JPS5857434B2 - Shinki Daikanjiyou Lacton Kagobutsuno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing macrocyclic lactone compounds.

More specifically, the present invention is based on the following general formula [) (wherein, R1 represents a hydrogen atom or a lower alkanoyl group, R2 represents a lower alkyl group, R4 represents a lower alkyl group, and R5 represents a lower alkyl group. , is -CH20H
The present invention relates to a method for producing a novel macrocyclic lactone compound represented by the group R'9 represents a 10H group, or R'3 together with R'g represents -CH-OH.

The present invention is based on the following general formula cm) (wherein, R3 represents a -CHO group or a -CH20H group,
R6 represents a hydrogen atom or a lower alkanoyl group, R7 represents a hydrogen atom or a lower alkanoyl group, R1, R2,
R4, R5, A and B have the same meanings as above) A macrocyclic lactone compound represented by the following is treated with an acid anhydride in an organic solvent to obtain a compound represented by the above general formula [II] from the reaction mixture. A method for producing a novel macrocyclic lactone compound, which is characterized in that the novel macrocyclic lactone compound represented by the general formula [II] obtained by the present invention can be used as a pharmaceutical intermediate, especially as a synthetic macrolide antibiotic. It is a compound useful as an intermediate for

The macrocyclic lactone compound represented by the general formula [m) used as a starting material in carrying out the present invention is the following general formula CTV) (wherein R1, R2, R3, R4, R5, R6, R7 ,
A and B have the same meanings as above) is selectively mixed into a compound [ (2)] to N-oxide with an oxidizing agent such as hydrogen peroxide, performic acid, peracetic acid, perbenzoic acid, etc.

Specific examples of the compound represented by the above general formula [IV] include leucomycin A1, A3, A4, A5,
A6, A7, A8, A9 (Special Publication No. 45-27393
~27397 Publication, Special Publication No. 1977-27798~277
No. 99 The Journal of An
tibiotics Vol. 21, 9, pp. 532-538, 1968), leucomycin U, V (Special Publication No. 48-4555), B-5050A, B,
C, D, E, F (Special Publication No. 47-7351)
, Magnamycin, Magnamycin B (Index
of AntibioticsFrom Act
inomycetes 194-195.1967)
, 5F837.5F837A2, A3, A4 (Special Public Showa 4
7-3158), YL-704A, B (Special Publication No. 4
6-28836, Japanese Patent Application Laid-open No. 48-4486)
Examples include.

In addition, compounds in which R3 in the general formula [[] is a -CH20H group are compared to conventional macrolide antibiotics in which R3 in the general formula [■] is a -CH0 group, as described in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry).
fMedicinal Chemistry)1
5(10) 1011-1015 (1972), or by treatment with a reducing agent such as sodium borate, or in the general formula [■], R3 represents a -CHO group and A represents an H>C< group. The compound may be treated with aluminum isopropoxyde-cyclohexanone in an organic solvent such as toluene to cause intramolecular redox.

In addition, the reaction of the present invention is carried out using the general formula [I
The compound represented by II) is treated with an acid anhydride to remove the glycosidic-bonded dimethylamine sugar N-oxide to obtain a compound represented by the general formula [ID].

Therefore, the starting material used in the present invention is not limited in any way as long as it is a dimethylamino sugar N-oxide compound glycosidically bonded to the macrocyclic lactone, such as leucomase A1, A3, A4, A6,
Kitasamycin, leucomycin U, V, B-505OA consisting of A6, A7, A8, A9 or mixtures thereof
, B, C, D, E, F, Magnamycin, Magnamycin B, 5F837.5F837A2, A3, A4, YL
-704A, B and other macrocyclic rough I/N compounds, or compounds obtained by oxidizing, reducing, or acylating them as necessary, and compounds in which the dimethylamino group of the compound is N-oxidized.

In the present invention, the macrocyclic lactone compound represented by the general formula [■] is dissolved in an organic solvent.

The organic solvent used here may be any organic solvent that dissolves the compound represented by the general formula [111) and is inert, such as benzene, toluene, methylene chloride, ethylene chloride, chloroform, acetone, acetic acid. Examples include ethyl, butyl acetate, dioxane, methanol, ethanol, and tetrahydrofuran.

