JPS6222789A - Beta-n-substituted aminothiol ester and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is alkyl or aryl; R<2> is aralkyl). EXAMPLE:Phenylthioester of 3-benzylamino-2-(1-hydroxyethyl)-5-trimethylsilyl-4- pentinic acid expressed by formula II. USE:A synthetic intermediate for beta-lactam compounds. PREPARATION:A beta-hydroxythiol ester expressed by formula III, e.g. S- phenyl-3(R)-hydroxybutanethioate, is reacted with a boron compound expressed by formula IV, e.g. 9-borabicyclo[3.3.1]nonyltrifluoromethanesulfonate, in the presence of a tertiary amine to give a reaction mixture, which is then reacted with an imine expressed by the formula R<2>-N=CH-CidenticalC-SiMe3, e.g. N-3- trimethylsilylpropylidenebenzylamine and then treated with H2O2.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to β-N-ti substituted This invention relates to a method for producing aminothioaminothiol esters.

The β-N-substituted aminothiol ester of the present invention represented by general formula (I) can be converted into carbapenem β-lactam antibiotics such as chenamycin. Carbapenem β-lactam antibiotics exhibit excellent antibacterial activity against almost all bacteria, including Bacteria aeruginosa, and their strength is much greater than that of conventional drugs, and they also have excellent β-lactamase stability.

Therefore, they are a group of substances that have great expectations as second generation β-lactum antibiotics.

[Conventional technology]

Carbapenem filament β-lactam antibiotics have low productivity through fermentation, and at present they have to rely on chemical synthesis for industrial purposes. This can be said to be completely different from conventional penicillin and cephalosporin antibiotics.

Various carbapenem β-lactam antibiotics are currently in the clinical stage, but the synthetic intermediates that form the backbone of these compounds are represented by the general formula (wherein B! and W are retention groups). β
- It is a substance well known to those skilled in the art that it is a lactam.

Conventionally, methods for producing β-lactams represented by the above general formula (...) include l) monocyclic β-lactams having a side chain at the 4-position using asymmetric synthesis using optically active amino acids or enzymes;
- A method of constructing a lactam ring and then introducing a side chain at the 3-position, 2) A method of selectively constructing asymmetric carbons corresponding to the 3-, 4-, and 11-positions using special means, and then β-lactam and 3) constructing a monocyclic β-lactam having a side chain at the 3-position from L-threonine, optically active penicillin, etc.
A method is known in which a 4-position side chain is then introduced [Masayuki Shibuya, Journal of the Society of Organic Synthetic Chemistry, 41.62 (1983)
).

[Problem that the invention seeks to solve]

However, method 1) is relatively difficult to detect and introduce into the 3-position, is unsuitable for large-scale synthesis, and is difficult to employ as an industrial production method. Furthermore, although method 2) is an industrially adopted method, it has the disadvantage that the manufacturing process is long and includes optical resolution. Furthermore, the above 3
Although the method (2) can obtain the desired optically active substance, it has the drawback of requiring a long number of manufacturing steps. Very recently, a short-step synthesis method using optically active 3-hydroxybutyric acid was announced [J
,Am,Chem,Soc,,103.4819(19
84) ;Chem.

Lett, 1927 (19B4); Chem, Lef
t,, 651 (1985); Tet, Lett,, z
s, 937 (t9ss); Tet.

bett,,z! 2. xs23 (x9ss)), but it is unsatisfactory in terms of stereoselectivity and yield.

As a result of intensive studies to solve the above problems, the present inventors have found that β-N-
The substituted aminothiol ester compound has the general formula (1)
The present inventors have discovered that it is an excellent synthetic intermediate for the β-lactam compound represented by the formula, and have completed the present invention.

[Means for Solving the Problem] The β-N-substituted aminothiol ester of the present invention represented by the general formula (1) is prepared in the presence of a tertiary amine by the general formula (wherein R is an alkyl group or aryl group) and the general formula
・(In the formula, It and R are an alkyl group or a cycloalkyl group, and form a shell together with boron bonded together.) The reaction mixture i obtained is then reacted with a boron compound represented by It is produced by reacting an imine represented by the general formula % (in the formula, R2 is an aralkyl group), followed by treatment with hydrogen peroxide.

