JPH07242595A - Production of alpha-fluorocycloalkenones - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject compound useful as a synthetic intermediate for fluorine-containing organic compounds by adding molecular fluorine diluted with an inert gas to a 2-cycloalkene-1-ol. CONSTITUTION:1-10V/V% of molecular fluorine diluted with an inert gas such as nitrogen is added to a compound of formula I [(n) is 1 or 2] to provide the objective compound of formula II. The compound of formula II is oxidized with an oxidizing agent (e.g. chromium trioxide) and further, reacted with a base (e.g. triethylamine) to give the objective 2-fluoro-2-cycloalkene-1-one of formula III. Molecular fluorine diluted with an inert gas is added to the compound of formula IV [R and R' each is H or a 1-6C alkyl; (n) is 1 or 2] and the resultant addition product is treated with a base to afford the objective 2-fluoro-2-cycloalkene-1-one of formula V. Further, molecular fluorine is added to cis-2-cyclopentene-1,4-diol and the resultant meso type difluorodiol is asymmetrically treated, oxidized and treated with a base to provide the obiective optically active 4-acetoxy-2-fluoro-2-cyclopentene-1-one.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing .alpha.-fluorocycloalkenones utilizing the addition reaction of molecular fluorine.

[0002]

2. Description of the Related Art In recent years, researches on fluorinated medicines and agrochemicals utilizing the characteristics of fluorine atoms have been actively conducted, and many new physiologically active substances have been reported. In addition, a means for injecting a drug into which ¹⁸ F, which is a radioisotope, is introduced into a living body to analyze the kinetics and action mechanism of the drug has become important. Furthermore, the usefulness of fluorine-containing compounds has been attracting attention in the field of functional materials such as liquid crystals. Therefore, developing an efficient method for synthesizing a fluorine-containing organic compound has become one of the important issues in modern organic synthesis.

Methods for synthesizing fluorine-containing organic compounds are roughly classified into two. The first is a method of direct fluorination using an appropriate fluorinating agent at any stage of the synthetic route. The second is a method of constructing a more complicated fluorine-containing compound by using a synthetic block containing fluorine as a starting material. This method is useful for efficiently synthesizing a physiologically active substance having fluorine introduced at a specific site.

[0004]

In the above first method, it is difficult to introduce a specific number of fluorine into carbon at a specific site of an organic compound. Further, the fluorine-containing synthetic block used in the second method is unexpectedly small, and development of a highly applicable synthetic block is desired.

On the other hand, cyclopentenones and cyclohexenones have a wide range of functions such as Michael receptors and parent diene bodies, and are widely used as synthetic intermediates for physiologically active compounds. Therefore, α, β-unsaturated-α-fluorocycloalkanones (hereinafter referred to as α-fluorocycloalkenones) are expected to be extremely useful as fluorine-containing building blocks having the same function.

[0006]

From the above viewpoints, the present inventors have studied the synthesis of α-fluorocycloalkenones, which uses the addition of molecular fluorine as a key reaction. Fluorinating agents include molecular fluorine, electrophilic fluorinating agents, and nucleophilic fluorinating agents. Although molecular fluorine is an electrophilic fluorinating agent, it is extremely highly reactive and not only performs addition to alkene but also substitution reaction of hydrogen atom bonded to carbon. The reason why molecular fluorine is selected as the fluorinating agent is that molecular fluorine diluted with nitrogen gas can be obtained inexpensively, and secondly, there are surprisingly few reaction examples in which molecular fluorine is directly added to alkenes and alkenones. This is because the reactivity has not been fully elucidated.

As a result, the present inventors have found that α-fluorocycloalkenones are synthesized by the method shown below.

[Synthesis 1] 2-cycloalkene-1-o
2-fluoro-2-siku using fluorination reaction of alcohol
Synthesis of loalkene-1-ones Molecular fluorine is added to 2-cycloalkene-1-ols, and the adduct is subjected to base treatment after oxidation to synthesize 2-fluoro-2-cycloalkene-1-one. succeeded in.

[0009]

[Chemical 18] [Synthesis 2] Fluorine of 2-cycloalkene-1-ones
2-Fluoro-2-cycloalkene-1
- Synthesis of-ones 2-cycloalkene-1-ones by adding molecular fluorine, the adduct with base treatment, and succeeded in the synthesis of 2-fluoro-2-cycloalkene-1-one body. On this occasion,
The effect of substituents on the efficiency of molecular fluorine addition was found. Moreover, the stereochemistry (cis selectivity) of fluorine addition was also confirmed.

[0010]

[Chemical 19] [Synthesis 3] optically active 4-acetoxy-2-fluoro
Synthesis of 2-cyclopenten-1-one Molecular fluorine was added to cis-2-cyclopentene-1,4-diol to obtain a meso-type difluorodiol body as a main product. Synthesis of optically pure (R) -4-acetoxy-2-fluoro-2-cyclopenten-1-one by subjecting the diol to asymmetry by lipase-catalyzed monoacetylation, followed by oxidation reaction and base treatment. succeeded in. This compound is expected to be useful as an enantiomerically controlled synthetic intermediate for a fluorine-containing physiologically active compound.

[0011]

[Chemical 20] [Synthesis 4] 2-Fluoro-2-cycloalkene-1-
Diels-Alder reaction of ones and light [2+
2] Cycloaddition reaction 2-fluoro-2 synthesized in [Synthesis 1] to [Synthesis 3]
In order to demonstrate the usefulness of -cycloalkene-1-ones as a building block, its Diels-Alder reaction was examined, and the following results were obtained. Ie Danish
Through the [4 + 2] adduct obtained by the reaction with efsky diene, we succeeded in highly stereoselectively synthesizing a bicyclic compound having fluorine introduced at the ring junction. further,
It was also demonstrated that the α-fluorocycloalkenone body functions as an enone component even in the photo [2 + 2] addition reaction.

