JPS58425B2 - Erythromycin fragment compound and its production method - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula: (In the formula, R represents hydrogen or a lower alkyl group.

) and a method for producing the same.

The compound of interest of the present invention is a macrolide antibiotic, such as erythromycin A, which exhibits strong antibacterial activity against Gram-positive bacteria and is widely used for bacterial infections due to its low toxicity. It is useful as an important intermediate in the synthesis of

[R1-desosamyl group, R2
-cladinosyl group] That is, in the synthesis of erythromycin A, an important issue is stereoselective synthesis of the 10 asymmetric centers on the ring on page 14.

According to the present invention, an erythromycin fragment compound (■) containing the above-mentioned asymmetric center can be stereoselectively synthesized as shown in the Examples below.

The present invention will be explained in detail below.

First, the starting material used in the present invention has the general formula:
In the formula, R represents hydrogen or a lower alkyl group.

), and the present inventors have previously discovered a method for stereoselectively synthesizing these compounds (Japanese Patent Application No. 155/1983,
(See specification No. 06).

First, the corresponding aldehyde prisoner and α-halogenoester (
B) in the presence of Zn [Liformatsky (
Reformat sky reaction] The resulting β-hydroxy ester (C)L threo
) body and erythro body],
Treatment with oxidizing agents such as Jones' reagent, pyridinium chromate-dimethylformamide, trifluoroacetic acid-pyridine-dimethyl sulfoxide etc. provides the β-ketoester (0).

(In the formula, X represents halogen and R represents hydrogen or a lower alkyl group.

) The obtained β-ketoester (D) was converted into Zn(BH4)2
By reacting with the following as a reducing agent, the starting material erythro hydroxyester (I) can be obtained extremely stereoselectively and in high yield.

[In the formula, R is the same as above.

] In the above step, for example, β-ketoester (D)
An ether solution of Zn(BHl)2 is added to the ether solution under ice cooling and stirred.

After the reaction, water and 10% hydrochloric acid solution are added, and the mixture is extracted with ether.

The ether layer is washed with a saturated NaHCO3 aqueous solution and a saturated saline solution in a conventional manner, and then dried with MgSO4 or the like.

By distilling off the solvent to obtain a crude product, and further subjecting it to preparative chromatography, the target erythro hydroxyester (I) can be obtained in high yield.

In this case, as the solvent used, ethers such as ether and tetrahydrofuran are preferable.

Further, this reaction is preferably carried out under ice cooling, and the reaction proceeds sufficiently in a reaction time of about 5 minutes to 1 hour.

The amount of z n (BH4) 2 used is about 1.5 to 3 times the amount of the starting material (molar ratio).
is optimal.

The above reaction is characterized in that Zn2H4)2 is used as a reducing agent.

That is, when other reducing agents are used, the desired erythrohydroxy ester (I) can be obtained stereoselectively and in high yield.
can't get it.

That is, when LtA7H4 is used, stereoselectivity is high, but the ester is reduced to the primary alcohol.

Also, when L i BH4 is used, the ester is reduced to the primary alcohol.

When N a BH4 is used, a mixture of Eri-30 and threo isomers is obtained, and the stereoselectivity is low.

From the above points, in the above reaction, z n (
It is essential to use BH4)2.

Using the thus obtained erythromycin hydroxy ester as a starting material, the erythromycin fragment compound of the present invention is produced through the following steps.

Sunawachi then t-epoxidizes the erythro hydroxy ester (I) to obtain the epoxy compound (n). As the epoxidizing agent, it is best to use an alkyl hydroperoxide in the presence of a vanadium or molybdenum compound catalyst. Yes, t-BuooH-VO(CH2C6CH2C
OCH3), t-BuooH-Mo(CO)6, etc. can be used.

Aromatic hydrocarbons such as benzene and toluene are suitable as the solvent, the reaction temperature is suitably from ice-cooling to room temperature, and the reaction time is suitably about 30 minutes to 3 hours.

Next, when the obtained epoxy compound (I) is subjected to catalytic reduction, cleavage of the epoxy moiety and intramolecular ring closure occur, and a lactone compound (■) is obtained.

As the catalytic reduction catalyst used, Pd-C, PtO2, Raney nickel, etc. can be used, and as the solvent,
Alcohols such as methanol and ethanol are suitable.

This reaction proceeds satisfactorily in about 1 to 12 hours at room temperature in a hydrogen stream.

Next, the obtained lactone compound is isopropylidened in the presence of an acid to obtain isopropylidene-lactone compound (IV).

As the isopropylidene agent, acetone, 2-methoxypropene, dimethoxypropane, etc. can be used, and the acid is p-toluenesulfonic acid (p'TsO
H), camphorsulfonic acid, etc. are suitable.

