JPH03246290A - Production of pyrane derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject compound useful as an intermediate for synthesis of 1beta-methylthienamycins having a strong and wide-range anti-bacterial effect by carrying out methylation, oxidative cleavage, oximation, etc., of a new compound synthesized from a cyclopentane derivative, etc. CONSTITUTION:A new compound of formula I is methylated using a methylation agent in the presence of a base in an inert solvent to obtain a compound of formula II. The above-mentioned compound of formula II is subjected to oxidative cleavage in a solvent using an oxidative agent to obtain a compound of formula III. The resultant compound of formula III is then subjected to oximation in a solvent using a hydroxylamine, etc., to obtain a compound of formula IV (Z form can be readily isomerized to E form by oxidation treatment). The obtained compound of formula IV is subjected to Beckmann rearrangement in an organic amine as an inner solvent using a reactive agent to obtain a compound of formula V. A hydroxy-protecting group in the compound of formula V is subsequently eliminated and then oxidized in a solvent using Jone's reagent, etc., thus providing the objective compound of formula VI.

Description

[Detailed description of the invention] Formula (I), which is a useful intermediate in the synthesis of The present invention relates to a method for producing a pyran derivative represented by

1β-Methylchenamycin is represented by the formula (A) and is derived from Streptomyces cattleya (Stre-ptomyc
It is a non-natural carbabenem antibiotic produced by modifying the 1-position of chenamycin produced by S. es cattlea with a methyl group. The antibiotic has the advantage of exhibiting potent and broad-spectrum antibacterial activity similar to chenamycin, and superior resistance to inactivation by renal dehydropeptidase compared to chenamycin.

Because of these advantages, 1β-methylchenamycin derivatives have attracted attention, and various synthetic methods have been developed. Examples of these methods include the following methods.

(a) “Heterocycles”
) J 1984, 219 (b) [Tetrahedron Lett. J 987 28.

07 α'1 (wise; βl' to see 65:35 However, none of the conventional methods was satisfactory in terms of stereoselectivity of the methyl group to be introduced.

The present inventors synthesized compound (C), which is a synthetic intermediate for chenamycin, using a cyclobentane derivative (B) that is easily obtained from Q-carvone, and synthesized compound (C), which is a synthetic intermediate for chenamycin. A method for synthesizing (D) has already been established ([Journal of Chemical Society Chemical Communication (J. Chem.
Sac. , Chew. Commun. )J19g
9, 646). This method gives chenamycin with very good stereoselectivity.

(D) Therefore, in the synthesis of the 1β-methylchenamycin derivative, in order to utilize the same stereoselective reaction as described above, the synthetic intermediate corresponding to the above compound (C) is expressed by the above formula (I). The present invention was completed by considering a compound and discovering that a synthetic intermediate compound can be stereoselectively synthesized using the compound represented by the above formula (II) which can be easily obtained from ρ-carboxylic acid.

1β-Methylchenamycin derivative (A) The synthesis process of the pyran derivative according to the present invention is expressed as follows.

(■) (Ill) (■) (stomach) (Vl VIl (■) +11 Next, each step in the above synthesis process will be explained in detail.

Nishiyu I This step (a) is a step of methylating the compound represented by formula (n). The methylation reaction is carried out in the presence of a base such as lithium diisopropylamide, lithium hexamethyldisilazide, lithium isopropylcyclohequinylamide in an inert solvent such as tetrahydrofuran, ether, hexamethylphosphoric triamide, or dioxane. This is done using a methylating agent such as methyl chloride.

This step is based on the formula (I) obtained by the methylation reaction.
This is a step of oxidatively cleaving the compound represented by II). In the oxidative cleavage, ozone, osmium tetroxide-sodium periodate, potassium permanganate, ruthenium tetroxide, etc. can be used as an oxidizing agent, and as a solvent, ethyl acetate, acetone, dichloromethane, te
rt-butanol, tetrahydrofuran, dioxane,
Water or mixtures thereof can be used.

This step is based on the formula (rV) obtained by the oxidative cleavage.
This is a step of converting the compound represented by the following into an oxime. The oximation is carried out using hydroxylamine or its hydrochloride in the presence or absence of a base such as pyridine or sodium acetate in a solvent such as dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, or ethyl acetate.

In this reaction, two geometric isomers, E-form and 2-isomer, are obtained, but these can be easily separated, and the 2-isomer, which is a by-product, is isomerized to E-form by acid treatment.