[0012]

[Chemical 21] The present invention has been completed based on such knowledge, and the first aspect thereof is as follows.

[Chemical formula 22] (Wherein n represents 1 or 2) 2-cycloalkene-1-ol represented by the following formula, wherein molecular fluorine diluted with an inert gas is added:

[Chemical formula 23] (In the formula, n represents the same meaning as described above).

The second aspect of the present invention is

[Chemical formula 24] (In the formula, n represents 1 or 2) 2-cycloalkene-1-ol is added with molecular fluorine diluted with an inert gas to obtain the following formula.

[Chemical 25] (Wherein n represents the same meaning as described above), a compound represented by the following formula, characterized in that the compound is oxidized with an oxidizing agent and further reacted with a base.

[Chemical formula 26] (In the formula, n represents the same meaning as described above) and is a method for producing 2-fluoro-2-cycloalkene-1-one.

A third aspect of the present invention is as follows:

[Chemical 27] (In the formula, R and R ′ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)
The following formula characterized by adding molecular fluorine diluted with an inert gas to 2-cycloalkene-1-one represented by

[Chemical 28] (In the formula, R, R ′ and n have the same meanings as described above).

A fourth aspect of the present invention is as follows:

[Chemical 29] (In the formula, R and R ′ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)
By adding molecular fluorine diluted with an inert gas to 2-cycloalkene-1-one represented by

[Chemical 30] (Wherein R, R ′, and n have the same meanings as described above), and the compound of the following formula characterized by reacting this compound with a base:

[Chemical 31] (In the formula, R, R ′, and n have the same meanings as described above.) The method for producing 2-fluoro-2-cycloalkene-1-one.

A fifth aspect of the present invention is the following formula:

[Chemical 32] The following formula characterized by adding molecular fluorine diluted with an inert gas to cis-2-cyclopentene-1,4-diol represented by

[Chemical 33] Is a method for producing the compound represented by.

The sixth aspect of the present invention is as follows.

[Chemical 34] By adding molecular fluorine diluted with an inert gas to cis-2-cyclopentene-1,4-diol represented by

[Chemical 35] A compound represented by the following formula is prepared by using this compound with lipase as a catalyst.

[Chemical 36] (Wherein Ac represents an acyl group) is reacted with a compound represented by the following formula

[Chemical 37] (Wherein Ac represents the same meaning as described above), and then the compound is oxidized with an oxidizing agent and then reacted with a base.

[Chemical 38] (Wherein Ac represents the same meaning as described above) 4-
Acyloxy-2-fluoro-2-cyclopentene-1
-On manufacturing method.

Molecular fluorine diluted with an inert gas is used as the fluorinating agent in the present invention. Examples of the inert gas for dilution include gases such as nitrogen, helium, neon and argon, and nitrogen is particularly preferable. The concentration of molecular fluorination is not particularly limited as long as fluorine can be used, but a preferable range is 1-10 v / v%, particularly preferably 5 v.
/ V%.

The oxidizing agent used in the present invention may be any of those known per se such as permanganic acid and its salts, chromium oxide, chromic acid and its related compounds, nitric acid and its related compounds, peroxides, oxyacids and their salts. Can be selected. Among them, chromium oxide is preferable, and one example thereof is chromium trioxide.

The base used in the present invention includes
It can be arbitrarily selected from conventionally known compounds. Amines are preferable bases, of which tertiary amines are preferable, and trialkylamines such as trimethylamine and triethylamine are particularly suitable.

The substituent R at the 2-position and the substituent R'at the 3-position of the starting 2-cycloalkene-1-ones in the third and fourth aspects of the present invention may be the same or different. It may be a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. As the alkyl group having 1 to 6 carbon atoms, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-
Examples include a pentyl group and n-hexyl group.

In the sixth aspect of the present invention, the acyl group of the compound having an acyl group used in the reaction of the second step has an alkylcarbonyl group having 1 to 6 carbon atoms (for example,
Acetyl group), arylcarbonyl group (for example, benzoyl group), heterocyclic carbonyl group (for example, 2-, 3- and 4-pyridylcarbonyl group), alkenylcarbonyl group having 2 to 6 carbon atoms (for example, allylcarbonyl group) ) And the like.

The progress and results of each reaction will be described in detail below.

[Synthesis 1] 2-cycloalkene-1-o
2-fluoro-2-siku using fluorination reaction of alcohol
Synthetic molecular fluorine of loalkene-1-ones is a reagent that is difficult to use because of its strong oxidizing power and explosive reaction with organic compounds. However, recently, a method of using fluorine gas diluted with an inert gas such as nitrogen has been developed, and direct fluorination with fluorine gas has become easy. Rozen et al. Have successfully added molecular fluorine to olefins by this method. This addition is generally cis-selective, and very recently Kaneko et al.
The mechanism of addition was elucidated based on initio calculation.

As described above, the fluorocycloalkenone compound is considered to be extremely useful as a fluorine-containing building block. However, although 3-fluorocyclopentenone is known (see Japanese Patent Application Laid-Open No. 62-242640), there is no synthetic example of 2-fluorocyclopentenone. In addition, 2-fluorocyclohexenone is Sent
Although synthesized by On et al., the operation is complicated and the yield is low.

The present inventors fluorinated 2-cycloalkene-1-ols with diluted molecular fluorine,
It was considered that the 2-fluorocycloalkenone compound could be synthesized by the subsequent oxidation reaction and base treatment. 2-cycloalkene-
As 1-ol, racemic 2-cyclopenten-1-ol (I- is considered in consideration of easy availability and wide range of usage.
1a) and 2-cyclohexenon-1-ol (I-
I chose 1b).