This reaction is preferably carried out in the presence of a dehydrating agent such as magnesium sulfate, and the reaction proceeds satisfactorily in about 1 to 12 hours at room temperature.

The isopropylidene-lactone compound (IV
) can be reduced to obtain the erythromycin fragment compound (■) which is the object of the present invention.

As a reducing agent, lithium aluminum hydride (
LiAAH4) is most suitable, and ethers such as ether and tetrahydrofuran are suitable as the solvent.

This reaction proceeds satisfactorily in about 3 to 12 hours at room temperature.

An example of the process of the present invention is as follows.

The present invention will be explained in detail below by way of examples.

Example 1 Erythro hydroxyester (I) (R=C2H5)
To a toluene solution (20TLl) of (760m9) was added a small amount of ■0 (CH2COCH2COCH3) and then 70% t-BuooH (1ynl) under an argon stream, and the mixture was stirred for 2.5 hours under ice cooling.

After the reaction, an aqueous NaH803 solution was added and extracted with ether.

The ether layer was washed with a saturated Na'HCOs aqueous solution and saturated brine, and then dried over magnesium sulfate.

When the solvent is distilled off, the epoxy body (1) (R=C2H5) (
750 mg) of oil are obtained.

This product was used in the reaction of Example 2 without being purified.

(II) Physical properties of (R2C2H3) ■, R1(C
HC13):X/max3400.1720cm-IN
-M-Ro (CDCls, 60 MHz): Example 2 Epoxy body (n) (R'=C2H5) (750~)
10% Pd-C (a small amount) was added to a methanol solution (30 mg) of , and the mixture was stirred at room temperature for 30 minutes under a hydrogen stream.

After the reaction, the catalyst is separated from the furnace and the solvent is distilled off to form a lactone (■
) (R=C2H5) (432 mg) is obtained.

When recrystallized from ether/hexane, it becomes colorless prismatic crystals.

(1) Physical properties of (R2C2H3) m, p,: 102-103°C 1, R, (CHC73): νmax 3400.1
770c1rL-IN-M, R, (CDC7a, 6
0 MHz) ”δ1.03 (t, j = 7H
z; 3H) 1.35 (d, j = 7Hz; 3H) 1.42 (s: 3H) 2, 80 (quintet, j = 7Hz:
/H) Example 3 Lactone body (III) (R= C2H3) (432
A small amount of p-Ts in an acetone solution (40 mJ) of
Add OH magnesium sulfate and stir overnight at room temperature.

After the reaction, the magnesium sulfate is removed from the furnace, the solvent is distilled off, ether is added, and the mixture is washed with a 10% Na2CO3 aqueous solution and saturated brine.

When the solvent is distilled off, isopropylidene-lactone (IV
) (R=C2H5X 3771n9) is obtained.

Recrystallization from ether/hexane gives colorless needle-shaped crystals.

7(IV) Physical properties of (R2C2H3) m, p,: about 200-220°C (sublimation) I, R, (CHC4+)
”νmax 1770cm-1N, M, R, (CD
Cl3: 100 MHz): δ0.97 (t
, j = 7Hz: 3H) 2.68 (q, d
, j=8Hz, j=IHz: IH) 3.56
(d, d, j=9Hz, j=4Hz:LH) 3.77
(a, j=IH2; IH) Example 4 Isopropylidene-lactone (■) (R= C2H
5) Li A to the ether solution (7yd) of (53~)
Add 13 H4 (601n9) and stir overnight at room temperature.

After the reaction, add H20 (60 μl), 15% NaOH (60 μl)
), H20 (180 μl), then an appropriate amount of magnesium sulfate was added, and the precipitate was filtered.

Upon evaporation of the solvent, the erythromycin fragment (V)
(R=C2H5) (51 mg) is obtained.

When recrystallized from n-hexane, colorless prismatic crystals are obtained.

(V) Physical properties of (R=C2H5) m, p,: 75-77°C 1, R, (CHC73) Rainbow max 3400 cIn-
1N, M, R, (CDCl3: 100 MHz)
: δ0.97 (t, j = 7Hz: 3H) 0.98 (d, j = 7Hz; 3H) 1.12
(s; 3H) 1.29 (s; 3H) 1.34 (s: 3H) Example 5 Erythro hydroxyester (I) (R=H) (19
A small amount of vO (CH2C
OCH2COCH3), then under a stream of argon, 70
Add %t-BuOOH (480 ml) and cool on ice for 3 minutes.
Stir for an hour.

After the reaction, an aqueous NaH803 solution was added and extracted with ether.

The ether layer was washed with a saturated aqueous solution of NaHCo and saturated brine, and then dried over magnesium sulfate.

When the solvent is distilled off, the epoxy compound (II) (R=H) (21
7 mg) is obtained as a crude oil.

