JPH03157365A - Production of beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain the title compound in high yield by reacting a specific starting compound with a diazomalonic diester, then reducing, halogenating and then reacting the resulting substance with a dialkylacetal derivative and successively with trialkyltin hydride compound. CONSTITUTION:A compound shown by formula I (R is H, 1-6C alkyl, etc.; R<1> is H or N-protecting group) is reacted with a diazomalonic diester shown by formula II (R<2> and R<3> are 1-6C alkyl, etc.) to give a compound shown by formula III. Then this compound is reduced, one hydroxyl group of the formed substance is halogenated to give a compound shown by formula IV. Then this compound is reacted with a compound shown by formula V (R<4> and R<5> are 1-6C alkyl) in the presence of an acid or a hydroxyl group of a compound wherein R<1> of the compound shown by formula IV is not H is protected to give a compound, which is reacted with a trialkyltin hydride compound shown by formula VI (Alkyl is 1-6C alkyl) in the presence of a radical polymerization initiator to give a compound shown by formula VII or formula VIII.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing β-lactam compounds.

BACKGROUND TECHNOLOGY Penicillin and cephalosporin antibiotics, which have a broad antibacterial spectrum, have been known as useful antibiotics that have been widely used and have shown excellent effects against various infectious diseases. Furthermore, since chenamycin was discovered from nature (Japanese Patent Application Laid-Open No. 73191/1982), methods for obtaining various carbapenem compounds purely synthetically have been reported. Furthermore, recently, compounds in which the methylene group at position 1 of the carbapenem skeleton has been substituted with various alkyl groups have been synthesized.
-Methylcarbapenem compounds have been reported to have superior stability both chemically and in vivo compared to conventional 1-position unsubstituted carbapenem compounds, and are extremely useful as antibacterial agents. However, the synthesis method requires long and complicated reaction steps, and there are few satisfactory reports on methods in which the introduction of a methyl group at the 1-position is carried out stereoselectively.

On the other hand, the β-lactam compound represented by -arson ■ or 11 is J, Org, Cham, 52.2563
(1987) has led to highly selective intermediates for the synthesis of 1-methylcarbapenem. The present inventors established a method for obtaining the β-lactam compound represented by I or H in short steps and easy operations, and completed the present invention.

(In the formula, R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a 1-hydroxyalkyl group having 1 to 6 carbon atoms, the hydroxyl group of which may be protected, and R1 is a hydrogen atom or a protected nitrogen atom. group, R4 and R5 are the same or different alkyl groups having 1 to 6 carbon atoms, or R4 and R5 combine with each other to form an alkylene daughter to represent a 5- to 7-membered cycloalkyl group, R6 means a protecting group for a hydroxyl group) <Structure of the Invention> The present invention is based on the formula 1 6, and R+ means a hydrogen atom or a protecting group for a nitrogen atom). or an aralkyl group containing a phenyl group which may be substituted with a methoxy group or a nitro group) is reacted with a diazomalonic acid diester represented by the formula 2 (wherein R, R', R', R3 are The compound of formula 2 is reduced to a compound of formula 3 (wherein R, R' are equal to the definitions above), and the compound of formula 3 is converted into a compound of formula One of the hydroxyl groups of the compound is halogenated to convert it into a compound represented by formula 4 (wherein R and R' are as defined above and X means a halogen atom), and in this formula 4, R1 is hydrogen. In the presence of an acid in a compound that is an atom, the formula % formula % (wherein R4 and R5 are the same or different and have a carbon number of 1 to 6
or R4 and R5 may combine with each other to form an alkylene chain to form a 5- or 67-membered cycloalkyl group) or each of these carbonyl compounds. A dialkyl acetal derivative having an alkyl chain having 1 to 6 carbon atoms is reacted to obtain a compound represented by formula 5 (wherein R, R', and X are as defined above, and R6 means a hydroxyl protecting group). A trialkyltin hydride compound represented by the formula (Alkyl) 5snH (in the formula, Alkyl means an alkyl group having 1 to 6 carbon atoms) is added to the compound of formula 5 or 6 as a radical initiator. Formula I, wherein R, R', R', X are as defined above.
Alternatively, in formula 4, R1
In compounds where is not a hydrogen atom, the hydroxyl group is protected (in the formula,
R, R', R5 are as defined above) or formula II (wherein R, R', R6 are as defined above).