Next, an acid anhydride is added to this, and as the acid anhydride used in the present invention, in addition to a single acid anhydride, a mixed acid anhydride can also be used, and preferably, for example, acetic anhydride is used. Trichloroacetic anhydride, monochloroacetic anhydride, etc. can also be used.

The amount of acid anhydride added is usually about 3 to 10 times the mole, preferably about 6 times the mole of the macrocyclic lactone compound represented by the general formula [1111). It's okay.

The production rate of compound [■] by this reaction varies depending on the organic solvent used. For example, if chloroform, acetic acid/L/L/, acetone, tetrahydrofuran, dioxane, methanol, etc. are used as the organic solvent, compound [■] will be produced. The production rate of I[) is good.

After injecting the reaction solution obtained as above into water,
Neutralization and then extraction from this with an organic solvent immiscible with water, such as benzene, ethyl acetate, chloroform, etc., and the organic solvent layer is collected and concentrated to obtain the general formula [■
] A coarse powder of the compound represented by is obtained.

Next, to purify this crude powder, first dissolve it in a small amount of an organic solvent such as benzene, chloroform, acetone, or methanol, pass it through a column packed with silica gel, etc., and add an elution solvent to it. The resulting fraction containing the compound [II] was collected and concentrated to give a purified compound of the general formula CI, l or C.
A novel macrocyclic lactone compound represented by II, 1 is obtained.

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

Example 1 To a solution of 100 ml of chloroform in which leucomycin As-N-oxide 101 obtained as described below was dissolved, 7 rul of acetic anhydride was added and refluxed for 1 hour, and then poured into 300 mg of ice water. After neutralizing with an aqueous sodium hydrogen carbonate solution, the chloroform layer was collected, and the chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water in that order, and then anhydrous sodium sulfate was added and the resulting chloroform was filtered. Dry the layers under vacuum.

Next, 5 g of the obtained powder was dissolved in a small amount of benzene, and this was dissolved in 200 g of silica gel (Kieselgel G: manufactured by Merck & Co., Ltd.).
? The elution was carried out through a column (diameter 2.5 cm) packed with 500 mg of benzene:acetone at a flow rate of 0.25 mg/min (benzene:acetone 10 = 1.9:118:1). ,7:
1, 6 two 1, 5: 1, 4.5: 1.4 two 1
．． Elute using a concentration gradient of 3.5:1.
1) with Rf value of 20, only one point of 67 is shown] and concentration gradient of 4.5: IC benzene:acetone (2:1)
Rf value: 0.36, Rf value of 20, 30 for chloroform:methanol (721) was shown, and a 20% sulfuric acid aqueous solution was sprayed on this, and the temperature was heated at 110°C for 4 minutes.
Collect the fraction which shows yellow-brown spots on heating.

The concentration gradient 4.5:10 fractions were then combined and dried under reduced pressure to obtain a white powder ([HA)).

The physicochemical properties of [nA,l are as follows.

■ Elemental analysis value, molecular formula, and measured molecular weight C261.94H28.03 N:0 Calculated value C:62.59 H28.24N2 〇C22H340s (molecular weight 426.246) ■ Melting point: 96-97℃ ■ Specific rotation reduction 5: +16.4° (C: 0.5, ethanol) ■ Ultraviolet absorption spectrum (i) Diacetyl CIIA measured in ethanol) (
The ultraviolet absorption spectrum at a concentration of 25γ/Ult is as shown in Figure 1, and λmax: 232mμ ε217
．． It has maximum absorption at 340.

Note that diacetyl CIIA) was obtained as follows.

That is, [IIA) 100~ was dissolved in 2 ml of pyridine, 0.8 M of acetic anhydride was added thereto, and then the mixture was dissolved at room temperature for 24 hours.
After the reaction, the mixture was poured into ice water, washed with 20% aqueous sodium bicarbonate solution, the resulting precipitate was extracted with ethyl acetate, and the extract was dried over anhydrous sulfuric acid. was evaporated, and the residue was further purified by silica gel chromatography using benzene-acetone (1521) to obtain a white powder of diacetyl [I
IA, 180 years [□, p, 84-85°C, specific rotation angle 5: +33.4° (C: 0.5, ethanol)] was obtained.

