JPH0320287A - Production of beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain the subject compound, having a silyl ether group at the 4-position and useful as an intermediate convertible into various derivatives by reducing a specific beta-lactam compound with an organometallic compound in an organic solvent. CONSTITUTION:An N-sulfonyl beta-lactam compound expressed by formula I (R represents OH-protecting group; R<2> to R<4> represent 1-6C alkyl, phenyl or aralkyl; X<1> represents halogen) [example; 3-(1-tert.-butyldimethyl-silyloxyethyl)-1- chlorosulfonyl-4-trimethylsilyloxy-ozetidin-2-one] is reduced in an organic solvent (example; toluene) with an organometallic compound expressed by the formula R<5>-M [R<5> represents (substituted) alkyl, (substituted) phenyl or aralkyl; M represents (halogeno)metal] (preferably phenylmagnesium chloride or benzyl- magnesium chloride) preferably at -30 deg.C to ambient temperature the objective compound expressed by formula II.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a method for producing a β-lactam compound having a hydroxyethyl group with a protected hydroxyl group at the 31-position and a silyl ether group at the 41-position. .

The β-lactam compound according to the present invention has a highly reactive silyl ether group at the 41-position and is a useful intermediate that can be converted into various derivatives. For example, by performing a substitution reaction on the 41-position silyl ether group of the compound of the present invention, 3-(l-hydroxyethyl), which is useful in the production of chenamycin, which is known as a fourth-generation β-lactam antibiotic -4-acetoxyazetidin-2-one, 3-(l-hydroxyethyl)-4-haloazetidine-2-
On can be obtained.

[Prior art/Issues to be solved by the invention 1i] The present inventors have already filed an application regarding a β-lactam compound having a silyl ether group at the 4-1 position and a method for producing the same (
(See Japanese Unexamined Patent Publication No. 81-18791).

Regarding the reductive elimination of the N-protecting group of the β-lactam ring during the production process, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium borohydride, lithium borohydride, etc. It has been limited to systems using metal hydride compounds, Raney nickel, mercabutanes, and alkali metal one-electron acceptors.

Reductive deprotection in these systems, for example, aluminum hydroxide for aluminum hydride compounds, disulfide for mercabutanes, and disulfide for alkali metal one-electron acceptor systems. In the case of A, it is difficult to remove the electron acceptor, and in other systems, there is a problem that the yield is slightly lower than that of the above.

The present inventors conducted further studies and found that a β-lactam compound having a silyl ether group at the 4-position and in which the nitrogen atom of the β-lactam ring is unsubstituted can be produced with high yield and without difficulty in removing by-products. The present invention was completed by discovering a new synthetic method for reductively deriving N-halosulfonyl derivatives using a method that does not involve the use of N-halosulfonyl derivatives.

[Means for Solving the Problems] The present invention is based on the general formula: A β-lactam compound represented by the general formula (■): RS -M (1)υ (wherein, Ri is a hydroxyl protecting group, R2 R3 and The present invention relates to a method for producing a β-lactam compound represented by R4 each representing the same or different lower alkyl group, phenyl group, or aralkyl group of Ct to C●.

That is, general formula (l): (wherein Rs is an alkyl group or a substituted alkyl group, a phenyl group or a substituted phenyl group, or an aralkyl group,
A β-lactam compound represented by the general formula: (wherein RI R2 R3 and R◆ are the same as above), which is reduced by an organometallic compound represented by X represents a metal or a metal halide. Concerning the manufacturing method.