According to the literature (Jean-Louis Lu
che, J. Am. Chem. Soc. , 100 , 22
26 (1978) and Jean-Louis Luc.
he, Lydia Rodriguez-Hahn and Pierre Crabbe, J .; Chem. So
c. Chem. Commun. , 1978, 60
1), I- synthesized from 2-cyclopenten-1-one
1a to fluorotrichloromethane - chloroform - ethanol (5: 4: 1, v / v) in 5% 2 equivalents F ₂ /
N ₂ gas was passed at −78 ° C. The fluorine gas in the system was sufficiently purged with nitrogen gas, and the reaction solution was washed with a saturated sodium hydrogen carbonate aqueous solution in order to neutralize by-produced hydrogen fluoride. The solvent was distilled off, and an extremely complicated reaction mixture presumed to contain the difluoro compound (I-2a) was obtained [ ¹ H-NM
R spectrum, gas chromatography (GLC) and thin layer chromatography (TLC)]. This was stirred without refining with chromium (VI) oxide in acetic acid under ice cooling to obtain a mixture presumed to contain the ketone body (I-3a). This was stirred with triethylamine in ether at room temperature, the product was purified by preparative thin layer chromatography (PTLC), and the total yield of 2-fluoro-2-cyclopenten-1-one (I-4a) was 13%. (Chart I-1).

[0028]

[Chemical Formula 39] In the same manner, I-1b was fluorinated, and this was oxidized and then treated with a base to obtain 2-fluoro-2-cyclohexen-1-one (I-4b) in a total yield of 5%. I-1b was obtained in a yield of 13% (Chart I-2).

[0029]

[Chemical 40] Fluorine adducts of I-1a and I-1b (I-2a, I-2b)
Was not attempted because the reaction mixture was extremely complex. This complexity is due to the presence of stereoisomers in I-2 and the by-product of the product (I-7, I-8) involving the ethoxyl group derived from ethanol used as a solvent (actually, ¹ A strong ethoxyl group signal was observed in the 1 H-NMR spectrum). Note that I
The production mechanism of -7 and I-8 is based on the proposed reaction mechanism, and the height ion pair intermediate (I-5, I-
It is presumed that 6) is generated, and then an ethoxyl group is added without adding a fluorine anion (Chart).
I-3).

[0030]

[Chemical 41] The low yield of I-4 was due to the low yield in the difluorination of I-1 and the oxidation of I-2, as well as the high volatility of I-4 that could not be captured quantitatively. it is conceivable that.

[Synthesis 2] 2-cycloalkene-1-o
2-fluoro-2-cyclo using fluorination reaction of amines
The addition of synthetic molecular fluorine of alken-1- ones to alkenes is an electrophilic reaction,
It is considered that direct fluorination of the conjugated enone system, which is an electron-deficient olefin system, is difficult to proceed. However, an adduct of molecular fluorine to a conjugated enone has been obtained in the steroid system. That is, Merritt et al. From cholestenone (A) to 4,5-difluoro body (B)
Was obtained in a yield of 60-70% (RF.
Merritt and T.W. E. Stevens, J.M. A
m. Chem. Soc. , 88 , 1822 (196
6)). Kaneko et al. Recently re-tested the fluorination of A and added B (1
7%) and a rearrangement (C, 7%; D, 13%) were also produced (A. Toyota, J. Ch.
iba, Y. Sugita, M .; Sats and C.I. Ka
neko, Chem. Pharm. Bull. , 42 ,
459 (1994)). Barto et al.
From the n-16-en-20-one derivative (E), 40% of the difluoro compound (F) together with the rearranged compound (G, 12%).
It was reported that the yield was obtained (DH Barton,
J. L. James, R.M. H. Hesse, M .; M. P
echet and S.M. Rozen, J .; Chem. So
c. , Perkin Trans. 1,1982,11
05).

[0032]

[Chemical 42] It is also known that molecular fluorine is added to the alkene part of the 1,3-dioxin-4-one compound (H) (M. Sato, C. Kaneko, T. Iwaok).
a, Y. Kobayashi and T.K. Iida, J .; Ch
em. Soc. Chem. Commun. , 199
1,699 and T.W. Iwaoka, T .; Muroha
shi, M .; Sato. And C.I. Kaneko, Tet
rahedron: Asymmetry, 3 , 1025
(1992)).

[0033]

[Chemical 43] The above findings suggest that even in an enone system, when an electron-donating group (alkyl group or hetero atom) is introduced at the α-position or β-position, molecular fluorine is easily added.

On the other hand, as described above, cyclopentenone and cyclohexenones are useful as highly functional building blocks. The present inventors examined the fluorination of these cycloalkenones and the subsequent synthesis of a 2-fluorocycloalkenone compound by a base treatment.

[Synthesis 2-1] 2-cyclopentene-1
2-Fluoro-2-si using a fluorination reaction of one-ones
Synthesis of Clopenten-1-ones 2 -Cyclopenten-1 -one (II-1a) and its 2-, 3-, or 4-position substitution products (II-1b to II-1f)
Was selected and the addition reaction of molecular fluorine was examined for these.

According to the fluorination method of [Synthesis 1], II-1a
(2.5 mmol) was fluorinated using 3 equivalents of fluorine ( ¹ H-NMR spectrum analysis confirmed that about half of II-1a was consumed). Difluoro form (II
-2a) was presumed to be treated with triethylamine at room temperature without purification to give I-4a in a total yield of 24%. At this time, 13% of II-1a was recovered. In addition, II-1a (20 mmol) was fluorinated with 5 equivalents of fluorine, and the reaction mixture was treated with triethylamine and purified to obtain I-4a in a total yield of 16% (C
hart II-1).

[0037]

[Chemical 44] The yield of I-4a by this method was higher than the yield of the method of [Synthesis 1] (total yield 13%). It is considered that this improvement in yield was not due to the process of fluorination, but rather due to the improvement in the subsequent steps. In other words, this method does not require an oxidation process and uses a low boiling point solvent (dichloromethane, pentane) in the purification step.
The highly volatile final product could be isolated efficiently.

