JPH03264572A - Fluorine-containing 2-butenolide derivative - Google Patents

Abstract

NEW MATERIAL:A fluorine-containing 2-butenolide derivative shown by formula I (n is 0-2; R<1> and R<2> are H or protecting group). EXAMPLE:A compound wherein n in formula I is 0 and both R<1> and R<2> are t-butyldimethylsilyl. USE:An intermediate for anti-cancer drug and antimicrobial agents. Having optical activity. PREPARATION:A furan shown by formula III is reacted with n-BuLi and a compound shown by formula R<1>Cl in a solvent such as tetrahydrofuran and then reacted with n-BuLi and a compound shown by formula IV to form a compound shown by formula II, which is then reduced with a reducing agent such as NaBH4 in a solvent such as ethanol, then with acetyl chloride and further asymmetrically hydrolyzed with esterase to give compounds shown by formula V and formula VI. The compound shown by formula V is reacted with R<2>Cl, oxidized with an oxidizing agent such as magnesium monoperoxyphthalate and further with D-camphorsulfoniic acid to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel and useful fluorine-containing 2-butenolide derivative.

[Conventional technology]

Although various butenolide derivatives have been known (for example, JP-A-60-142974), fluorine-containing 2-butenolide derivatives (hereinafter referred to as compound (I)) represented by the general formula CI) described below ) is unknown.

[Problem to be solved by the invention]

An object of the present invention is to provide a novel fluorine-containing 2-butenolide derivative represented by the general formula (1) described below, which is useful as a synthetic intermediate.

[Means to solve the problem]

The present invention relates to the following fluorine-containing 2-butenolide derivatives.

(1) A fluorine-containing 2-butenolide derivative represented by the general formula (wherein, n is Oll or 2, R1 and R2 are H atoms or protective groups, and may be the same or different).

(2) n is O, and R1 and R2 are both t
-The fluorine-containing 2-butenolide derivative described in (1) above, which is a butyldimethylsilyl group.

The fluorine-containing 2-butenolide derivative of the present invention is a novel and useful compound represented by the above-mentioned formula CI), and has optical activity. Examples of R1 or R2 in the -format (1) include an alkyl group, a haloalkyl group, an alkenyl group, an aralkyl group, an aryl group, a haloaryl group, and a trialkylsilyl group.

Typical fluorine-containing 2-butenolide derivatives of the present invention include the following.

3 (In the formula, n is Oll or 2.) The fluorine-containing 2-butenolide derivative of the present invention, for example, using furan as a starting material, can be produced according to the following reaction formula (A) &.

3- - (II) [■ a] (IV-a) (III-b) (IV-b) \R1 ■] CI) 5- 508- (Note) a) n-BuLi; R'CQ (e.g. t -butyldimethylsilyl chloride); n-BuLi;
CHnF3-,,C02Et (e.g. CF3Co2Et
) /tetrahydrofuranb) NaBH, /EtO
H c) AcCQ, pyridine/CH2CQ2d) esterase/H20 e) R2CIII (e.g. t-butyldimethylsilyl chloride), imidazole/dimethylformamide f) Magnesium monoperoxyphthalate/cola g) Lithium diisopropylamide; D-camphor D-camphorsulfonic ac
id) /tetrahydrofuran Bu-butyl group Et=ethyl group R1=same as R1 in the above-format [■].

R2 = indicates the same as R2 in -format [I] above.

n = indicates the same as n in -format [I] above.

Ac=acetyl group (CH,C0-) In the reaction formula [A], first, furan is reacted with n-BuLi and R''CQ (R
1 indicates the same as R1 in the above-mentioned type CI). For example, react with t-butyldimethylsilyl chloride etc.),
followed by n-BuLi and CHnF3-y, C02Et
(for example, CF3CO7Et, etc.) to form a compound (
II), and then this compound [■] was dissolved in sodium borohydride (NaBH, ) in a solvent such as ethanol.
Compound [I[r-a] is synthesized by reduction with a reducing agent such as, and then this compound [■-a] is reacted with acetyl chloride in the presence of a base such as pyridine in a solvent such as methylene chloride. This compound (IV-a) (this compound is a racemate) is then asymmetrically hydrolyzed with an esterase to form a compound (m
-b) and [IV-b], and then the above compound (m-
b) (alcohol) in the presence of a base such as imidazole in a solvent such as dimethylformamide
2 indicates the same as R2 in the above-mentioned -format [1]. For example, compound (V) is synthesized by reacting with t-butyldimethylsilyl chloride, etc.), and this compound (V) is then reacted with an oxidizing agent such as magnesium monoperoxyphthalate in a solvent such as chloroform. Compound [■] is synthesized by oxidation, and then this compound [V
I] is stirred in a solvent such as tetrahydrofuran in the presence of lithium diisopropylamide, and further D-camphorsulfonic acid is added and stirring is continued to obtain the target compound [1].