[Operations/Examples] Specific examples of R1, which is a protecting group for the 3-position hydroxyethyl group in the general formula circle, include the general formula N2R6 (wherein R@R7 and R8 are each the same or different). C1 to C● lower alkyl group, phenyl group or aralkyl group);
For example, tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, inbutyldimethylsilyl group, dimethyl-(l62-dimethylprobyl)silyl group, dimethyl-(1,1.2-}
Other examples include trialkylsilyl groups such as (trimethylpropyl)silyl group, tft-butyl group, penzyl group, trichloroethoxycarbonyl group, tart-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group, and the like. Preferably, an iert-butyldimethylsilyl group, an isopropyldimethylsilyl group, or a dimethyl-(1.1.2-}limethylbutopyl)-silyl group, which is stable during the reaction and can be selectively deprotected by acid treatment. and dimethyl-(1,2-dimethylbubutyl)silyl group.

Also, R2 R3 and R4 of the β-lactam compound circle
are the same or different groups selected from lower alkyl groups at C+-06 such as methyl, ethyl, isobutyl, 1.1.2-trimethylpropyl, phenyl groups and aralkyl groups such as penzyl and P-nitropenzyl groups. However, preferably R2. Optimally, H3 and R4 are both methyl.

Further, XI represents a halogen atom, preferably a chlorine atom.

The reaction of the present invention is shown in Reaction Formula 1 below. Reaction formula 1: (1) (1) + By-product The raw material N-sulfonyl β-lactam compound (1) in the above reaction is 3=(1-tert-butyldimethylsilyloxyethyl)-1-chlorosulfonyl- 4-
Trimethylsilyloxyazetidin-2-one, 3-(
1-tert-butyldimethylsilyloxyethyl)-1
-chlorosulfonyl-4-triethylsilyloxyazetidin-2-one, 3-(1-tert-butyldimethylsilyloxyethyl)-1-chlorosulfonyl-4-dimethylisopropylsilyloxyazetidin-2-one, 3- (1-tert-butyldimethylsilyloxyethyl)-4-tert-butyldimethylsilyloxy 1-
Chlorosulfonyl-azetidin-2-one, l-chlorosulfonyl-3-(l-dimethylisopropylsilyloxyethyl)-4-trimethylsilyloxyazetidine-
2-one, l-chlorosulfonyl-3-[1-(dimethyl-(1.1.2-trimethylpropyl)monosilyloxy)ethyl]-4-trimethylsilyloxyazetidin-2-one, l-chlorosulfonyl Sulfonyl-3-(1-ter
t-Butyldiphenylsilyloxyethyl)-44-limethylsilyloxyazetidin-2-one, l-chlorosulfonyl-3-[1-(dimethyl-(l,2-dimethylprobyl)silyloxy)ethyl]-4 - trimethylsilyloxyazetidine-2-one, 3-(1-tert-
butoxyethyl)-1-koosulfonyl-4-trimethylsilyloxyazetidin-2-one, 3-(1-
tert-ptoxyethyl)-1-chlorosulfonyl-
4-triethylsilyloxyazetidin-2-one, a
-(i-penzyloxyethyl)-1-chlorosulfonyl-4-trimethylsilyloxyazetidin-2-one, 3-(1-tert-butylcarbonyloxyethyl)-1-chlorosulfonyl-4-trimethylsilyloxy Azetidin-2-one, 3-(1-penzyloxytriponyloxyethyl)-1-chlorosulfonyl-4-
Trimethylsilyloxyazetidin-2-one, 8-(
1-penzoyloxyethyl)-1-chlorosulfonyl-4-trimethylsilyloxyazetidin-2-one,
l-chlorosulfonyl-3-(1-p-nitrobenzyloxylponyloxyethyl)-4-}limethylsilyloxyazetidin-2-one, 1-chlorosulfonyl-4-trimethylsilyloxy-3- (1-trimethylsilyloxyethyl)-azetidin-2-one, etc. can be employed. Preferably, 3-(1-tert-butyldimethylsilyloxyethyl)-1-chlorosulfonyl-4
-trimethylsilyloxyazetidine-2-one, l-
Chlorosulfonyl-3-[1- (dimethyl-(1.1
．． 2-trimethylprobyl)silyloxy>ethyl]-4
-trimethylsilyloxyazetidin-2-one, l-chlorosulfonyl-3-(l-dimethylisopropylsilyloxy)ethyl-4-trimethylsilyloxyazetidin-2-one, and the like.