Step 1 (This step is to convert the formula (V) obtained by the oxime formation into
This is a step in which a compound represented by is subjected to a Beckmann rearrangement reaction.

As a reactant, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, phosphorus pentoxide, sulfuric acid, etc. are used, and dichloromethane,
The Beckmann rearrangement reaction can be carried out in an inert solvent such as chloroform or benzene, or in an organic amine such as pyridine or triethylamine.

This step is based on the formula (
This is a step of deprotecting the hydroxyl protecting group of the compound represented by VI). For the deprotection, various deprotection reactions commonly used in the art may be used; for example, for debenzylation, catalytic hydrogenation using palladium or the like as a catalyst is preferably used.

This step is a step of oxidizing the hydroxyl group of the compound represented by formula (■) obtained by the deprotection.

In the oxidation reaction, Jones reagent, pyridinium dichromate, pyridinium chlorochromate, ruthenium tetroxide, and oxygen can be used as the oxidizing agent, and as the solvent, dimethylformamide, acetone,
Dichloromethane, carbon tetrachloride, water or mixtures thereof can be used.

According to the present invention, the pyran derivative represented by formula (I), which is a useful synthetic intermediate for 1β-methylchenamycin, can be stereoselectively synthesized through the series of reactions described above.

In addition, the formula (n
Although the compound represented by ) is a new substance, it can be easily synthesized from known cyclopentane derivatives according to the reaction scheme shown below.

t-nim next, To explain the invention in more detail, good An example, which is a suitable specific example, is shown below. The present invention is but not limited to.

Example A synthesis of xo-2H-pyran-3-carvone (4R95R,6R)-5 according to the synthesis scheme below.
-benzyloxymethyl-3,4,5,6-tetrahydro-6-methyl-4-(1-methylethynyl)-2H-
A desired pyran compound (I) was synthesized using pyran-2-one (1) as a raw material.

(1) (2) (3) (4b) (5) (6) (+) 1 3R4S 5R5R-5-Benzyloxymethylithium A solution of isopropylcyclohexylamide (115 mmol) in tetrahydrofuran (180 mQ) =
At 78°C, (4R,5R,6R)-5-benzyloxymethyl-3,4,5,6-tetrahydro-6-methyl-4-(1-methylethynyl)-2H-pyran-2-one ( 1) 6.35 g (23 mmol) of tetrahydrofuran solution 40- was added dropwise and stirred at -20°C for 1 hour. Cool again to -78°C and add 16.3 g of methyl iodide (
After stirring for 1 hour, 8.5 mmol of acetic acid was added.
3 g was added dropwise. Saturated brine was added to the reaction solution, extracted with ethyl acetate, the extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and 2.1 g (31.5%) of compound (2) was obtained from the hexane-ethyl acetate fraction.
) was obtained. Thereafter, 4.07 g (64.1%) of starting compound (1) was recovered by further elution with the same developing solvent.

The physical data of the obtained compound (2) are as follows.

MS spectrum (C+Jt40a): Theoretical value (m/z) 288.1725 Actual value (m/z
) 288.1725 NMR spectrum (CDCQ
a, 270MHz) 61.22 (3H, d, J=
6.7Hz), 1.40 (3H, d, J=6.1Hz)
1.63 (3H, s) 1.67 (IHdddd J=
2.4Hz 3.7Hz9.8Hz, 9.8Hz),
2.41 (LH, dq, J=11.0Hz, 6.7Hz
) 2.49 (LH, dd, J=11.0Hz, 9.8H
z), 3.38 (IH, ddJ=3.7Hz, 9.8H
z), 3.48 (IH, dd, J=2.4Hz, 9.8
Hz) 4.37 (IH, d, J=11.6Hz), 4.
45 (IH, d, J=11.6Hz) 4.56 (IH,
dq, J-9, 8Hz, 6.1Hz), 4.87 (IH
,S).

4.94 (LHlS), 7.26-7.38 (5H, m
) 36-cymethyl-2H-pyran-2-one Shima Shikyoshi 1
4.73 g (8
16.4 mmol) was dissolved in 100 g of tetrahydrofuran, 100 g of an aqueous solution containing catalytic amounts of osmium tetroxide and 7.73 g of sodium periodate were added, and the mixture was stirred at room temperature for 4 hours. After adding 100% of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium sulfite solution and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and compound (3) was obtained from the hexane-ethyl acetate stream.
3.09 g (64.9%) was obtained.