In such a production method, t-butyldimethylsilyl chloride is used as R'CQ, ClnF3-nCO2E
When CF3CO2Et is used as t, lipase P described below is used as esterase, and t-butyldimethylsilyl chloride is used as R2CQ, the above-format [1-a]
An optically active compound represented by is obtained.

The esterase used to asymmetrically hydrolyze compound (IV-a) has the ability to selectively hydrolyze racemic ester bonds, and for example, lipase, riboprotein lipase, etc. can be preferably used. Commercially available esterases can also be used, such as Lipase P (
Manufactured by Ohno Pharmaceutical Co., Ltd., trade name, Pseudomonas origin),
Lipase AP (manufactured by Ohno Pharmaceutical Co., Ltd., trade name, Aspergillus origin), Lipase MY (manufactured by Meito Sangyo Co., Ltd., trade name, Candida origin), Lipase PL (Meito Sangyo C
Co., Ltd., product name, alkaline earth metal origin), Talypase (Tanabe Seiyaku Co., Ltd., product name, Rhizopus origin), Lipase Saiken (Osaka Bacteria Research Disruption, product name, Rhizopus origin), Lipase■ (manufactured by Sigma, trade name, origin of Geotrichum candidum).

When the compound [IV-a] is asymmetrically hydrolyzed and the lipase P is used, a dextrorotatory compound (m-b) and a levorotatory compound (IV-b) are generated. Furthermore, when the lipase MY is used, a levorotatory compound (m-b) and a dextrorotatory compound (IV-b) are produced. From the dextro (left) compound (IV-b) to the corresponding dextro (left) compound (m-
To obtain b), chemical hydrolysis with an alkali or the like is sufficient.

The fluorine-containing 2-butenolide derivative of the present invention is used as an intermediate for anticancer agents and antibacterial agents. At this time, the above-mentioned format [■
When R1 and R2 in ] are protecting groups, these protecting groups are substituted with hydrogen atoms or other functional groups and used in the synthesis reaction.

〔Effect of the invention〕

According to the present invention, a novel fluorine-containing 2 represented by the above-mentioned form (1) is useful as an intermediate for anticancer agents and antibacterial agents.
-butenolide derivatives are obtained.

〔Example〕

Next, examples of the present invention will be described.

Example 1 ■ Synthesis of compound [11] Furan 14 was placed in a 500 mQ Mitsuro flask purged with nitrogen.
．． Add 5 mQ (205 mmol) and 170 mQ of tetrahydrofuran, and at a reaction temperature of -30°C, n-B
uLi (2,5M.

82'mQ, 205 mmol, Bu is a butyl group) was added dropwise, and the mixture was stirred for 1 hour. Then, at this temperature, t-butyldimethylsilyl chloride (30.15 g,
200mmol) of tetrahydrofuran solution (30mQ
) was reacted. The reaction mixture was kept at this temperature for 1 hour, then returned to room temperature and continued stirring for 1 hour, and the whole mixture was stirred at 130°C.
After cooling again to ℃, the same amount of n-BuLi (2,
5M, 82+nD, 205mmol) and 1
Stir for an hour and add 24.4 mQ of ethyl trifluoroacetate.
(205 mmol) in tetrahydrofuran solution (30 m
fl) was added dropwise at -78°C. Stirring was continued for 1 hour and then at room temperature for 1 hour.