The above N-sulfonyl β-lactam compound (1) is
It can be synthesized by reacting enol silyl ethers synthesized from 3-hydroxybutyric acid as a starting material and sulfonylisocyanates (see JP-A-61-1879L Publication N). As the sulfonyl isocyanate, for example, a sulfonyl isocyanate in which a halogen atom is bonded to a sulfonyl group, such as chlorosulfonyl isocyanate, can be used.

The raw material N-sulfonyl β-lactam compound (1
) is shown in reaction formula 2 below.

Reaction formula 2: [Left below] (.I) A reaction in which the substituent on the nitrogen atom of the N-sulfonyl-β-lactam compound (1) produced by the above reaction is reductively eliminated to obtain the target compound (self). Let's talk about.

This reduction reaction is carried out in an organic solvent using the general formula (l): RS =
M (1) (wherein RS is an alkyl group or a substituted alkyl group, a phenyl group or a substituted phenyl group, or an aralkyl group,
This is carried out by allowing an organometallic compound represented by (M represents a metal or a metal halide) to act on the β-lactam compound (1). As RS, for example, methyl group, ethyl group, n-probyl group, isoprotel group, n-
In addition to alkyl groups such as butyl group and t-butyl group, substituted alkyl groups, phenyl groups such as phenyl group and tolyl group, and aralkyl groups such as substituted phenyl group and benzyl group are used, and M is, for example, lithium, potassium and metal halides such as magnesium chloride, magnesium bromide, and magnesium iodide. More specifically, the general formula M:R9
-Mg-X2 (V) (wherein R9 is an alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, or an aralkyl group; Examples include organolithium compounds represented by Li (4) (in the formula, ``H'' represents a C1 to CI lower alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, or an aralkyl group). That is, examples of organometallic compounds include n-butyllithium, phenyllithium, ethylmagnesium chloride, ethylmagnesium bromide, n-probylmagnesium chloride, n-probylmagnesium bromide, isobrobylmagnesium chloride, and isoprobil. Magnesium bromide, isoprobylmagnesium iodide, phenylmagnesium chloride, phenylmagnesium bromide, benzylmagnesium chloride, benzylmagnesium bromide and the like are used; in particular, phenylmagnesium chloride and benzylmagnesium chloride are preferably used.

Examples of the solvent used in the reduction reaction include inert organic solvents such as toluene, hexane, ether, and tetrahydrofuran, and a mixed solvent system may also be used. Further, in a reaction using a Grignard reagent or the like, a solvent different from the solvent for synthesizing the Grignard reagent from the alkyl halide and Mg may be used for the reduction reaction.

The reduction reaction may be carried out at any temperature between -ioo<0>C and around the boiling point of the solvent, more preferably between -30<0>C and around room temperature. The halosulfonlactam as a raw material may be added to a reducing agent, or the reducing agent may be added to a solution of the halosulfonlactam.

After this reduction reaction, the desired N-unsubstituted β-lactam compound can be obtained by hydrolysis, washing with water, and concentration according to a conventional method.

According to the method of the present invention, by-product metals are easily distilled off as harmless salts by washing with water, and alkyl halides are easily distilled off together with the solvent by concentration.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.

Reference Example 1 [Production of 3-(1-tert-butyldimethylsilyloxyethyl)-1-chlorosulfonyl-4-trimethylsilyloxyazetidin-2-one] 35 μg of chlorosulfonyl isocyanate was added to toluene d
-8C and cooled to -78°C under an argon gas atmosphere, and 100 g of 3-ielt-butyldimethylsilyloxybut-l-nyltrimethylsilyl ether was added while keeping the temperature below -70°C.