■ A compound with an infrared absorption spectrum [■A] was dissolved in chloroform, and the compound was dissolved in chloroform.
The infrared absorption spectrum measured by loading it into a 1 mm cell is as shown in Figure 2, and is 3600.344013.
000.2940.2880.2840.1730.1
450.1440.1425.1372.1305.1
235.1178.1144.1123.1109.1
079.1049.1023.990.905.850
It has an absorption band at each wave number of crfL-1.

■ Nuclear magnetic resonance spectrum [IIA] at 10 MHz in deuterated chloroform
The nuclear magnetic resonance spectrum of is shown in FIG. 3 (internal reference TMS).

From the above results, the structure of [nA) is recognized as follows.

The leucomycin A3-N-oxide used in this example was obtained as follows.

Chloroform 35 in which leucomycin A322P was dissolved
In 0rILl, under stirring, meta-chloroperbenzoic acid 51
Added 110 mA of a chloroform solution in which was dissolved, cooled to 5°C and allowed to react for 30 minutes. The mixture was further left at room temperature for 2 hours, and a 10% aqueous solution of sulfur and lithium was added to remove excess meta-chloroperbenzoic acid. Let it break down.

The chloroform layer obtained by filtering this was washed with a 5% aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution to recover the chloroform layer, which was dried by adding anhydrous sodium sulfate and further concentrated under reduced pressure. Concentrate to 30ml and add 450ml of ethyl ether to this.
ml was added to obtain 19.5P of white precipitate, which was further recrystallized from ethyl acetate-ethyl ether to obtain light-colored needle-like crystals.

This product had a melting point of 133-134°C, a specific optical rotation (b) of 19.0° (C: 0.5, ethanol), and was recognized as leucomycin A3-N oxide.

Example 2 9-dehydro-17-hydroxymethyl-leucomycin A3-N-oxide 1.21 obtained as follows
Add 0% acetic anhydride to 20rne of a chloroform solution in which
．． 7ml was added and refluxed for 1.5 hours, then poured into ice water, further neutralized with a sodium bicarbonate solution, and the chloroform layer was collected. The mixture is washed with water, then anhydrous sodium sulfate is added, and the chloroform layer obtained by filtration is dried under reduced pressure.

Next, the obtained residue 12 was dissolved in a small amount of chloroform, and this was poured into a column (diameter 2.5
CrrL) at a flow rate of 0.25rILl using chloroform:methanol (60:1) as the elution solvent.
3 mg/minute was collected, fraction numbers 200 to 230 were collected, combined, and dried under reduced pressure to obtain a white powder.

The physicochemical properties of this white powder are as follows.

■ Melting point 267-69℃ ■ Specific optical rotation ■ 5: +54.2° (C: 0.5, ethanol) ■
Ultraviolet absorption spectrum The ultraviolet absorption spectrum of this compound (concentration 12.5γ/ml) measured in ethanol is as shown in FIG.
It has maximum absorption at 60.

■ Infrared absorption spectrum 0.1rnl of this compound dissolved in chloroform! The infrared absorption spectrum measured by loading the cell with 3480.3040.3000.2 is as shown in Figure 5.
970.2810.2790.1745.1740.1
690.1640.1600.1463.1440.1
382.1370.1350.1310, 1260.1
245.1190.1130.1105.1060.1
It has an absorption band at each wavenumber of 010cIrL-1.

(2) Nuclear Magnetic Resonance Spectrum The nuclear magnetic resonance spectrum of this compound in deuterated chloroform at 100 MHz is shown in Figure 6 (internal standard TMS).

From the above measurements, this compound is recognized to have the following structure.

The above 9-dehydro-17-hydroxymethyl-leucomycin A3-N-oxide was obtained as follows.

Leucomycin A3101 is dissolved in a solution of 80 ml of anhydrous toluene and 25 ml of cyclohexanone, to which is added 20 ml of an anhydrous toluene solution containing 7 g of aluminum isopropoxide, which is refluxed for 40 minutes and then kept stirring for 1 hour.