MS spectrum (C+vH2204): Theoretical value (m/
z) 290.1518 Actual measurement value (m/z) 29
0.1523 NMR spectrum (CDCQ, 270
MHz) δ: 1.22 (3H, d, J = 6.7Hz),
1.35 (3H, d, J = 62.01 (LH, dddd
, J=3.7Hz, 4.3Hz, 9.8Hz7Hz) 10.4Hz) OHz 6.7Hz) 3.39 (LHldd J=4.3Hz 10.4 48 (IH, d, J=11°7Hz), 7.27 2.19 (3H, s), 2.73 (LH, dq, J=1
12.98 (IH, dd, J=11.0Hz, lO, 4
Hz) J=3.7Hz, 10.4Hz), 3.44(L
H, ddHz), 4.41 (IHld, J-11, 6H
2), 46Hz), 4.49 (IH, dq, J=9.8
Hz, 67.40 (58 m) Compound (3) obtained in the above step 2) 56.8 mg (0
, 2 mmol), pyridine 217■ (027 mmol)
and 16.3 μm (0.24 mmol) of hydroxylamine hydrochloride were dissolved in 2 ml of methanol and stirred at room temperature for 2 hours. After adding 10-liters of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain 36.5 μm (592%) of compound (4a) from the hexane-ethyl acetate fraction;
By further elution with the same developing solvent, compound (4
bH6,4■ (266%) was obtained.

MS spectrum (CI7H2JO4): Theoretical value (m/z
) 305.1626 Actual value (m/Z) 3051
63O NMR spectrum (CDCQs, 270MHz)
δ: 1.25 (3H, d, J=6.7Hz), 1.38
(3H, d, J=6.7Hz).

1.84 (3H, s), 2.58 (IH, dq, J=
11.6Hz, 6.7Hz) 2.69 (IH, dd, J
=11.6Hz, 10.4Hz), 3.33(LH, d
d.

J=3.1Hz, 9.8Hz), 3.45(IH, dd
, J=3.1Hz 9.8Hz)4.34(IH,d
, J=11.6Hz), 4.44(IH,d, J=11
．． 6Hz) 4.53 (IH, dq, J=9.8Hz, 6
．． 1Hz), 7.26-7.37 (5H.

m), 8.81 (LH, br s) 1111 MS spectrum (C+JtsNOt): Theoretical value (m/
z) 305.1626 Actual measurement value (m/z) 30
5.1621 NMR spectrum (CDCQ s,
270MHz) δ: 1.28 (3H, dj=7.3Hz
), 1.39 (3H, d, J=6.1Hz).

1.83 (3H, s), 2.12-2.20 (IH, m
), 2.81-2.87 (IHm) 3.36 (IH, d
d, J=3.7Hz, 10.4Hz), 3.41(I
H, m) 3.49 (IH, dd, J=3.1Hz, 10
．． 4Hz), 4J8 (IH, d, J=11.6Hz),
4.47 (IH, d, J = 11.6Hz), 4.53 (
IH, dqJ=9.8Hz 6.1Hz), 7.25
-7.37 (5H, m), 9.16 (IHbr s) Next, the obtained compound (4b) was isomerized to compound (4a). That is, the compound (4bH33) (0.44 mmol) was dissolved in 2 ml of ether, 100 μ (0.53 mmol) of p-toluenesulfonic acid was added, and 2
Stir for hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, stirred for 10 minutes, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain 97 mm (732%) of compound (4a) from the hexane-ethyl acetate fraction, and then further elution with the same developing solvent yielded starting compound (4b) 2.
7■ (205%) was recovered.

Compound (4a) obtained in the above step 3) 100■ (03
3 mmol) was dissolved in 1 ml of pyridine, and 100 mmol of phosphorus oxychloride (0.66 mmol) was added dropwise under cooling.
The mixture was stirred at ℃ for 1 hour. Add 10 mQ of water to the reaction solution,
After stirring for an hour, the mixture was extracted with ethyl acetate. After washing the extract with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, and 82 cm (820%) of compound (5) was obtained from the hexane-ethyl acetate fraction.

mp: 122°C 5 [α co: -28° (c=2.897.
CHCf:i, the compound obtained in step 4) above (
5) Dissolve 195μ (0.64 mmol) in ethanol 2-4 drops of 2N-hydrochloric acid and 10% palladium-carbon 5
The mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the solvent of the filtrate was distilled off. The residue was subjected to silica gel chromatography, and 137 μm (100%) of compound (6) was obtained from the ethyl acetate-methanol fraction.