The β-hydroxythiol ester represented by the general formula (button) is a compound that can be easily obtained by protecting the hydroxyl group of β-hydroxycarboxylic acid, followed by dehydration condensation with the corresponding mercaptan, and then deprotection (see below) (See reference side).As the β-hydroxythiol ester represented by the general formula (If), for example, S-phenyl-
3...)-Hydroxybutanethioate, 8-1-butyl-34-hydroxybutanethioate, S-ethyl-3
σ()-Hydroxybutanethioate, S-5ec-
Butyl-3(R)-hydroxybutanethioate, S-
n-propyl-34-hydroxybutanethioate,
S-isopropyl-3(R)-hydroxybutanethioate and the like can be used. On the other hand, boron compounds represented by the above general formula are easily available industrially, such as 9-borabicyclo(3,'3.1)nonyltrifluoromethanesulfonate, dicyclohentyltrifluoromethanesulfonyloxyboron, di-n -butyltrifluoromethanesulfonyloxyboron, etc. can be used.

The reaction between the β-hydroxythiol Nisder represented by the general formula (I) and the boron compound represented by the general formula θV) needs to be carried out in the presence of a tertiary amine. Examples of the tertiary amine include diisopropylethylamine, triethylamine, trimethylamine, and tributylamine, but it is preferable to use diisopropylethylamine in order to carry out the reaction efficiently.

This reaction is carried out in a solvent. Solvents include methylene chloride, chloroform, 1,2-dichloroethylene and other halogenated hydrogen-based solvents, diethyl ether, tetrahydrofuran (THF), dimethoxyethane (1)M
Ether systems such as E), aromatic hydrocarbon systems such as toluene and xylene can be used.

The reaction normally proceeds smoothly at a temperature ranging from -78"C to room temperature.

The reaction mixture obtained by the above reaction has the above general formula (V)
It reacts with the imine represented by

The imine represented by the above general formula (1) is 1. N-
3-Tri°methylsilylprovinylidenebenzylamine % N3-)limethylsilylprovinylidene IJ 7' and the like can be used.

The solvent used in the reaction with the imine is the same as the solvent used in the reaction between the β-hydroxythiol ester and the boron compound.

The reaction proceeds easily at a temperature ranging from 8°C to room temperature.

In the present invention, β-N-Wt represented by the general formula (1) is obtained by reacting imine and then treating with hydrogen peroxide.
It is an aminothioaminothiol ester. As hydrogen peroxide, a solution of about 30% water is usually used. The amount of hydrogen peroxide used is 1 to 50% per β-hydroxythiol ester.
This is my child. During the hydrogen peroxide treatment, it is desirable to cool the reaction solution to 5° C. to room temperature.゛Hereinafter, the present invention will be further explained in detail with reference to Reference Examples and Examples.

Reference Example 1 Silyloxy) Methyl 3-hydroxybutyrate/L15.91g (50mmO
1), imidazo-/L/ 3.7411 (55 mmol
) was dissolved in 20 ml of M, and 8.2911 (55 mmol) of 1-butyldimethylsilyl chloride was added to this.
Added several times.

After stirring at room temperature for 30 minutes, ice water was added and extracted three times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
O,51Ffi-)-3-t-butyldimethylsilyloxybutyrate methyl was obtained. Yield 91%.

TI, C: 0.4 (hexane diethyl ether 20
:l).

II? , :(neat)l　735cIIL.

NMR: JO. 0 3 , 0.0 6 (eac
h 3H;su, 0.8 5(90;s), t. zo(3
<i;ci J:5).

2, 4 2 (211; m), 3.7 5 (aH
;s), 4.2 5(iH;m).

MS:l15,133,159(M-(Me+(X)(
Me)).

175 (M-Bu), 217 (M-Me).

[α] 6°-31.75° (c-1, 9 4, C
-FICl 3).

Reference Example 2 (3.5 BE (15.4 mmol) of methyl-3-3-t-butyldimethylsilyloxybutyrate, 30
To the methanol solution was added 30% of IN potassium hydroxide, and the mixture was stirred for 15 hours. Most of the methanol was distilled off, acidified with IN hydrochloric acid and extracted with diethyl ether.

The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.18Ii (-)-3.
-1-Butyldimethylsilyloxybutyric acid was obtained.