After the reaction is complete, the reaction solution is poured into ice water with stirring, and vinegar [
After extraction with ethyl, the ethyl acetate layer was added with anhydrous sulfuric acid.
-') ram was added, filtered and concentrated, and the residue was purified using silica gel (35
Of) chromatographically purified 9-dehydro-1
7-Hydroxymethyl-leucomycin A3'5.4
A white powder of P was obtained.

The physical properties of this material are as follows.

■ Specific optical rotation: 67° (C: 0.55, ethanol) ■ Ultraviolet absorption spectrum The results of measuring the ultraviolet absorption spectrum of this compound dissolved in ethanol are: λmax: 280 mμ ε2 260
It has maximum absorption at 00.

■ Infrared absorption spectrum This compound was dissolved in carbon tetrachloride (concentration 161n910, 3
5mA? ) The obtained solution was loaded into a cell of 0.1 mm and the infrared absorption spectrum was measured.
2900.2880.2830.2790.1740.
1685.1638.1595.1450.1373.
1295.1250, 1230.1165.1120.
1085.1055.1030.1000, CIrL-
It has an absorption band at each wave number of 1.

Next, this 9-dehydro-17-hydroxymethyl-leucomycin A345? was dissolved in 80 ml of chloroform, and 30 ml of a chloroform solution containing 1.22 g of meta-chloroperbenzoic acid was added thereto under stirring, reacted for 30 minutes, cooled to 75°C, and left at room temperature for 2 hours. and add 10% thorium sulfite aqueous solution,
Excess meta-chloroperbenzoic acid is destroyed.

The chloroform layer obtained by filtering this was washed with a 5% aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution to recover the chloroform layer, which was then added with anhydrous sodium sulfate, dried, and further concentrated under reduced pressure. and concentrated to 10 rne, and to this was added 140 ml of ether.
was added to obtain a white precipitate of 4.21, and then ethyl acetate was added.
Recrystallization from ethyl ether gave white needle-like crystals of 9-dehydro-17-hydroxymethyl-leucomycin A3-N-oxide (melting point 122-123°C).

Example 3 7 ml of acetic anhydride was added to a 10 ome solution of chloroform in which 10 g of Icomycin A3-N-oxide was dissolved, and the mixture was refluxed for 1 hour.Then, this was poured into 300 ml of water, and this was further neutralized with an aqueous sodium bicarbonate solution. After cooling, the chloroform layer is collected, and the chloroform layer is washed with a saturated aqueous sodium bicarbonate solution and water in this order, and then anhydrous sodium sulfate is added thereto, filtered, and the resulting chloroform layer is dried under reduced pressure.

Next, the obtained powder 52 was dissolved in a small amount of a mixed solvent of chloroform and methanol (6021), passed through a column (diameter 2.5 cm) packed with 200 g of silica gel, and chloroform:methanol (6021) was used as the elution solvent. 60:1
) at a flow rate of 0.25 rul for 1 minute.
Separate 1g each and obtain the fraction number 300～
350 [Benzene: Rf in acetone (221)
A. Only one point of 0.36 is shown, which is further sprayed with an aqueous sulfuric acid solution and heated at 110°C for 4 minutes to show a yellowish brown point], which are combined and dried under reduced pressure to form a white powder. Obtained.

This substance was confirmed to be the same substance as [IIA) in Example 1 above.

Example 4 To 30 ml of chloroform in which magnamycin 2z was dissolved, 8rflI3 of chloroform in which 0.51 of meta-chloroperbenzoic acid was dissolved was added under stirring, cooled to 5°C, and reacted for 30 minutes, and then allowed to cool to room temperature for 2 hours. Leave it for 1
Excess meta-chloroperbenzoic acid is decomposed by adding 0% aqueous sodium sulfite solution.

The chloroform layer obtained by filtering this was washed with 5% sodium hydrogen carbonate and then with a saturated aqueous sodium chloride solution to recover the chloroform layer, which was dried by adding anhydrous sodium sulfate and further concentrated under reduced pressure. 2r
Concentrate to fLl and add 150 mA of ethyl ether to give 1.71 g of white magnamycin-N-oxide.
I got it.