mp: 179-180℃ 5 [α]: +57.3° (c=0.968.C
HCQ s) Compound (6) obtained in the above step 5) 50
0 mg (2.33 mmol) in dimethylformamide 6
3 g of pyridimium dichromate (7,
97 mmol) and stirred at room temperature for 12 hours. The reaction solution was subjected to silica gel chromatography, and the crude compound (1) was obtained from the ethyl acetate-methanol-acetic acid stream, and the crude compound (1) was obtained from the ethyl acetate-methanol-acetic acid stream, and the desired compound (I) 391 was again subjected to silica gel chromatography, and the desired compound (I) 391 was obtained from the chloroform-methanol-acetic acid stream.
■ (73.5%) was obtained.

mp: 193℃ 5 [α]: +27.9° (c=1994.E
tOH) MS spectrum (C+.HI6NO11) Theoretical value (m/z) 229.0949 Actual value (m/z
) 229.0948NMR spectrum (CDCQs
, 270MHz) δ1.34 (3H, d, J=6.7
Hz), 1.42 (3H, d, J=6.1Hz) 1.9
6 (3H, s), 2.52 (IHldq, J=11.1
Hz, 6.7Hz) 2.60 (IHdd, J=11.0
Hz, 10.4Hz), 4.28 (LH, dd each J=
11.0Hz), 4.58 (IH, dq, J=10.
4Hz, 6.1Hz) Furthermore, the compound according to the invention (I
) is useful for the synthesis of 1β-methylchenamycins, the compound (
I), and the literature ("Tetrahedron Letters" 1
987 28, 83), and compound (7) was obtained.

(1) (7) Various spectral data of the obtained compound (7) can be found in the literature (
The values were consistent with those described in [Heterocycles J 1984.21.29), and the specific light absorption and melting point were also consistent.

mp: 118-121°C (Literature value 120-121°C
) Reference Example Regarding compound (1) used in the production method according to the present invention,
It was synthesized according to the following synthesis scheme.

(8) (9) (1θ) (11) (1) Literature (Heterocycles J 1987.26.149
18.8 g of (2R/S, 3S, 4R)-3-hydroxymethyl-2methyl-4-(1-methylethynyl)cyclopentanone ethylene acetal (8) described in 1) (
88 mmol) in 360 ml of dimethylformamide and, under cooling, 8.9 g of 60% sodium hydride (
After stirring for 30 minutes, 30 g (175 mmol) of benzyl bromide was added dropwise. After further stirring at room temperature for 3 hours, ice water was added, and the mixture was extracted with benzene.

The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, and the compound (
9) Obtained 240g (89.6%).

MS spectrum (C+JsgOs) Theoretical value 302.1883 Actual value 302.1883 NMR spectrum (CDCQ s, 270MHz)
δ0.99 (3Hd, J=7.3Hz), 1.67 (3
Hs), 1.73 (IH, m) 1.76 (IH, dd,
J=10.4Hz, 13.4Hz), 1.95(LH,
dd.

J=9.2Hz, 13.4Hz), 2.05(IH, d
q, J=9.8Hz, 6.7Hz), 2.53(LH,
ddd, J=9.2Hz, 9.8Hz, 10.4Hz)
3.40 (IH, dd, J = 5 5Hz, 9.8Hz) 3.47 (IH, dd J = 3.7Hz 5.5Hz), 3 78-3.94 (4H1m), 4.48 (2H5) 4.73 (2H, s), 7.21-7.36 (5H, m
) Compound (9) obtained in step 1) 24 g (79
mmol) was dissolved in acetone IQ, 750 μm (39 mmol) of p-toluenesulfonic acid was added, and the solution was dissolved at room temperature for 12 mmol.
Stir for hours. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, acetone was distilled off, and the mixture was extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain compound (10) 19. from the hexane-ethyl acetate fraction.
5 g (95.1%) were obtained.

MS spectrum (C+7H2202): Theoretical value (m/
z) 258.1620 Actual measurement value (m/z) 258
．． 1620 NMR spectrum (CDCclg, 27
0MHz) 61.10 (3H, d, J=6.7Hz)
, 1.68 (3H, s), 1.81 (IH, m) 2.1
1 (LH, dd, J=11.6Hz, 18.3Hz),
2.28 (LH, dqJ=11.6Hz, 6.7Hz)
, 2.44 (IH, dd, J=18.3Hz, 7.9H
z), 2.80 (LH, ddd, J=11.6Hz, 1
1.6Hz, 7.9Hz) 3.47-3.58 (2H,
m), 4.49 (2H, s), 4.82 (2H, s).