Yield 95% TLC: 0.2 (hexane:diethyl ether 20:l
).

IR: (neat) 1710cm.

NMIL: a 0.09 (6H; s), 0.88 (9H
;i), r. 20M8:110,137,197,21
8(M).

[α]6°- 1 2.5 0' (=Q.9 6
;chloroform).

Reference example 3 (-)-3-t-butyldimethylsilyloxybutyric acid 3,
18g (19.2mmol), thiophenol 2.26Wll (22mmol)
N,N'-dicyclohexylcarbodiimide 4,53& (22 mmol) was dissolved in methylene chloride.
was added at room temperature for 2 hours, filtered, and the filtrate was concentrated and distilled (110-116'o10, 3rnmH).
g) By doing so, (-)-3-t-butyldimethylsilyloxybutyric acid phenylthioester 5,00I
i (yield: 83 h).

TLC: 0.3 (hexane: diethyl ether 20:
l).

IR (neat) 1 7 1 0 cm-'.

NMR: JO. 07 (6H; s), 0.91 (9H;
s), 1.22 (3H; d J = 5), 2.6
1, 2.8 7 (each tHHddJ =]
5,7), 4.34 (tH,m), 7.4
1(5)(;s).

MS: l 15.159 (M-(Me+C08Ph))
, 253 (M-Bu), 295 (M-Me).

[α] is also '-fi5.91'', t(C=O, Q 8 ,
coctρ.

Reference example 4 ←)-3-t-butyldimethylsilyloxybutyric acid phenylthioester 3.261 (10.4 mmolλ),
Acetic acid:T11F:water (3:l:1) 50m/was added,
The mixture was stirred at 0°C for 24 hours. This was concentrated and distilled (12
8-130″O10,8mmHg) By doing so,
(-)-3-L nitroxybutyric acid hunyl thioester at 1.91,9. It was obtained in a yield of 94 cm.

TLC: o, 35 (hexane: diethyl ether 1:
1).

IRE(neat)3440, 1705cIIL-'
.

Connection a 1.20 (3H; d J-6), 2.82 (
2J(;d J=(i).

3.0 CIH; br s ), 4.22 (out; m)
, 7.36 (5H; lri.

M8: 110 (PhSH), 137 (Lo8Ph), 1
96(M).

[α) jo-42,2571 (c=x, 42, cu
es3).

Example 1 Ph80CNHCH2Pb 3-trimethylsilyl-2-propynal 1.511
(12, Ommol), benzylamine 1.3 ta
z (12, Ommol) was stirred in 10-diethyl ether for 30 minutes, and the solvent was distilled off under reduced pressure. This residue was distilled under reduced pressure (oil bath temperature 120υ~130'0/1mfnHg
) L/The obtained imine was immediately used in the following reaction. (-)-3-hydroxybutyric acid phenylthioester 1
．． 963Ii (10, Ommol) was dissolved in 40 m methylene chloride, and diisopropylethylamine 4.00 d (23, Ommol) 9-BB was added at -78°C.
N) Add 5.94 g (22, Ommol) of 7L/-t.

Raise the temperature to -25℃ over 1 hour, -30'0 to -20℃
After stirring at °C for 1 hour, the previously prepared 40 m methylene chloride solution of imine was added dropwise to the mixture over about 20 minutes at the same temperature. The temperature was raised to room temperature over 1.5 hours, and the mixture was further stirred for 1 hour. After cooling the reaction solution to -35°C to -40°C, add 60ml of phosphate buffer (pH 7,0).
/ - Jl/ 60 m % 31 ts A mixed solution of hydrogen peroxide solution 30 resistant was added over about 20 minutes.

The temperature was raised to 0°C over 30 minutes, and after stirring vigorously for 1 hour at room temperature, it was extracted twice with methylene chloride, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. did. The concentrated solution was purified with a silica gel column (c-300; developing solvent: hexane: diethyl ether 3:2) to obtain 3-benzylamino-2-(1-hydroxyethyl).
-5-trimethylsilyl-4-pentynic acid phenylthioester 2.054II was obtained. Yield: 50 cm.

'I'LC: 0.41 (hexane:diethyl ether 3:2) IR: (neat) 3400, 2160.1700cI
L.