Dissolve 1.71 of this magnamycin-N-oxide in 20rrL of chloroform, and add 1.5a of acetic anhydride.
A' was added and refluxed for 1 hour, then poured into ice water, further neutralized with an aqueous sodium bicarbonate solution, and the chloroform layer was collected. The chloroform layer obtained by adding anhydrous sodium sulfate and filtering is dried under reduced pressure.

Next, this obtained powder 1.61 was dissolved in a small amount of benzene and passed through a column (diameter 2.5 cm) packed with silica gel 60y', using chloroformimethanol (6021) as an elution solvent. , flow velocity 0.25m
3rnl fractions were collected under the condition of 137 minutes, and fraction numbers 270 to 310 were collected, which were combined and dried under reduced pressure to form a white powder (ultraviolet absorption spectrum λmax: 24
0 mμ e219000) was obtained.

The compound thus obtained is recognized to have the following structure.

Example 5 Chloroform 3QU in which 0 icomycin A121 was dissolved
0.6?g of meta-chloroperbenzoic acid under stirring. Added 10ml of chloroform in which methane was dissolved, cooled to 5°C and reacted for 30 minutes. The mixture was further left at room temperature for 2 hours, and a 10% aqueous sodium sulfite solution was added to remove excess methane.
Decomposes chlorobenzoic acid.

The chloroform layer obtained by filtering this was washed with 5% sodium hydrogen carbonate and then with a saturated sodium chloride aqueous solution to recover the chloroform layer, which was dried by adding anhydrous sodium sulfate and further concentrated under reduced pressure for 3 hours.
Concentrate to nl and add 220 mg of ethyl ether to give 1.9 mL of white leucomycin A1-N-oxide.
I got 2.

1.91 of this leucomycin A1-N-oxide was dissolved in 30 ml of chloroform, and 1.5 ml of acetic anhydride was added to the solution.
The mixture was then poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, and the chloroform layer was collected. After washing in this order, anhydrous sodium sulfate is added and filtered, and the obtained chloroform layer is dried under reduced pressure.

Next, 1.81 g of this obtained powder was dissolved in a small amount of benzene, and this was poured into a column (diameter 2) packed with 75 g of silica gel.
．． 5 cm), using chloroformimethanol (60:1) as the elution solvent, with a flow rate of 0.25 m.
The fractions were separated in 3rnl portions under the condition of g/min, and fraction numbers 300 to 350 were collected, which were combined and dried under reduced pressure to form a white powder (ultraviolet absorption spectrum λmax: 232
mμe: 18100) was obtained.

The compound thus obtained is recognized to have the following structure.

[Brief explanation of the drawing]

Figure 1 shows the ultraviolet absorption spectrum of the diacetyl CIIA) compound obtained in Example 1, and Figure 2 shows the infrared absorption spectrum of the [■A] compound obtained in Example 1.
Figure 3 shows the nuclear magnetic resonance spectrum of the compound [nA] obtained in Example 1, Figure 4 shows the ultraviolet absorption spectrum of the compound obtained in Example 2, and Figure 5 shows the nuclear magnetic resonance spectrum of the compound [nA] obtained in Example 2. FIG. 6 shows the infrared absorption spectrum of the compound obtained in Example 2, and FIG. 7 shows the infrared absorption spectrum of 9-dehydro-17-hydroxymethyl-leucomycin A3. The absorption spectrum is shown.

Claims (1)

[Claims] 1 The following general formula [■] [In the formula, R1 represents a hydrogen atom or a lower alkanoyl group, R2 represents a lower alkyl group, and R represents a -CR2 group or -
L represents a CH2oH group, R4 represents a lower alkyl group, R
6 represents a lower alkyl group, R6 represents a hydrogen atom or a lower alkanoyl group, R7 represents a hydrogen atom or a lower alkanoyl group, and a macrocyclic lactone compound represented by
The reaction mixture was treated with an acid anhydride in an organic solvent, and the reaction mixture was extracted with the following general formula [) (wherein, R'3 represents a -CH2oH group, R'g represents a 10H group, or R1 and R6 together represent -CH- Indicates OH,
R1, R2, R4, R5, A and B have the same meanings as above) A method for producing a novel macrocyclic lactone compound, which is characterized by obtaining a compound represented by