Approximately 25+nQ of 3N hydrochloric acid was added to this reaction mixture to form a solution p.
H was adjusted to 6, the solvent was distilled off, condensate (200+nQ) was added, extracted with ethyl acetate (300mQx 3), and the organic solvent layer was further washed with saturated aqueous NaHCO3 (100mD). After drying with anhydrous MgSO4, the solvent was distilled off to obtain a ketone (compound [■]).

Compound [11] was purified without purification at this stage.
This was used in the next reduction reaction. The analysis results of compound (II) are as follows.

Ketone (compound [■]) Large amount 278.345 Boiling point 89-93℃ (4mmHg) 1HNMR (CDCQ3) δ0,32 (6H,S)
, δ0.96 (98,s).

δ6.85 (IH, d, J=3.7Hz).

δ7.51 (IH, dq, J=3.7Hz, 1.2
Hz)13CNMR(CDCQ,)δ-6,54(s)
, δ16.87(s).

10- 11- 626.28(s).

δ 116.86 (q, J = 290.5Hz).

6123.38(s).

δ 124.09 (q, J = 2.7Hz).

δ 147.10 (s), δ 151.07 (s)
.

6171.23 (S) ”F NMR (CDCf13) δ 4.0 (s) I
R(neat) 2950.2900.2850
cm-”(CH3).

1700cm-' (C-0) ■ Synthesis of compound (m-a) Compound [■] obtained in the above ■ and ethanol (200+J)
Cool a 500 mfl eggplant-shaped flask containing 2.27 g (60 mm
ol) was added and stirred at room temperature overnight. 3N after distilling off the solvent
The reaction was stopped by adding an aqueous hydrochloric acid solution.

The mixture was extracted three times with methylene chloride (200 mQ), washed with saturated brine (roomQ), and anhydrous MgSO4
After drying with
(156 mmol) was obtained (yield 78%: total yield of two steps of ketone synthesis and its reduction). This compound (II
The analysis results for I-a) are as follows.

Alcohol (compound Cm-8)) Large quantity 280.362 Boiling point 75-77°C (0,8 mmHg) 18 NMR
(CDCQ,) δ0.32 (6H, s), 60.9
1 (9H, s).

δ2.96 (LH, d, J=4.7Hz).

δ5.06 (IH, m).

δ6.49 (LH, d, J=3.3Hz).

δ6.63 (IH, d, J=3.3Hz)”CNMR
(CDC et al.) δ-6,72 (s), δ-6,70 (s)
.

δ16.58 (s), δ-6,54 (s).

δ67.39 (q, J=34.1Hz).

6109.76(s), 6121.71(s).

δ123,65 (q, J=282.9Hz).

δ151.40,161.02(s) ”F NMR(CD(43)60.1(d, J=6.
4Hz) IR (neat) 3375cm-'(O
H), 2950.2925°2875, 2850cm
-1(CH,) ■Synthesis of compound (IV-a) 43.62g (155m
mol) of compound (III-a) obtained in the above ①, 160 mQ of methylene chloride and 13.27 mQ of acetyl chloride (
186 mmol), cooled to 0°C, and added pyridine 15
．． After adding 10 mQ (186 mmol) dropwise and stirring at room temperature overnight, water (200 mQ) was added to terminate the reaction.

After separating this organic solvent layer, the aqueous layer was further separated using methylene chloride (
Extract with 200n+UX 2), saturated NaHCO, water (
After washing with 100 mQ), drying with anhydrous MgSO4, and distilling off the solvent, the acetate (compound [IV
-a]) was purified. The yield at this time was 46.97g (1
46 mmol) (yield 94%). Compound (T
The analysis results of V-a) are as follows.

Acetate (Compound 1: IV-a)) Large quantity 322.399 Boiling point 75-78°C (0.7mmHg)” HNMR
CDCf3) δ0.23 (6H, s), δ0.91
(9H, s).

δ2.17 (3H, S).

δ6.34 (IH, q, J=6.7l-1z).

66.55 (LH, d, J=1.6Hz).

δ 6.62 (IH, d, J=1.6Hz)”CNM
R (CDCf13) δ-6,73(s), δ
16.54 (s).

620.26 (s), δ 26.01 (s).

δ 65.74 (q, J = 35.1Hz).