Next, fluorination of the 2- or 3-position-substituted 2-cyclopentenone compound was examined. These fluorinations were performed by changing the solvent to fluorotrichloromethane-chloroform (5: 4, v / v) to avoid reaction complexity due to the involvement of ethanol in the solvent.

2-methyl-2-cyclopentenone (II-
1d) was fluorinated with 3 equivalents of fluorine, and the reaction mixture was analyzed by ¹ H-NMR spectrum. As a result, the raw material disappeared almost completely. The mixture was purified by PTLC and the cis adduct (cis-II-2d) was isolated in 20% yield (Chart II-4).

[0040]

[Chemical formula 45] The stereochemistry of cis-II-2d is the coupling constant between the 3-position proton and the 2-position fluorine in the ¹ H-NMR spectrum,
Nuclear Overhause with 3-position proton and 2-position methyl group
It was estimated from the results of the r-effect (nOe) experiment (Chart).
II-5). In general, addition of fluorine to an alkene is cis-selective, and the fact that the 2-methyl-2-cyclohexenone fluorine adduct described below can be determined to be a cis-form, it is presumed that II-2d is also a cis-form. Is reasonable.

[0041]

[Chemical formula 46] When 3-acetoxy-2-cyclopentenone (II-1e) was fluorinated, no raw material recovery was observed. In this reaction, 2-fluoro-3-acetoxy-2-cyclopentenone (II-3e) was obtained as the main product in a yield of 1
Obtained at 5%. In addition, the dialuro form (II-2e) was not isolated (Chart II-6).

[0042]

[Chemical 47] When 3-methyl-2-cyclopentenone (II-1f) was fluorinated, the yield of highly polar 2-fluoro-3-methyl-2-cyclopentenone (II-3f) was 13%.
Thus, less polar 2-fluoro-3-fluoromethyl-2-cyclopentenone (II-7) was obtained in a yield of 5%.
In addition, according to the 500 MHz ¹ H-NMR spectrum, II
The ratio of -3f to II-7 was 2.2: 1. No raw material recovery was observed in this reaction either. In addition, the difluoro form (II
-2f) was also not isolated (Chart II-7).

[0043]

[Chemical 48] The above results are summarized in Table 1.

[0044]

[Table 1] The 2- or 3-position substitution products (II-1d to 1f) were more easily fluorinated than the non-substitution products (II-1a) ( ¹ H-NM
The raw material was almost consumed by R spectrum analysis). However, the yield of the performance product was lower in II-1d to 1f. It is considered that one of the reasons for this low yield is that the reaction product could not be quantitatively isolated due to the complicated reaction.

The non-substituted compound and the 2-methyl compound produced a difluoro compound, while the 3-substituted compound did not isolate the difluoro compound, but a 2-fluorocyclopentenone compound was obtained all at once. This difference can be explained as follows. That is, in the former, the height ion pair intermediate (II
-8) to give the difluoro form. On the other hand, in the latter case, the cation of the intermediate (II-9) is stabilized, and at the same time, it is presumed that elimination of the 2nd-position proton takes precedence over F ⁻ attack due to steric hindrance (Chart II-8).

[0046]

[Chemical 49] [Synthesis 2-2] 2-cyclohexen-1-ones
2-Fluoro-2-cyclohexene using fluorination reaction
Synthesis of -1-ones 2-Cyclohexen-1-one (II-8a) and its 2- or 3-position methyl compound (II-8b, II-8c) were selected, and addition reaction of molecular fluorine was examined for them. .

According to the fluorination method of [Synthesis 1], II-8a
(2 mmol) was fluorinated with 3 equivalents of fluorine ( ¹ H-NMR spectrum analysis confirmed that a small amount of II-8a was consumed). The reaction mixture presumed to contain the difluoro compound (II-9a) was treated with triethylamine at room temperature without purification, and the total yield of I-4b was 12
Earned in%. At this time, 5% of II-8a was recovered. II-8
When a (10 mmol) was fluorinated with 4 equivalents of fluorine, about half the amount of raw material was recovered ( ¹ H-N
Analyzed by MR spectrum). This reaction mixture was similarly treated with a base and then purified to obtain I-4b in a total yield of 17%.
At the same time, 18% of II-8a was recovered (Chart II-
9).

[0048]

[Chemical 50] The yield of I-4b by this method was improved compared with the yield (5%) by the method of [Synthesis 1]. I in [Synthesis 2-1]
It is believed that the yield was improved for the same reason as described for -4b.

Next, fluorination of the 2-position or 3-position methyl compound was examined. Fluorination was performed in a fluorotrichloromethane-chloroform (5: 4, v / v) solvent, similarly to the 2- or 3-position-substituted cyclopentenone compound of [Synthesis 2-1].

According to the literature (“Organic Synt
hesis ", Coll. Vol. 4, John Wi.
ley and Sons, Inc. , New Yor
k, 1963, p. 162), the 2-position methyl compound (II-8b) synthesized from 2-methylcyclohexan-1-one was fluorinated with 3 equivalents of fluorine to give a cis adduct (ci).
s-II-9b) was isolated with a yield of 14%. In this reaction, II-8b was almost consumed (Chart II-1
0).

[0051]

[Chemical 51] The stereochemistry of II-8b was determined by the following ¹ H-NMR spectral data. Between the 3-position proton and the 2-position, 3-position fluorine and 4-position proton, the binding constant shown in Chart II-11 (J = 17.0, 48.0, 8.5, 3.
0 Hz) is observed. The coupling constant (8.5 Hz) between the 3-position proton and the 4-position axial proton indicates that the 3-position proton has an axial configuration. Further, in general, in the cyclohexane system (II-10), Chart II-12 is used.
II-9b was assigned as a cis-difluoro body because it showed a binding constant as shown in. The predicted conformation and binding constant of the transdifluoro body (II-9b ') are as shown in the figure. In this case, the coupling constant between the 3-position proton and the 4-position proton is about 5 Hz, and the coupling constant between the 3-position proton and the 2-position fluorine is expected to be about 11.5 Hz, which do not match the measured values. The coupling constant (17.0 Hz) between the 3-position proton and 2-position fluorine of II-9b is a general constant (3
4 Hz). It is presumed that this is because the cyclohexane ring cannot adopt a perfect chair conformation due to steric hindrance between the 2-position methyl group and the carbonyl group.