NMR: J O, 23 (9H; l), 1.25 (3H;
dJ=7).

2-92 (tH; t J -6) -3-6 to 3-
8 (2H; m) −4,03 (IH; d J=12)
, 4.3 (IH;m).

7.30 (5H; s), 7.39 (5H; s).

MS: 151.216,302 [M+-8Pb], 4
12(M'+1).

Reference example 5 3-benzylamino-2-(1-hydroxyethyl)-
5-) 2.054 g (5.0 mmol) of riftylsilyl-4-pentynic acid phenylthioester was added to 401 Tf
The mixture was dissolved in 4F, added with 31 liters of 4N potassium hydroxide, and stirred at room temperature for 3 hours. This was neutralized with 2N hydrochloric acid and extracted six times with ethyl acetate while salting out. The extract was dried over anhydrous magnesium sulfate and concentrated.

2゜2'- while heating under reflux and stirring vigorously.
Dipyridyl disulfide 1.32II (6, Orhmo
A 50% acetonitrile solution of 1) was added dropwise over 40 minutes. After further heating under reflux for 1 hour, the reaction solution was concentrated,
Purification was carried out twice using 50g' of silica gel chromatography (developing solvent: methylene chloride → diethyl ether) and 50g' of silica gel chromatography (intermembrane solvent: hexane:diethyl ether 1:4) to obtain l-benzyl-4-ethynyl- 3-(1-hydroxyethyl)-2-
Trans-isomer 801qJ trans-isomer 62■ of azetidinone was obtained. The sample for analysis of the trans isomer was obtained by recrystallization from diethyl ether.

Trans-isomer TLC: 0.75 (diethyl ether) mp: 134
℃.

IR: (chloroform) 34sO, 1745cII
L.

NMR: δ1.24 (3H; d J-6), 2.42 (
IH; d, r=t).

2.7 (IH; br s), 3.28 (xH; dd J
=5゜2.5), 4.1 (3H1m), 4.73
(IH; dJ=15).

7.29 (5H;s).

MS: 132, 186, 211, 229 (M+3°An
al:C14H1502N Calculated value C73,3
4 chi, H6, 59 excellent, N6. llchi.

measured value C73,45chi, H6,54excellent, N 6.10chi.

[α] 6°-20,45° (ε=1.00J Rorobo 1 Lum).

Cis-isomer TLC: 0.56 (diethyl ether) IR: (Chloropho 7 L/m) 3500, 1750 cin-'.

NMR: δt, 36 (3H; d, r==6), 2
．． 68 (tH; a J = 2).

' 2.7 (out; br s), 3.27 (out; d
d J=5゜6), 4.2 (31(;rn)
,4. '76 (out; d J=15).

7.38 (5H;s).

MS: 150,187.20'5,229 (M+).

[α] 6°-58.82° (c=1.2zJ loloform).

Reference Example 6 Trans isomer obtained in Reference Example 5, i.e. l-benzyl-4(S)-ethynyl-3(S)-[1(lo)-hydroxyethyl]-2-azetidinone 2σ6m,y(0,9
゜nnmol) was dissolved in 3W11 dimethylformamide, and to this was added t-butyldimethylsilyl chloride 180q (1', 2111 mo 1),
tv 82 very (t, zmmol) was added and stirred overnight at room temperature. After diluting the reaction solution with diethyl ether, water was added and extracted three times with diethyl ether.The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

This was purified by 10II silica gel column chromatography (developing solvent: hexane:diethyl ether 2:l), and 318'rILg of 1-benzyl-4(8)-ethynyl-3(S)-(1(equal-t) -butyldimethylsilyloxyethyl]-2-acetidinone was obtained.

Yield quantitative.

TLC: 0.36 (diethyl ether:hexane l:2
) HL: (riCIO Holb) 1750clI+
.

Sakaitan: δ0.06.0.09 (each 3H;s,)
, 0.86 (9H; s) , 1.24 (311; d
J=6), 2.43 (IH; dJ=2), 3-27
(if-1; dd J=3, 2.5).

4.2 (3HHm), 4.70 (IH; d, T
=15).

7.34 (5H;')・M8: 242.286 (M+-Bu) 32B (M
+-Me).

[α)I! , 0-11.62° (C21.00.chloroform).