After 1 hour, a portion of this reaction solution was taken out, and an IH-NMR spectrum was measured while cooling it to -70°C with liquid nitrogen. The 1-position proton (around 6.5 ppm, d) and the 2-position proton (5.2
Around pp1, the signal of 1) disappears, and a new signal of 6.2p
p-(LH.d) (lactam ring position 41), 2.8 ppm
(IH. Maro) 8-(L-tert-butyldimethylsilyloxyethyl)-1-chlorosulfonyl-4-trimethylsilyloxyazetidin-2-one was produced by generating a signal at the 31st position of the lactam ring. The formation of

Example 1 [(lR.4R)-3-[(R)-(1-tert-
Synthesis of butyldimethylsilyloxyethyl)]-4-trimethylsilyloxyazetidin-2-one] Chlorosulfonyl isocyanate 0. 7 ml of toluene was added to 10 ml of toluene and cooled to -70°C under an argon gas atmosphere, and 3-(R)-tert was added.
2.0 g of -butyldimethylsilyloxybut-1-nyltrimethylsilyl ether is added dropwise over about 5 minutes while keeping the reaction solution at -70°C or lower. After this reaction solution was left at -70°C or lower for 1 hour, 2. 4.4 ml of a tetrahydrofuran solution of OM phenylmagnesium chloride is added dropwise over about 10 minutes while keeping the internal temperature below -70°C. After the reaction solution was kept at −70° C. or below for 20 minutes, 2NH2SO4 was added to 200 ml of ice water to transfer the solution while keeping the pH at 3 to 7. toluene 10
After adding 0 ml for extraction and separating the layers, the toluene layer was dried over anhydrous sodium sulfate. By analyzing and quantifying this toluene layer by gas chromatography, the target product (3R.4R)-3-(R)-(1-tert
-butyldimethylsilyloxyethyl> -4-trimethylsilyloxyazetidin-2-one was produced in an amount of 1.30 g. Reaction yield: 56%.

Furthermore, after concentrating the dried toluene solution with an evaporator, 5+ nm of hexane was added and dissolved, and the temperature was kept at -30℃ for 3
After cooling for an hour, needle-like crystals were precipitated. This was filtered through a glass filter, quickly washed with 2 cc of cold hexane, and dried to obtain pure 3-(R)-[(R)-ter.
t-Butyldimethylsilyloxyethyl]-4-(R)-
}Limethylsilyloxyazetidin-2-one 0.8
I got g.

'H-NMR (90MHz. CDCI!) δ (p
pm): 0.09 (CHs x 2.s
), 0.20 (CHs x 3.s), 0.90
(CHs X 3,s), 1.26(CHs,d)
, 2.96 (IH.dd) , 4.13 (IH, m)
, 5.33 (lH.d), 7.23 (NH.broad
) s. p:95~9B'C Cal 2S--9.5° (c=1.0, CH
C# 3)D Example 2 [Synthesis of (3R.4R)-3-[(R)-1-tart-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one] Example 1 2. instead of the THF solution of phenylmagnesium chloride. OM benzylmagnesium chloride T
A similar operation was performed using 4.4 ml of the IIP solution, and it was found that 27 g of the target product 1 was produced (reaction yield: 55%).

Example 3 [Synthesis of (sR,4R)-s-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-}limethylsilyloxyazetidin-2-one] Chlorosulfonyl isocyanate 0. 35 ml was added to 5 cc of toluene, cooled to -78°C under an argon gas atmosphere, and 3-(R)-tert-butyldimethylsilyloxybutyl l-nyltrimethylsilyl ether 1.0
g was added dropwise, and the temperature was kept below -70°C for 1 hour. In a separate reaction vessel, magnesium (ribbon shape) 823 1
A phenylmagnesium bromide solution prepared from 2.7 ml of benzene bromide and 25 ml of TIP was cooled to -20°C under an argon atmosphere. The previously prepared cyclization reaction solution was transferred into this solution through a cooled transfer tube so that the temperature of the Grignard reaction solution was maintained at -lO<0>C or lower. At this time, care was taken not to allow the temperature of the cyclization reaction solution to rise above -70°C. After the liquid transfer is completed, the reaction liquid is heated to -15
Leave it at around ℃ for 15 minutes and add 2NH2 in 200ml of ice water.
Added while keeping 9H at 3-7 with SO4. After extraction with 200 ml of toluene, separation and drying, the toluene layer was analyzed by gas chromatography to obtain (SR,4R)-1-[(R)-l-tert-butyldimethylsilyloxyethyl 1- It was found that 0.82 g of 4-trimethylsilyloxyazetidin-2-one was contained (reaction yield 54%).

