, Gazzetta
Chimica Italiana, 114 , 225 (1984)). The reaction in this example is expressed by the following formula. [C] [C] [Table] *4: The molar ratio of production has not been determined.
*5: (a〓) was not confirmed by ¹ H-NMR.
*6: Values for lactams corresponding to (a〓) and (b〓).

Claims (1)

[Claims] 1. A method for producing β-aminoesters and β-aminothioesters, which comprises reacting a Schiff base with a ketene in the presence of a divalent tin alcoholate or a divalent tin thiolate and, if necessary, a Lewis acid.