Examples of the lower alkyl group of R in -Arson (1) or (II) include linear or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, lobutyl, and 5ec-butyl. It is possible,
Suitable examples include methyl and ethyl.

Further, R may be a l-hydroxy lower alkyl group, and the alkyl group portion of this l-hydroxy lower alkyl group may include the above-mentioned linear or branched alkyl groups having 1 to 4 carbon atoms. Examples of suitable 1-hydroxy lower alkyl groups include hydroxymethyl group and l-hydroxyethyl group. This hydroxyl group may be protected, and the protecting group for the hydroxyl group may be any commonly used one, preferably a lower alkoxycarbonyl group such as monobutyloxycarbonyl group: 2-ethyloxyiodide carbonyl group, 2.2.
Halogenoalkoxycarbonyl groups such as 2-)-dichloroethyloxycarbonyl group; benzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, p
- Aralkyloxycarbonyl groups such as nitrobenzyloxycarbonyl group and p-methoxybenzyloxycarbonyl group Substituted silyl groups such as trimethylsilyl group, shi-butyldimethylsilyl group, and shi-butyldiphenylmethylsilyl group: methoxymethyl 2-methoxyethoxymethyl group, methylthiomethyl group, and substituted methyl groups such as tetrahydropyranyl group.

The protecting group for the nitrogen atom of R+ may be one commonly used, but preferably trialkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group: p-methoxyphenyl group, 2,4-dimethoxyphenyl group. Substituted phenyl groups such as groups: benzyl group, p-methoxybenzyl group, 2
．． Mono- or diarylmethyl groups such as 4-dimethoxybenzyl group, diphenylmethyl group, di-p-ayucylmethyl group: Substituted methyl groups such as methoxymethyl group, 2-methoxyethoxymethyl group, methylthiomethyl group, and tetrahydropyranyl group There are many examples of this.

R6 may be any group commonly used as a protecting group for hydroxyl groups, preferably methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, t
-Lower alkoxycarbonyl groups such as butyloxycarbonyl group: 2-ethyloxycarbonyl iodide group,
Halogenoalkoxycarbonyl groups such as 2,2.2-trichloroethyloxycarbonyl group: such as benzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group aralkyloxycarbonyl groups Substituted silyl groups such as nitrimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylmethylsilyl group: methoxymethyl group, 2-methoxyethoxymethyl group, methylthiomethyl group, tetrahydropyranyl group Substituted methyl groups such as groups can be mentioned.

The manufacturing method of the present invention will be described in detail below.

The compound represented by the general formula 2 in step A is prepared, for example, in JP-A-61-20
It can be obtained by reacting a 4-funynylthioazetidine compound obtained by the method described in JP 7373 with a diazo compound in an inert solvent in the presence of a catalytic amount of an organometallic compound. A suitable organometallic compound includes rhodium (II) acetate dimer, and it is desirable to use an amount sufficient to allow the reaction to proceed sufficiently, preferably in an amount of 0.001 to 0.01 times the amount of raw material compound 1. It can be said that.

Suitable inert solvents include organic solvents such as dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, ethyl acetate, methyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, dimethylformamide, and mixed solvents thereof. can.

The reaction temperature can be suppressed or accelerated by appropriately cooling or heating, but preferably 20°C.
It can be carried out in a temperature range of 70°C.

Step B-a The compound represented by formula 3 can be carried out in the form of a general reduction reaction that leads an ester to an alcohol, and various transition agents can be used. However, suitable methods include, for example, metal hydride compounds such as boron hydride and aluminum hydride, and metal hydride complex compounds such as sodium borohydride and lithium aluminum hydride. in active solvent,
Mention may be made of the reduction method using diisobutylaluminum hydride.

Suitable inert solvents include organic solvents such as benzene, toluene, xylene, tetrahydrofuran, diethyl ether, and mixed solvents thereof.

In addition, the reaction temperature can be suppressed or promoted by cooling or heating as appropriate.
It can be carried out at a temperature in the range of 8°C to 20°C.