[0052]

[Chemical 52]

[Chemical 53] Finally, the 3-position methyl compound (II-8c) was fluorinated with 3 equivalents of fluorine, and the mixture was roughly separated by PTLC,
A crude difluoro body (II-9c) was obtained. P this again
After purification by TLC, hydrogen fluoride was removed (II
-11) was obtained as the main grade. At this time, II-9c
Almost disappeared (the ratio of II-9c to II-11 was about 1: 4 by 60 MHz ¹ H-NMR spectrum data analysis). Further, II-8c was fluorinated under the same conditions and treated with triethylamine at room temperature without isolating the product, and II-11 was obtained in a total yield of 13% (Chart II-13).

[0053]

[Chemical 54] II-9c was determined to be a cis form by ¹ H-NMR spectrum data analysis (coupling constants between the 2-position proton and the 2-position and 3-position fluorine were 47.0 and 30.0 Hz, respectively). Also, the easy elimination of hydrogen fluoride supports this three-dimensional structure (Chart II-14).

[0054]

[Chemical 55] The results regarding the fluorination of cyclohexenones are summarized in Table 2 above.

[0055]

[Table 2] As in the case of the cyclopentenone compound in [Synthesis 2-1], 2
The 3- or 3-position substitution products (II-8b, II-8c) were more easily fluorinated than the non-substitution products (II-8a). In addition, the cyclohexenone form is considered to have lower volatility than the cyclopentenone form, but the isolation yield of the product is about the same,
The result was lower. This result indicates that the cyclohexenone form is less fluorinated than the cyclopentenone form.

[Synthesis 3] Optically active 4-acetoxy-
Many synthetic physiologically active substances of 2-fluoro-2-cyclopenten-1-one have chirality. One of the methods of introducing fluorine into the specific position is a method of constructing a target molecule stepwise from a fluorine-containing chiral block. However, the number of usable fluorine-containing chiral blocks is unexpectedly small, and it is desired to create a versatile chiral block.

The chiral cyclopentenone form is useful as a versatile chiral block. In particular, 4-hydroxy-
2-Cyclopenten-1-one (A) is useful as a synthetic intermediate for prostanoids and cyclopentenoids.
The 3-position fluoro body (B-2) is the 3-position chloro body (B-
1)) (JP-A-62-242640). However, there is no synthetic example of the 2-fluoro compound (C) (Chart III-1).

[0058]

[Chemical 56] Therefore, the present inventors have made available 2-cyclopentene-
The synthesis of optically active 4-acetoxy-2-fluoro-2-cyclopenten-1-one (III-5) from 1,4-diol (III-1) was planned (Chart III-
2).

[0059]

[Chemical 57] In order to efficiently synthesize III-2a, the present inventors
-1a was investigated for fluorination.

First, III-1a was added to acetonitrile
Fluorinated at 35 ° C. with 1 equivalent of fluorine. Although the reaction was complicated, the fluoro compound (III-8, III-9, III
-10) and the ketone body (III-11) yield 4 respectively.
%, 9%, 3%, 18%. Also, IV-1a is 5%
Recovered (Chart III-4).

[0061]

[Chemical 58] Next, according to the fluorination method of [Synthesis 1], III-1a was used to prepare 3
When fluorinated with an equivalent amount of fluorine, cis-2,3-difluoro body (III-2a) was obtained as a main product in a yield of 16%. Further, a trans-2,3-difluoro body (III-6a) was obtained with a yield of 4%. When the reaction mixture was analyzed by GLC, the all-cis form (III-7a) was scarcely observed (Chart III-5).

[0062]

[Chemical 59] III-2a was stirred in vinyl acetate using lipase (AY, PS) as a catalyst to give a difluoromonoacetate compound [(-)
-III-3] was obtained with a yield of 54%. Also, a small amount of difluoromonoacetate compound (III-12) was obtained (Chart).
III-6). In addition, III-3 was obtained as a crystal. This was recrystallized from pentane-ether to give an optically pure sample.

[0063]

[Chemical 60] In this reaction, lipase AY and lipase PS were used as catalysts, respectively. When Lipase AY was used, the reaction time proceeded in a shorter time, but a small amount of III-2b was produced. When Lipase PS was used, almost no III-2b was produced, but the disappearance of III-2b took a long time (Table 3).

[0064]

[Table 3] The absolute structure of (-)-III-3 is the same as (R)-
α-methoxy-α- (trifluoromet
hyl) phenylacetic acid [(R)
-MTPA] and esterified at 500 MHz
^It was determined by ¹ H-NMR spectrum analysis (JA.
Dale and H.M. S. Mosher, J .; Am. Che
m. Soc. , 95 , 512 (1973) and D.M. P
arker, Chem. Rev. , 91 , 1441 (1
991). That is, (-)-III-3 is replaced with (R) -MT
Esterification with PA gave III-13. The 2- and 3-position protons of the cyclopentane ring were shielded by the phenyl group and observed on the high magnetic field side. Also, (-)-
The recrystallized mother liquor of III-3 was esterified with (R) -MTPA and the data of III-13 'was analyzed. As a result, the proton at the 5-position of the cyclopentane ring and the methyl acetoxyl group were shielded and observed on the high magnetic field side. (Chart III-7,
Table 4). In addition, after direct esterification of (-)-III-3 before recrystallization, 500 MHz ¹ H-NMR spectrum analysis was performed, and the main product (III-13) and sub-product (III-13 ') were analyzed.
The ratio of 22: 1 (90% de) could be calculated.