Reference example 7 1-benzyl-4(S)-ethynyl-3(S)-[l(
b)-1-butyldimethylsilyloxyethyl]-2-
0.015 ml of quinoline and 1.5 ml of petroleum ether were added to 103 mmol of azetidinone (0.30 mmol), and 1.5 ml of Lindlar catalyst was added thereto. Stir vigorously at room temperature for 12 hours under hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and petroleum ether 21, Lindlar catalyst 3
m:J was added and the reaction was further carried out for 36 hours under a hydrogen atmosphere. The reaction solution was subjected to log silica gel column chromatography (developing solvent: benzene:methylene chloride 1:1) to obtain a semi-reduced product containing the starting material, which was used in the following reaction without further purification.

The semi-reduced product containing the raw material was dissolved in 2 ml of Ti1l', and in an ice bath, 9-BBN TllF syneresis (0.6M) 1
．． After adding 1 mj (0.63 mmol) and stirring in a water bath for 1 hour, a solution of 9-BBN in 'rIIF (0.63 mmol) was added.
6M) 0.5 mj (0.3 mmol) was added, and the mixture was stirred in a water bath for 2 hours and at room temperature for 1 hour. Add 0.56stc of IJum to this reaction solution (4N hydroxide in a water bath)
2.3 mmol), 31% hydrogen peroxide solution 0.4 WLl
was added and stirred at room temperature for 1 hour. The reaction solution was diluted with diethyl ether, water was added, and extracted three times with diethyl ether. The extract was washed with a dilute aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Add this to 10g of silicage, 70cm of l-benzyl-
3(S)-[:l(b)-1-butyldimethylsilyloxyethyl]-4(R)-(2-hydroxyethyl)-
2-azetidinone was obtained.

Yield: 64 cm.

TLC: 0.3 (diethyl ether:hexane 3:
l).

IR: (Chloroform) 3460.1740 side.

NMR: 0.03, 0.07 (each 3H; s),
0.87 (9H; s).

1.26 (3H; d J = 6), 1.8 (2H; m
).

2-8 (IH; b r s ), 3-02 (I
H; dd J-2゜8), 3.6 (3H;
m), 4.2 (2H; m), 4.61 (lH
;'J=15)-7-3(5H;s).

+ M8: 306 (M-Bu), 348 (M+-Me)
.

[α] is also '-1,09° (C=1.20.chloroform).

Reference example 8 Sodium hydride (oil-based 50%) 13tI9 (0,2
6, and to this under a water bath, ■-benzyru3 (S)
-(l(R)-1-Butyldimethylsilyloxyethyl 910 minutes was stirred. To this was added 0.03 m of benzyl bromide (
0.25 mmol) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted three times with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was subjected to log silica gel column chromatography (developing solvent: hexane: diethyl ether l:i) to prepare f#, and l-benzyl-4()Q-(2-benzyloxyethyl)-3(S)-[1( R)-1-butyldimethylsilyloxyethyl]-2-azetidinone 46 capes were obtained. Yield: 58 cm.

This is described in the literature (T, Iimori and M, 5
hibasakiTetrahedron Lett,
26, 1523 (1985) and is efficiently converted to chenamycin.

〔Effect of the invention〕

The β-N-[converted aminothiol ester of the present invention represented by the general formula (I) is processed by the general formula (I) after forming a β-lactam term, protection of the hydroxyl group, partial reduction of the triple bond, and hydroboration reaction. The optically active β-lactam represented by [l] can be obtained in a short process and in high yield, and therefore can be an excellent and useful synthetic intermediate.

Claims (2)

[Claims] (1) β-N-substituted aminothiol ester represented by the general formula ▲ Numerical formula, chemical formula, table, etc.▼ (wherein R^1 is an alkyl group or an aryl group, R^2
is an aralkyl group. ). (2) In the presence of a tertiary amine, a β-hydroxythiol ester represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and a boron compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and then reacting the resulting reaction mixture with an imine represented by the general formula R^2-N=CH-C≡C-SiMe_3, followed by treatment with hydrogen peroxide. , chemical formulas, tables, etc. ▼ Method for producing β-N-substituted aminothiol ester represented by ^1 is an alkyl group or a cycloalkyl group, and can form a ring together with the boron bonded together.).