Example 4 [Synthesis of (3R.4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one] of the benzene bromide of Example 3 1.9m of ethyl bromide instead
By performing the same operation as in Example 3 using 1, 0.52 g of the target product was obtained (reaction yield 45%).

Example 5 [Synthesis of (3R.4R)-3-[(R)-tart-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one] Instead of benzene bromide in Example 3 Isobrovir bromide 2
．． By performing the same operation as in Example 3 using 4 ml, 0.511 g of the target product was obtained, and the reaction yield was 50%.

Example 6 [Synthesis of (SR.4R)-1-[(R)-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one] Magnesium 531■, benzene chloride 2.2ml and Tetrahydrofuran l. By adding 1 ml of toluene to a phenylmagnesium chloride solution prepared from 8 ml as a reducing agent, :l-(R)-
tart-butyldimethylsilyloxyethylbute-1-
A cyclization reaction product prepared at -70°C from 1.0 g of nyl-trimethylsilyl ether and 0.85 ml of chlorosulfonyl isocyanate was subjected to the same operation as in Example 3 to obtain 0.87 g of the target product (reaction yield: 5B%
).

Example 7 [Combination of (3R.4R)-3-[(R)-1-tert-butyldimethylsilytoxyethyl]-4-trimethylsilyloxyazetidin-2-one] In the same manner as in Example 3 , 1 g of 3-(R)-tert-butyldimethylsilyloxyethyl but-1-nyltrimethylsilyl ether and chlorosulfonyl isocyaner}0
．． The cyclization reaction product prepared from 35 ml at -70°C or less is -
The n-butyllithium solution was added to a 15% hexane solution of n-butyllithium while being kept at 70°C or lower, taking care not to allow the temperature to rise above 1BO°C. After the addition was completed, 0.52 g of the target product was obtained by performing hydrolysis, extraction, washing with water, and drying in the same manner as in Example 3 (reaction yield: 45%).

Example 8 [(3R.4R)-3-[(R)-1-[dimethyl-
Synthesis of (1,1.2-trimethylprobyl)silyloxy]ethyl]-4-}limethylsilyloxyazetidin-2-one] 3-(R)-tert-butyldimethylsilyloxybutene of Example 1 -3-(R)-[dimethyl-(1.1.
Using 2.21 g of 2-}limethylpropyl)silyloxy]-butyl-nyl' trimethylsilyl ether, the desired (3R.4R)-3-[(R )-1-[dimethyl (1.
1.2-trimethylpropyl)silyloxy]ethyl]-
4-trimethylsilyloxyazetidin-2-one 1.5
The reaction yield was 6o% when the toluene solution containing 1g was obtained. This toluene solution was concentrated using a rotary evaporator, and the toluene was completely distilled off using a vacuum pump. This residue has n-
5 ml of hexane was added, and the mixture was left in the refrigerator overnight, and the precipitated crystals were quickly filtered through a glass filter. After washing with cold hexane and drying, pure (aR,4R)-a-o-(
1.1 g of R)-[dimethyl-(1,1.2-trimethylpropyl)silyloxy]ethyl]-4-trimethylsilyloxyazetidin-2-one was obtained.