[0065]

[Chemical formula 61]

[Table 4] In order to confirm that the method for determining the absolute structure of (-)-III-3 by this method is correct, a similar experiment was conducted using a similar monoacetate compound (III-14). According to the literature (F. Theil, H. Stick, G. Win
ter and G.I. Reck, Tetrahedron, 4
7 , 7569 (1991)) and III-1a as lipase P
Monoacetylation under S-catalysis gave an approximately 3: 1 mixture of (-)-III-14 and (+)-III-14. This was directly esterified with (R) -MTPA to give III-
15 (main grader) and III-15 '(subgrade) were induced (Chart III-8). These 500MHz ¹ H
-NMR spectrum data are shown in Table 5.

As a result, it was confirmed that the structural determination of (-)-III-3 by (R) -MTPA esterification was appropriate.

[0067]

[Chemical formula 62]

[Table 5] Generally, lipase PS is a chiral secondary alcohol (A,
It is known to confirm the hydroxyl group of A in B) (Ch
art III-9).

[0068]

[Chemical formula 63] The present inventors have found that this selectivity is due to the tricyclic compound (III-1
3) found that it was retained. This time, it was revealed that the asymmetric recognition ability of lipase PS is retained even in the fluorinated cyclopentenol form (Chart).
III-10).

[0069]

[Chemical 64] Finally, III-3 was oxidized with chromium (VI) oxide in acetic acid under ice-cooling, and the reaction mixture presumed to contain the ketone body (III-4) was treated with triethylamine in ether at room temperature to give optically active 4 -Acetoxy-2-fluoro-2-cyclopenten-1-one [(+)-III-5] was obtained with a total yield of 21% from III-3. The optical rotation is

[Equation 1] (Chart III-11).

[0070]

[Chemical 65] As an oxidizing agent in the oxidation of III-3, PCC and P
DC also tried. However, if PCC or PDC is used, the post-treatment will be hindered. Therefore, chromium oxide (V
The method using I) gave better results. Also,
It is considered that (+)-III-5 had a low yield because of its high volatility.

[Synthesis 4] 2-Fluoro-2-cycloa
Diels-Alder Reaction of Lucen-1-ones and
And photo [2 + 2] cycloaddition reaction The Diels-Alder reaction is useful as a means for synthesizing a complex skeleton all at once, and at the same time, introducing substituents and functional groups in a stereo and regioselective manner.

In addition, light of a cyclic enone system and an alkene [2
The +2] cycloaddition reaction is useful as the most general synthetic method of cyclobutane form. Swenton is a light [2+] of 2-fluorocyclohexenone (A) and an alkene.
2] Cycloaddition reaction is reported (ML Green.
lee, E. L. Fritzen, Jr. , And J.
S. Swenton, J .; Org. Chem. , 43 ,
4512 (1978)). At this time, the 2,3-di-substituted cyclohexanone body (C) is mainly obtained from the cyclobutane body (B) (Chart IV-1). However, 2-fluoro-2-cycloalkene-1-
Little other reports are known about the on-body cycloaddition reaction.

[0073]

[Chemical formula 66] Therefore, the present inventors have demonstrated the usefulness of the 2-fluoro-2-cycloalkene-1-ones synthesized in [Synthesis 1] to [Synthesis 3] as synthetic intermediates.
The Is-Alder reaction and the photo [2 + 2] cycloaddition reaction were investigated.

2-Cyclopenten-1-one (II-1
a) (E. Dane and K. Eder, Justus
Liebigs Ann. Chem. , 539 , 207
(1939)) and 2-methyl-2-cyclopenten-1-one (II-1d) (US Pat. No. 2,179,80).
9) reacts with dienes under heating to produce Diels-Al
It has been reported to give a der adduct. Therefore,
2-Fluoro-2-cyclopenten-1-one (I-4
The reaction between a) and dienes was investigated.

I-4a and excess cyclopentadiene or 2,3-dimethyl-1,3-butadiene were sealed in a sealed tube.
Heated to 0 ° C. but only recovered I-4a.
This result suggests that the introduction of fluorine at the 2-position reduces its parent diene activity.

Next, as a more active diene, Danis
Using the hefsky diene (IV-1), the Diels
-Alder reaction was investigated.

I-4a was heated under reflux with 5 equivalents of IV-1 in xylene to quantitatively obtain an endo adduct (IV-2). This is stirred with potassium fluoride in tetrahydrofuran (THF) at room temperature to give a ketone body (IV-3).
Was obtained in a yield of 83% (Chart IV-2).

[0078]

[Chemical formula 67] The fact that IV-2 is an endo adduct means that IV-3 is 500
It was determined by analysis of MHz ¹ H-NMR spectrum.
That is, the distant coupling constant (J = 2.5 Hz) between the 3a-position proton and the 7-position proton indicates that these protons are in the W-type configuration and negates exo-IV-3 (Cha
rt IV-3).

[0079]

[Chemical 68] I-4b also gave a Diels-Alder adduct (IV-5) with IV-1. At this time, it took longer time for the raw materials to disappear. IV-5 was treated with potassium fluoride without isolation, and then introduced to IV-6 for isolation. The total yield from I-4b was 30% (Chart IV-
4).

[0080]

[Chemical 69] In the 500 MHz ¹ H-NMR spectrum of IV-6 as well, the 1-position proton adjacent to the methoxyl group is observed in the multiplet line, and therefore IV-6 is presumed to be an endo adduct (Chart IV-5). It is reported that the Diels-Alder reaction between IV-1 and the cyclic parent dienes is endo-selective (WJ Kout, HH).
iemstra and W.W. N. Spekamp, J .; Or
g. Chem. 57 , 1057 (1982) and T.W. Iwaoka, N .; Katagiri, M .; Sat
o and C.I. Kaneko, Chem. Pharm. Bu
ll. , 40 , 2319 (1992)).