(I) Physical properties of (R=H) 1, R, (CH(J!3): ” max 3400
, 1720 crrL-'N, M, R, (CDCa:
60 MHz): δ1.20 (d, j=7
．． 5Hz; 3H) 1.32 (s; 3H) 4.12 (d, j=4Hz: IH) 5.16
(s: 2H) Example 6 A small amount of 10% Pd-C is added to a methanol solution (13 ml) of the epoxy compound (I[XR=H) (217 mg), and the mixture is stirred at room temperature for 1 hour under a hydrogen stream.

After the reaction, the catalyst was separated from the furnace and the solvent was distilled off to form the lactone (II
I) (R=H) (128 hits) is obtained.

When recrystallized from ether/hexane, it becomes colorless prismatic crystals.

(1)
Physical properties of (R=H) m, p,: 64-65°C 1, R, (CHC13) Rainbow max 3400.177
0m-IN, MR, (CDCIIs, 60 MHz
): δ1.37 (d, j=8Hz, 3H)1
．． 43(s;3H) Example 7 A small amount of p-TsOH and magnesium sulfate were added to an acetone solution (20 ml) of lactone compound (III) (Ft=H) (128~), and the mixture was stirred at room temperature overnight.

After the reaction, the magnesium sulfate is filtered off, the solvent is distilled off, ether is added, and the mixture is washed with a 10% aqueous Na2CO3 solution and saturated brine.

When the solvent is distilled off, isopropylidene-lactone (IV)
(R=H) (89~) is obtained.

Recrystallization from hexane gives colorless needle-shaped crystals. (IV)
Physical properties of (R=H) m, p, near 2-74°C 1, R, (CH(J?3) Niji max 1770cr
n-'N, M, R, (CDCJ'3: 100 MHz
): δ1.34 (s; 3H) 1.36 (s: 3H) 1.40 (d, j=8Hz: 3H) 1.46 (s: 3H) 2.70 (q, d, j=8Hz, j = IH2; IH) 3.58 (d, j = 11H2; IH) 3.79
(d, j=1 iHz; IH) 3.84 (d,
j=IHz:IH) Example 8 Isopropylidene-lactone (IV) (R=H) (3
5rn9) (7) Add Li to the ether solution (6 ml)
Add AlH4 (50 drops) and stir overnight at room temperature.

After the reaction, H20 (50d), 15% NaOH (50μl
), add H20 (150 μl) and an appropriate amount of magnesium sulfate, and separate the precipitate.

When the solvent was distilled off, the erythromycin fragment (V) (
R=H) (36η) is obtained as a colorless oil.

(V) Physical properties of (R=H) 1, R, (CHCJ'3) Niji max3400cTL
-1N, M, R, (CDCJ?3: 60 M) (z'
): δ1.06 (d, j = 7.2Hz: 3H
)1.07 (s: 3H) 1.46 (s: 6H)

Claims (1)

[Scope of Claims] 1. An erythromycin fragment compound represented by the general formula: (wherein R represents hydrogen or a lower alkyl group). 2. The compound according to claim 1, wherein R is hydrogen. 3. The compound according to claim 1, wherein R is an ethyl group. 4 The compound represented by the general formula: (in the formula, R represents hydrogen or a lower alkyl group) is reduced to obtain the general formula: (in the formula, R represents hydrogen or a lower alkyl group).
In the formula, R is the same as above. ) A method for producing an erythromycin fragment compound, characterized by obtaining a compound represented by: 5 The compound represented by the general formula: (in the formula, R represents hydrogen or a lower alkyl group) is isopropylidened to form the general formula: (in the formula, R is the same as above) A method for producing an erythromycin fragment compound, which comprises obtaining a compound represented by the following formula, and reducing the compound to obtain a compound represented by the general formula (wherein R is the same as above). 6 A compound represented by the general formula: (wherein, R represents hydrogen or a lower alkyl group) is catalytically reduced to form a compound represented by the general formula: (wherein, R is the same as above). ) is obtained, the compound is isopropylidened to obtain a compound represented by the general formula: (wherein R is the same as above), and the compound is reduced to obtain the general formula: A method for producing an erythromycin fragment compound, which comprises obtaining a compound represented by the formula (wherein R is the same as defined above). 7 Erythro hydroxy ester represented by the general formula: (in the formula, R represents hydrogen or a lower alkyl group) is epoxidized to form the general formula: (in the formula, R represents the above-mentioned ) is obtained, the compound is catalytically reduced,
A compound represented by the general formula: (wherein, R is the same as above) is obtained, and the compound is isopropylidened to obtain 1 general formula: (wherein, R is the same as above). ) and reducing the compound to obtain a compound represented by the general formula: (wherein R is the same as above). .