δ 111.50 (s), δ 121.53 (s)
.

6122.61 (q, J=281.4Hz).

6148.55 (s), δ 161.64 (s
).

δ 168.91 (s) 1gF NMR (CDCQ3) δ 3.0 (d,
J=6.4Hz)IR(neat) 2950.
2925.2900°2850c+n71 (CH3),
1770 cm-1 (C=0) ■Asymmetric hydrolysis of compound (IV-a) Lipase P (Jinko Pharmaceutical Co., Ltd.) was placed in a 100 mR eggplant-shaped flask.
Co., Ltd., product name, Pseudomonas origin) 1.45g (
44,000 Units), 76 mQ of distilled water, and 2.45 g (7.6 mmol) of the compound (IV-a) obtained in the above (①) were added, and the mixture was kept at 40°C in a constant temperature bath and stirred for 22 hours.

Polymer flocculant (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., P713)
, trade name) and stirred for 5 minutes, insoluble matter was removed by filtration through Celite, extracted with ethyl acetate (100 mQ X3), and further washed with saturated brine (100 mfl). After drying with anhydrous MgSO4, the solvent was distilled off, and the product was subjected to silica gel column chromatography using a solvent of hexane:ethyl acetate = 10:1 (volume ratio), and the optically active alcohol (compound (m-b ))0.88g(3,
1 mmol) and acetate (compound [IV-b))1.
10 g (3.4 mmol) was separated and purified (yield: 8
8%). The analysis results of these compounds are as follows.

Note that C indicates concentration and ee indicates optical purity.

Alcohol (compound (m-b)) [α] is also '+14.98 (c 1.51. C) 1.
OH) 99.6%ee acetate (compound (IV-b
)) (α)5”-65,43(c 1.47. CH,0f
() 84.5% ee ■Synthesis of compound (V) 6.80 g (17.2 mmol) of the compound Cm-b obtained in the above (■) was placed in a nitrogen-substituted 100n+Q Mitsuro flask.
and dimethylformamide (15+11 fl), and 3.12 g of t-butyldimethylsilyl chloride (
20.7 mmol) in dimethylformamide solution (5 m
M) was added dropwise. Cool this to 0℃ and imidazole 1
．． A solution of 41 g (20.7 mmol) in dimethylformamide (15 mfl) was added dropwise. Next, this was stirred at room temperature overnight, water (50 mQ) was added to stop the reaction, and after extraction with hexane (100 mQX 3 ), saturated NaHC
Washed with O3 water (50+J).

After drying with anhydrous MgSO4, hexane:ethyl acetate=10
silica gel column chromatography using a solvent of 1:1 (volume ratio), and further purified by vacuum distillation,
Silyl ether (compound (V)) 6.80g (17,
2 mmol) was obtained (yield 100%). This compound [■
] The analysis results are as follows.

Silyl ether (compound [■]) Large quantity 394.625 Boiling point 93-95°C (0.8 mmHg)'HNMR (
CDCR,) δ-0,03(6H,s), δ0.0
8(6)1. s).

60.20 (181(,s).

δ5.02 (IH, dq, J=0.5.6.3Hz)
.

δ6.43 (IH, d, J=3.3Hz).

δ6.59 (IH, d, J=3.3Hz) 13CNM
R(CDCQ,) δ-6,71(s), δ-6,62(
s).

δ-5,72(s), δ-5,52(s).

δ 16.5], (s), 617.93 (s).

δ 25.27 (s), δ 26.07 (s).

δ 68.21 (q, J = 34.1Hz).

δ 109.3], (s), 8121.68(
s).

δ 123.72 (q, J = 283.1Hz).

δ 153.10. ], 59.93(s)! gF
NMR (CD(43) δ −0,1(d, J=6
．． 21+z)IR(neat) 2975.2
925.2900゜2850cm-'' (C13) ■ Synthesis of compound [Wl and (T - a) In a 50 mQ eggplant-shaped flask, put 1.18 g of the compound [V] obtained in the above (■).
3.0 mmol) and 12 mQ of chloroform were added, and 1.47 g of magnesium monoperoxyphthalate (4
, 5 mmol) was added. After refluxing for 30 hours, the mixture was filtered to remove insoluble materials, and washed with saturated Na11CO3 water (20 mfl).