[0081]

[Chemical 70] Next, the inventors of the present invention conducted light [2+] between I-4a and alkenes.
2] The cycloaddition reaction was examined.

I-4a and excess 2,3-dimethyl-2-
When the pentane solution with butene was irradiated with 350 nm light, the adducts (IV-7, IV-8) were obtained in 14% yield respectively.
Obtained at 20%. Since the non-adducts other than these adducts were not observed on TLC, it is considered that the low yield is due to their volatility. The structure of these grades is ¹
It could be determined based on 1 H-NMR, IR and MS spectral data. IV-8 was obtained as a single diastereomer, but its stereochemistry has not been determined. Swen
As proposed by Ton et al., both products are presumed to be produced via a biradical intermediate (IV-9) (Chart).
IV-6).

[0083]

[Chemical 71] As described above, even in the cyclopentenone form, the formation of the 2,3-di-substituted form has priority over the cyclobutane form.

In the above studies of [Synthesis 1] to [Synthesis 4], the present inventors have noticed that the fluorine-containing cycloalkenones are useful as the fluorine-containing synthetic block, and the fluorine-containing cycloalkenones containing a novel compound are noted. Successfully synthesized the body. Furthermore, the usefulness of these fluorine-containing cycloalkenone compounds as synthetic chemical intermediates was shown. The results are summarized below.

1) Addition of molecular fluorine to 2-cycloalkene-1-ols followed by oxidation and base treatment
2-Fluoro-2-cyclopenten-1-one (I-4
The synthesis of a) was successful for the first time. Also, 2-fluoro-2
-Cyclohexen-1-one (I-4b) could also be synthesized.

2) Successful addition reaction of molecular fluorine to 2-cycloalkene-1-ones having a substituent at the 2-position, 3-position or 4-position, and a substituent effect on the addition reaction were found. That is, it was found that the non-substituted product and the 2-position substituted product give a cis-2,3-difluoro compound, whereas the 3-position substituted product directly gives a 2-fluoro-2-cycloalkene-1-one compound. Further, the 2,3-difluoro-2-cycloalkene-1-one was treated with a base without isolation to give 2-fluoro-2-cyclopenten-1-one and 2-fluoro-2-cyclohexene-one.
1-one could be synthesized.

3) 2-Fluoro-2-cycloalkene-
As a method for synthesizing 1-one, it was clarified that it was more efficient to use a cycloalkenone compound as a starting material than a cycloalkenol compound. That is, although the latter method was slightly inferior in the addition efficiency in fluorination, the operation was extremely simple because the oxidation process was unnecessary, and the total yield was improved. Improved yields are expected by improving reaction conditions and isolation procedures.

4) cis-2-cyclopentene-1,4-
The meso-type difluorodiol compound was stereoselectively synthesized by adding molecular fluorine to the diol, and the asymmetric reaction could be efficiently carried out by the monoacetylation under the lipase catalyst. Subsequent oxidation and base treatment led to the successful synthesis of optically pure (R) -4-acetoxy-2-fluoro-2-cyclopenten-1-one [(+)-III-5].

5) 2-Fluoro-2-cyclopentene-
Diels-Ald of 1-one (I-4a) and 2-fluoro-2-cyclohexen-1-one (I-4b)
The er reaction was successful, and the stereoselective synthesis of the bicyclo skeleton in which fluorine was introduced at the bridgehead position was also successful. Also, the addition reaction of 2-fluoro-2-cyclopenten-1-one (I-4a) with an alkene was successful. These results are 2
-Shows that fluorocycloalkenes are useful as synthetic intermediates. In the future, these are considered to be widely applicable as fluorine-containing synthetic blocks.

[0090]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0091]

Example 1 2-Fluoro-2-cyclopenten-1-
one (I-4a ) racemic I-1a (420 mg, 5 mmol) fluorotrichloromethane-chloroform-ethanol (5:
4: 1,250 ml) solution with stirring at −78 ° C. with 2 equivalents of 5% F ₂ / N ₂ gas (flow rate 180 ml / min).
To conduct. The reaction solution is a saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated brine, the organic layer is dried over anhydrous magnesium sulfate and then concentrated. The obtained oily substance was dissolved in acetic acid (20 ml), and chromium (VI) oxide (1.0 g, 10 mm) was added to the solution.
ol) aqueous solution (2 ml) is added and the mixture is stirred under ice cooling for 4 hours. Water is added to the reaction solution and extracted with dichloromethane, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was mixed with ether (4 ml) and triethylamine (400 mg, 4 mmo).
1) is added and the mixture is stirred at room temperature for 2 hours. The reaction solution is diluted with ether and washed with 10% hydrochloric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was PTLC.
Attached to. Develop with hexane-ethyl acetate (5: 1), I
-4a (64 mg, 13%) is obtained as an oil.

I-4a: colorless oil.

High-resolution MS
m / z: (M ⁺ ) calculated value: C ₅ H ₅ FO: 100.032
4. Found: 100.0323. IR (CHCl ₃ ):
1725, 1650 cm ^-1 . ¹ H-NMR (500 MH
z, CDCl ₃ ) δ: 2.480 (2H, m, J = 4.
_{0Hz, C 5 -H 2),} 2.558-2.594 (2H,
_{m, C 4 -H 2),} 6.989 (1H, t, J = 3.0H
z, C ₃ -H).