1}1-NMR (90MHz. CDCl3) δ (pp
m): 0.02 (I1iH.s), 0.08 (9
H. s), 0.72 (OH, S), 0.75 (6H.d
), 1.12 (3H.d), 1.5 (IH, m), 2.
85 (IH.dd), 4.08 (lH.l), 5.2
8 (IH.d), 8.45 (NH.broad) Example 9 [(3R.4R)-3-[(R)-1-dimethylisopropylsilyloxyethyl]-4-trimethylsilyloxyazetidine-2 Synthesis of -one] Instead of 3-(R)-tert-butyldimethylsilyloxybuter l-nyltrimethylsilyl ether in Example 1, 3-(R)-tert-butyldimethylsilyloxybuter-1-niru Trimethylsilyl ether 1.9g
By performing similar operations using , object 1. l
It was confirmed by gas chromatography that 1g was changed (reaction yield 50%).

By recrystallizing this from n-hexane in the same manner as in Example 1, pure (IR,4R)-3-[(R)-
0.5 g of 1-dimethylisobrobylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was obtained.

'H-NMR (90MHz. CDC#3) δ (ppI
1): 0.0g (CH3 x 2.S), 0.2
1 (CH3 x 3, s), 1.29 (CHI, d)
, 1.75 (LH.s+), 1.98 (CHs
．． d), 3.05 (IH.dd), 4.20 (IH,
a), 5.35 (lH.d), 6.9 (NH.broa
d) [Effect of the invention] According to the production method of the present invention, β-lactam having a silyl ether group at the 41-position and the nitrogen atom of the β-lactam ring being unsubstituted
Lactam compounds (self) can be efficiently produced.

Claims (1)

[Claims] 1 General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a hydroxyl protecting group, R^2, R^3 and R^4 are respectively the same or different C_1 to C_6
lower alkyl group, phenyl group or aralkyl group,
^1 represents a halogen atom) in an organic solvent, a β-lactam compound represented by the general formula (II): R^5-M(II) (wherein R^5 is an alkyl group or a substituted alkyl group,
General formula (III) characterized by reduction by an organometallic compound represented by a phenyl group or a substituted phenyl group or an aralkyl group, M represents a metal or a metal halide: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) A method for producing a β-lactam compound represented by (wherein R^1, R^2, R^3 and R^4 are the same as above). 2 R^1 is the general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, R^6, R^7 and R^8 are the same or different lower grades of C_1 to C_6, respectively. The method according to claim 1, wherein the group is a group represented by an alkyl group, a phenyl group, or an aralkyl group. 3. The manufacturing method according to claim 1, wherein R^1 is a t-butyldimethylsilyl group. 4. The manufacturing method according to claim 1, wherein R^1 is a dimethylisopropylsilyl group. The method according to claim 1, wherein 5R^1 is a dimethyl-(1,1,2-trimethylpropyl)silyl group. 6. The manufacturing method according to claim 1, wherein R^2, R^3 and R^4 are methyl groups. 7. The production method according to claim 1, wherein X^1 is a chlorine atom. 8 The organometallic compound used for reduction has the general formula (V): R^9-Mg-X^2(V) (wherein R^9 is an alkyl group or a substituted alkyl group,
2. The method according to claim 1, which is a Grignard reagent represented by a phenyl group, a substituted phenyl group, or an aralkyl group, where X^2 represents a halogen atom. 9. The manufacturing method according to claim 8, wherein R^9 is a phenyl group. 10. The manufacturing method according to claim 8, wherein R^9 is a benzyl group. 11. The production method according to claim 8, wherein R^9 is an ethyl group. 12. The production method according to claim 8, wherein R^9 is an isopropyl group. 13 The organometallic compound used for reduction has the general formula (VI)
: Organolithium represented by R^1^0-Li(VI) (wherein R^1^0 represents a C_1 to C_6 lower alkyl group or substituted alkyl group, phenyl group, substituted phenyl group, or aralkyl group) The manufacturing method according to claim 1, which is a compound. 14. The manufacturing method according to claim 13, wherein 14 R^1^0 is an n-butyl group.