Step C The compound represented by general formula 4 can be easily obtained by halogenation or sulfonic acid esterification of alcohol, -
These reactions can be carried out by methods known to boat fishing. A preferred method is to use various halogenating agents such as thionyl chloride, thionyl bromide or carbon tetrachloride-triphenylphosphine halogen compounds such as alkyl-triphenylphosphine phosphorus in the presence or absence of a base. It can also be obtained by reacting methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. in an inert solvent in the presence of a base. Particularly suitable examples include methanesulfonyl chloride and thionyl chloride.

Suitable inert solvents include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene,
Ethyl acetate, methyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, dimethylformamide,
Examples include organic solvents such as pyridine and mixed solvents thereof.

Suitable bases include pyridine, 4-dimethylaminopyrine, diisopropylethylamine, N,N-dimethylaniline, and the like. Particularly suitable examples include triethylamine and diisopropylethylamine.

The reaction temperature can be suppressed or accelerated by cooling or heating as appropriate, but the reaction temperature can be suitably carried out in the range of -20°C to 0°C.

The compound represented by the general formula 5 is obtained by converting compound 4 into -
Arson R'COR' [In the formula, 83 and R4 represent the same or different lower alkyl groups, or R3 and R4 combine with each other to represent an alkylene group to form a 5- to 7-membered cycloalkyl group. ] It is obtained by subjecting it to a dehydration reaction with a carbonyl compound represented by the formula or an aminoacetalization reaction with its di-lower alkyl acetal conductor. In general, various reactions that lead an amino alcohol to an aminoacetal can be applied to this reaction. be.

Regarding the carbonyl compound 83 and R4 used in this reaction, methyl, ethyl, propyl, butyl, etc. have 1 to 1 carbon atoms.
A 5- to 7-membered cycloalkyl group can be used to represent four lower alkyl groups or alkylene chains that are bonded to each other.

Suitable inert solvents used in this reaction include organic solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, dimethylsulfoxide, dimethylformamide, and the like. Mixed solvents of these can be mentioned.

Suitable acids used in this reaction include sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid;
Examples include acids such as sulfuric acid and hydrochloric acid, Lewis acids such as zinc chloride, boron trifluoride etherate, and boron tribromide;
Particularly preferred are boron trifluoride etherate, +
1-)-Luenesulfonic acid may be mentioned.

Regarding the amount of acid as a catalyst, it is desirable to use an amount that is sufficient for the reaction to proceed sufficiently, but it is preferable to use an amount of acid that is sufficient to allow the reaction to proceed sufficiently. It can be said to be 2.1 times the amount of O2N.

In addition, the reaction temperature can be controlled or promoted by cooling or heating as appropriate.
It can be carried out at a temperature in the range of 0°C to 20°C.

Compounds represented by the general formula 6 derived from compounds in which R' is not a hydrogen atom in the general formula 4 include, for example, alkyloxycarbonyl halides, aralkyloxycarbonyl halides, trialkylsilyl halides, alkoxyalkyl halides, etc. (a compound in which R1 is not hydrogen) in the presence of a base in a solvent inert to the reaction.

Suitable bases include pyridine, 4-dimethylaminopyrine, diisopropylethylamine, N,N-dimethylaniline, and the like. Particularly suitable examples include triethylamine and diisopropylethylamine.

Suitable inert solvents include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene,
Ethyl acetate, methyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, dimethylformamide,
Examples include organic solvents such as pyridine and mixed solvents thereof.

Step E - Compounds of formula (1) or (2)r can be obtained by applying various known methods for converting β-hydroxy or chlorosulfide into an alkene, such as in -arson 5 or 6. For example, Tetra-hedron Le
Alkenes of general formula T or H can be obtained radically according to the method described in J. T. Tters, 1977, 4223.

An example of this method is to use Dorido.

Particularly suitable catalysts include radical initiators such as azobisisobutyronitrile, which should be used in an amount sufficient to allow the reaction to proceed sufficiently, but preferably from 0.01 to 0.0% of the starting compound. It can be said to be .001 times the amount.

Suitable inert solvents used in this reaction include organic solvents such as benzene, toluene, and xylene, and mixed solvents thereof.

The reaction temperature can be suppressed or accelerated by appropriately cooling or heating, but preferably 20
It can be carried out in the range of 100°C to 100°C.

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to this.