7.22-7.35 (5H, m) Compound (10) obtained in the above step 2) 225■ (08
7 mmol) in dichloromethane, 870 μm (87 mmol) of potassium hydrogen carbonate and 750 μm (4.35 mmol) of m-chloroperbenzoic acid were added, and after stirring at room temperature for 3 hours, dimethyl chloride was dissolved under ice water. sulfide 540m
g (8.7 mmol) was added. After stirring for another 6 hours,
The solid matter was filtered off, and the solvent of the filtrate was distilled off. The residue was subjected to silica gel column chromatography, and from the hexane-ethyl acetate fraction, compound (11) 247μ (97.5%) was obtained.
) was obtained.

MS spectrum (C0JtxOh) Theoretical value (m/Z) 290.1519 Actual value (m/z
) 290.1519NMR spectrum (CDCQ
s, 270MHz) δ125 and 127 (total 3H,
s), 1.36 and 1.38 (total 3H1 d each,
J = 6, 1 Hz and J = 6.7 Hz), 1.53 and 180 (total IH, each m), 2.07 and 217 (total I
H, each m) 244 and 2.57 (total IH, each dd,
J=3.7Hz, 16.5Hz and J=16.5Hz 4
．． 3Hz) 2.53-2.57 (2H, m), 2.6
8 and 274 (total LH, each dd, each J = 6, 5H
z, 16, 5Hz) 347 and 360 (total IH,
dd, J=3.1Hz, 9.8Hz and J=3.7H respectively
z, 9.8Hz), 3.53 and 3.65 (total IH, each dd, respectively J = 3.1Hz, 9.8Hz), 4.3
6-4.55 (3H, m) 7.27-7.39 (5H,
m) 4"1 of -1 1.87 g (22.8 mmol) of sodium acetate, 1.8 g (12 mmol) of sodium iodide and 1.
8 g (27.5 mmol) were suspended in 8 mQ acetic acid,
Compound (11) obtained in step 3) 0.8g (2,
3 mQ of an acetic acid solution of (fromimole) was added dropwise, and after stirring for 10 minutes, Hensen's solution was added to the reaction solution and filtered. After washing the filtrate with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and from the hexane-ethyl acetate fraction, the desired compound (1) was obtained at 455 μl (
60.2%) was obtained.

MS spectrum (C+, H220m) Theoretical value (m/z) 274.1570 Actual value (m/z)
z) 274.1573 NMR spectrum (CDC1
2m, 27 (1MHz) δ1.39 (3H, d, J=
6.1Hz), 1.60 (IH, ddd J=3.1
Hz3.1Hz, 9.8Hz, 9.8Hz), 1.66
(3H,s), 2.44(IHdd, J=6.7Hz,
16.5Hz), 2.70 (IH, dd, J=7.9H
z17.1Hz), 2.87 (IH, ddd, J=6.
7Hz, 7.9Hz, 9.8Hz) 3.43 (IH, d
d, J=3.1Hz, 9.2Hz), 3.51(IH,
dd, J3.1Hz, 9.2Hz), 4.45 (2H,
s), 4.47 (IH, dq, J9.8Hz 6.1
Hz) 4.76 (LH, s), 4.80 (IH, s),
7.26-7.39 (51(, m) As stated above, the method according to the present invention uses inexpensive O-
Bilane derivatives, which are important intermediates for the synthesis of 1β-methylchenamycins, can be synthesized stereoselectively and using a cyclopentane derivative that can be easily prepared from carvone and has the stereochemistry required for 1β-methylchenamycins. Can be synthesized efficiently.

Claims (1)

[Claims] In the method for producing a pyran derivative represented by formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼, (a) formula (I
I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Methylate the compound represented by (b) The resulting formula (I
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Oxidative cleavage of the compound represented by (c) The obtained formula (I
V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound represented by is converted into an oxime, and (d) the resulting formula (
V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Subjecting the compound represented by Beckmann rearrangement reaction, (e)
A method for producing a pyran derivative, which is characterized by deprotecting the hydroxyl protecting group of a compound represented by the obtained formula (VI) ▲Mathical formula, chemical formula, table, etc.▼ and then oxidizing the hydroxyl group.