This aqueous layer was further extracted with ethyl acetate (15mQX 2 ), dried over gso4, and the solvent was distilled off. The obtained crude product was passed through a column using a small amount of silica gel, and the solvent (methylene chloride) was distilled off to obtain a 3-butenolide derivative (compound [■]). Since this compound is thermally and chromatographically unstable, it was used in the next reaction without further purification.

Add 0.63 mQ (4.5 mmol) of diisopropylamine and 3 mQ of tetrahydrofuran to a 20 mQ nitro flask purged with nitrogen, and add n-BuLi (2
,5M, 12mQ, 3mmo1. ) was added dropwise and stirred for 10 minutes. Next, the above 3-butenolide derivative (compound [
) was added dropwise and stirred at the same temperature for 20 minutes.
A tetrahydrofuran solution (2 mQ) of 1) was added, and the mixture was stirred for 1 hour. After terminating the reaction by adding water (10 mQ), extraction was performed with ethyl acetate (10 mQX 3 ), and this was washed with saturated brine (1,0 +++ Il).

After drying with anhydrous MgSO4, the solvent was distilled off, and the fluorine-containing 2
-0.59 g of butenolide derivative (compound (I-8))
(1.4 mmol, yield 48%, abundance ratio of diastereomers 8:2) and 0.24 g (0.6 mmol) of silyl ether (compound [■]), which is the raw material for peracid oxidation.
, yield 20%). The analysis results of these compounds are as follows.

Large amount of 3-butenolide derivative (compound [■]) 410.
624”F NMR (CI+212) δ0.4(d, J=6
．． 0Hz).

60.7 (d, J=6.414z) (diastereomer) Fluorine-containing 2-butenolide derivative (compound (I-8))
Large quantity 410.624 Boiling point 100-105℃ (0.7mmHg) IR (ne
at) 2975.2950.2900°2875
cm-'(CH3), 1.775cm-'(C=0)
.

1600 cm-' (C=0) diastereomer (a); 1HNMR (COCO2) δ0.04-0.21 (
12H, m).

δ0.80 (9H, s).

60.90 (98,s).

δ4.38 (LH2dq, J=2-5,7.2H2)1
δ5.12 (IH, dd, J=1.6.2.5Hz)
.

δ7.48-7.50 (LH, m) "CNMR (CDC(13) δ -6,70~-5,
13 (note).

616.35 (s), δ 1.7.77 (s).

825.12-26.53 (note).

671.15 (q, J=31.1Hz).

δ 80.92 (s).

δ 125.41 (q, J = 284.6Hz).

δ 136.21 (s), δ 160.65 (
s).

δ 175.0 (s) 19F NMR (CDI, Q,) 62.8 (d,
J=7.2Hz) Diastereomer (b); 'HNMR (COCO2) δ0.04-0.21
(12H, m).

60.88 (9H, s).

δ0.89 (914, s).

δ4.08(LH, dq, J=5.0.6.5Flz
).

δ4.99 (IH, dd, J=1.6.5.0Hz)
.

δ7.48~7.50 (LH, m) 13CNMR (COCO2) δ-6,70~-5,1
3 (note).

δ 16.40 (s), δ 17.85 (s).

625.12-26.53 (note).

671.91 (q, J=31.2Hz).

δ81.82 (s).

δ 126.87 (q, J = 297.3Hz).

6135.69(S), 6160.21(s).

6174.80 (s) 19F NMR (CDCR,) δ 3.6 (d,
J=6.0Hz) (Note) Due to 13CNMH of the mixture of diastereomers (a) and (b), (a), (b)
Not sure which peak.

The fluorine-containing 2-butenolide derivative thus obtained is used as an intermediate for anticancer agents and antibacterial agents.

Claims (2)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] (In the formula, n is 0, 1 or 2, and R^1 and R^2 are H atoms or protective groups. may be the same or different.) A fluorine-containing 2-butenolide derivative represented by: (2) The fluorine-containing 2-butenolide derivative according to claim 1, wherein n is 0 and R^1 and R^2 are both t-butyldimethylsilyl groups.