(IR.
Dissolve in 20 ml of mixed solvent (v/v), heat to reflux,
Dimethyldiazomalonate 210 mg anhydrous benzene-dichloromethane (1:1. v/v) mixed solvent 4
0 ml of the solution was slowly added dropwise. After heating under reflux for 24 hours with stirring, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the title compound from a hexane-benzene-acetone (50:50:3. v/v) stream. 1!11 og were obtained as a colorless oil.

IR:V! R:'g@-':3400.1740.17
20.16[i0′H-NMR(270M)lz, C
DC13) δ: 0.07.0.08 (6H, each s).

0.88(98,s), 1.13(3f(,d, J
-ff, 11(z).

3.24 (IL d, J-1,2Hz), 3. [i
2.3.66 (6H8 each S), 4.24 (18, dq
, J-1,8&6.7Hz)4.36(l)1.
d, J-1,8Hz), 5.77(1)1. br
-s).

7.2-7.5 (5H, m).

MS:tn/z: 410(M”-tflu)High
MSH Calcd for C+ALJO6SiS:M”-t
BLl, m/z 410.1092Found:M”
-tBu, m/z 410.1097 240 rng of the compound obtained in Example 1 was added to 5 G of anhydrous tetrahydrofuran.
diisobutylaluminum hydride (DIBAL) dissolved in +1 and heated at −78° C. under nitrogen flow.

1 mol/1. After adding 3 ml of toluene solution), the reaction mixture was stirred at room temperature for 3 hours and cooled to 0 °C.
1 ml of isopropanol was added and stirred for 1 hour.

Aqueous ammonium chloride solution was added to the reaction mixture until the aluminum compound was completely precipitated (pH 3.5-4.0).
) and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate to obtain 114 mg of the title compound as yellow crystals.

'H-NMR (270 MI (z, CD30D) δ: 0
．． 07.0.08(8)1. Each S).

0.86(9)1. s), 1.28 (38, d,
J-6, 1) 1z).

3.30(2)1. brs), 3.47(1)1.
dd, J-1,8&5.8H1), 3.54(I
H, d, J-11, 6112), 3.81 (IH,
d, J=11.8Hz), 3.63(1)1. d
, J-11,6H2), 3.70(IH,d, J
-11,6H2), 3.83(IH,d, J-1,
8Hz), 4.08(18,dq, J-5,8,&
δ, IHz), 7.4-7.7 (5H, m).

MS; mHz: 354 (M"-tBu) High M
S; Ca1cd for l+a)I2JO45iS:M”
-tBu, l/Z 354.1194 Found: M
"-tBu, mHz 354.1189 A solution of 0.03 ml of dinone methanesulfonyl chloride in 5 ml of anhydrous pyridine was mixed with 140 mg of the compound obtained in Example 2 and 0.06111 of triethylamine under a nitrogen stream.
It was gradually added dropwise to a solution of 1 in 5 ml of anhydrous pyridine at 0°C, and the reaction mixture was stirred at 0°C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with saturated KH5O4 aqueous solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and hexane-
110 tIlg of the title compound was obtained as white crystals from a stream of ethyl acetate (10:1. v/v).

IR Nijim! ! ! :"cm-':1760'H-NM
R(270M)IZ, CDC13)δ:0.18.0
．． 19 (6H, each S).

0,! 17(9)1. S), 1.39 (3H,
d, J-8, 1H2).

1.69(l)I, brs), 3.30(IH
, dd, J-1,2&6.7Hz), 3.51(
IH, d, J-13, 4) IZ), 3.62 (IF
I, d, J-13,4Hz), 3.86(I
H, J-12, 2Hz).

4.03 (IH, d, J=1.2Hz), 4.1
1DH, d, J-12, 2) 1z), 4.27 (L
H, dq, J-6, 1 & 8.7Hz).

6.15 (IH, brs), 7.29-7.53 (
5H, m).

MS; mHz: 372 (M”-tBu), 414 (M
"-Me) High MS; Ca1cd for C,, H23NC10, Si
S: M"-tBu, m/2372.0855Fou
nd:M”-tBu, mHz 372.0848 100 mg of the compound obtained in Example 3 was dissolved in 5 ml of anhydrous dichloromethane, and after cooling to 0°C, 17 ml of 2,2-dimethoxypropane Q and a catalytic amount of boron trifluoride were added. Ride diethyl etherate was added.

After stirring at room temperature for 4 hours, triethylamine was added to the reaction mixture until the complex precipitated, and the mixture was stirred for 30 minutes.

The reaction mixture was diluted with dichloromethane, washed with saturated brine and saturated Na2)1cO3 aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound 85I was obtained from a hexane-ethyl acetate (8:2. v/v) stream.
1 g of I was obtained as a yellow oil.

■R；ν! R 13cm-”: 1730'H-NMR (
2) OhLH2, (:DC13) δ:O,OIi
, 0.12 (6H, each S) 0.89 (9) 1. S
), 1.35 (3H, d, J-6, 11 (Z).

1.23.1.68(6)1. each S), :1.53(
1)1. dd, J-2,4 & 2.5Hz), 3
．． 57 (IH, d, J-12, 2) 1z) 3.73 (
IH, d, J-12, 28Z), 3.76(1)1
．． d.

J-12, 28Z), 3.82 (IH, d, J-1
2,28Z).

4.08 (IH, d, J・2.5H1), 4.28
(IH, dq.

J-2, 5 & 6.1) 12), 7.26-7.68
(5)1. m) MS; mHz: 454 (M”-Me)
, 412(M"-'Bu)High MS; Ca1cd for Cz2HsJC1(hsis:M
"-Me, m/z Found: M"-Me, m/z 454.11i39 454.1639 57 mg of the compound obtained in Cuttane Example 4 was mixed with anhydrous benzene 2 &
4) IZ), 4. l5-4.34 (3H, m)4
．． 96,5.08 (2L brs) MS: m/z: 3
10 (M”-Me), 2611 (M”-tB
L+).

166(M”-CHiC)10-tBDMSi)High
h MS; Calcd for C, 6) t2.
No, Si:M"-Me, m/z 310.18
28 Found: M”-Me, m/z 310.1
A solution of 828 ml and a catalytic amount of azobisisobutyronitrile (AIBN) in 15 ml of anhydrous benzene was gradually added dropwise over 6 hours. After further heating and centrifuging for 16 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Hexane-ethyl acetate (10:1.
The title compound 34.7B was obtained as a yellow oil from the v/v) stream.

IR, gap13as-':1750'H-NMR (
270MHz, (:DC13)δ:0.07.0.0
8 (6H, 5 each).

Claims (1)

[Claims] Formula 1 ▲ Numerical formulas, chemical formulas, tables, etc. 1-Hydroxyalkyl group, and R^1 means a hydrogen atom or a protecting group for a nitrogen atom), there are formulas, mathematical formulas, chemical formulas, tables, etc. (in the formula, R^2 and R^3 each independently has 1 to 6 carbon atoms
or an aralkyl group containing a phenyl group that may be substituted with a methoxy group or a nitro group) is reacted with a diazomalonic acid diester represented by formula 2 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (formula (R, R^1, R^2, R^3 are equivalent to the above definitions), and this compound of formula 2 is reduced to form formula 3. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and R^1 are the same as the above definitions.) One of the hydroxyl groups of the compound of formula 3 is halogenated to form formula 4 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( In the formula 4, R, R^1 are the same as the above definitions, and X means a halogen atom). Formula R^4COR^5 (In the formula, R^4 and R^5 have the same or different carbon number 1
-6 alkyl group, or R^4 and R^5 may combine with each other to form an alkylene chain to form a 5- to 7-membered cycloalkyl group); or By reacting dialkyl acetal derivatives in which each alkyl chain of this carbonyl compound has 1 to 6 carbon atoms, the formula 5 ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R, R^4, R^5 , X is as defined above), or in formula 4, R
In compounds where ^1 is not a hydrogen atom, the hydroxyl group is protected and the formula 6 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R, R^1, and
means a protecting group for a hydroxyl group) and convert the compound of formula 5 or formula 6 into a compound represented by the formula (Alkyl)_3SnH (wherein, Alkyl means an alkyl group having 1 to 6 carbon atoms). Formula I, which is characterized by reacting a trialkyltin hydride compound in the presence of a radical initiator ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R, R^4, R^5 are as defined above. ) or formula II ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R, R^1, R^6 are equal to the above definitions) A method for producing a β-lactam compound represented by