[0094]

Example 2 2-Fluoro-2-cyclohexen-1-o
ne (I-4b ) Racemic I-1b (490 mg, 5 mmol) fluorotrichloromethane-chloroform-ethanol (5:
4: 1,250 ml) solution with stirring at −78 ° C. with 2 equivalents of 5% F ₂ / N ₂ gas (flow rate 180 ml / min).
To conduct. The reaction solution is a saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated brine, the organic layer is dried over anhydrous magnesium sulfate and then concentrated. The obtained oily substance was dissolved in acetic acid (20 ml), and chromium (VI) oxide (1.0 g, 10 mm) was added to the solution.
ol) aqueous solution (2 ml) is added and the mixture is stirred under ice cooling for 4 hours. Water is added to the reaction solution and extracted with dichloromethane, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was mixed with ether (4 ml) and triethylamine (1.0 g, 10 mmo).
1) is added and the mixture is stirred at room temperature for 2 hours. The reaction solution is diluted with ether and washed with 10% hydrochloric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was PTLC.
Attached to. Developing with hexane-dichloromethane (1: 3), I-4b (13 mg, 5%) and I-1b (33 m
g, 13%) as an oil.

I-4b: colorless oil. High-resolution MS m / z: (M
⁺ ) Calculated: C ₆ H ₇ FO: 114.0481. Measured value:
114.0473. IR (CHCl _3): 1700,1
655 cm ^-1 . ¹ H-NMR (500 MHz, CDC
l ₃ ) δ: 2.042 (2H, tt, J = 6.5, 5.
_{5Hz, C 5 -H 2),} 2.466 (2H, dq, J =
_{4.5,5.5Hz, C 4 -H 2),} 2.552 (2H,
_{dt, J = 2.5,6.5Hz, C 6} -H 2), 6.47
1 (1H, dt, J = 14.0, 4.5 Hz, C ₃ −
H ₂ ). ¹ H-NMR data were in agreement with literature data.

[0096]

Example 3 2-Fluoro-2-cyclopenten-1-
one (II-4a ) (A) Fluorination using 3 equivalents of fluorine gas II-1a (205 mg, 2.5 mmol) of fluorotrichloromethane-chloroform-ethanol (5: 4:
1,125 ml) solution, while stirring at −78 ° C., 3 equivalents of 5% F ₂ / N ₂ gas (flow rate 180 ml / min) is passed. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer is dried over anhydrous magnesium sulfate and concentrated. Ether (2 ml) and triethylamine (300 mg, 3 mmol) are added to the residue and the mixture is stirred at room temperature for 5 hours. Add 10% hydrochloric acid (5 ml) to the reaction mixture and add 1 more.
After stirring for 0 minutes, it is extracted with pentane-ether (1: 1). The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue is subjected to PTLC. Developing with pentane-dichloromethane (2: 1), I-4a (60 mg, 24%)
And II-1a (33 mg, 16%) as an oil.

(B) Fluorination using 5 equivalents of fluorine gas II-1a (1642 mg, 20 mmol) of fluorotrichloromethane-chloroform-ethanol (5: 4:
1,250 ml) solution and 3 equivalents of 5% F ₂ / N ₂ gas (flow rate 705 ml / min) are passed through while stirring at −78 ° C. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer is dried over anhydrous magnesium sulfate and concentrated. Ether (15 ml) and triethylamine (2500 mg, 25 mmol) were added to the residue and the mixture was stirred at room temperature for 5 minutes.
Stir for hours. 10% Hydrochloric acid (40 ml) was added to the reaction solution, and the mixture was further stirred for 10 minutes, then pentane-ether (1: 1).
Extract with. The organic layer is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, distillation under reduced pressure (90 mmHg /
93-96 ° C) to give I-4a (320 mg, 16%) as an oil.

I-4a: colorless oil. The instrument data matched the data of I-4a obtained in [Synthesis 1].

[0099]

Example 4 cis-2,3-Difluoro-2-methyl
cyclopentan-1-one (cis-II-2
d) II-1d (240 mg, 2.5 mmol) fluorotrichloromethane-chloroform (5: 4, 113 ml)
The solution was stirred at −78 ° C. with 3 equivalents of 5% F ₂ / N ₂
Gas (flow rate 180 ml / min) is conducted. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and then concentrated, and the residue is subjected to PTLC. Hexane-ethyl acetate (5: 1)
Then, the obtained main product is attached to PTLC again. Developing with hexane-dichloromethane (1: 1), cis-
II-2d (67 mg, 20%) is obtained as an oil.

Cis-II-2d: colorless oily substance. High-resolution MS m / z: (M
⁺ ) Calculated: C ₆ H ₈ F ₂ O: 134.0543. Measured value:
134.0524. IR (CHCl ₃ ): 1770 ⁻¹ . ¹
H-NMR (500 MHz, CDCl ₃ ) δ: 1.44
5 (3H, dd, J = 22.5,1.2Hz, C 2 -M
e), 2.101-2.250 (1H, m, C ₄ −
H), 2.334-2.444 (2H, m , C 4 -H,
_{C 5 -H), 2.596 (1H} , dt, J = 20.0,
_{10.0Hz, C 5 -H), 4.919} (1H, dq,
_{J = 52.5,3.5Hz, C 3 -H)} .

[0101]

Example 5 3-Acetoxy-2-fluoro-2-cycl
openten-1-one (II-3e) II-1e (420 mg, 3 mmol) in a solution of fluorotrichloromethane-chloroform (5: 4,135 ml) at −78 ° C. with stirring 3 equivalents of 5% F ₂ / N. ₂ gases (flow rate 180 ml / min) are conducted. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was mixed with P
Subject to TLC. Development with hexane-ethyl acetate (3: 1) gave II-3e (35 mg, 15%) as an oil.

II-3e: colorless oily substance. High-resolution MS m / z: (M
⁺⁾ _{Calculated: C 7 H 7 FO 3:} 158.0379. Measured value:
158.0380. IR (CDCl ₃ ): 1790, 1
730, 1680 cm ^-1 . ¹ H-NMR (300 MH
z, CDCl ₃ ) δ: 2.330 (3H, s, OA
c), 2.517-2.550 (2H, m , C 5 -
H ₂ ), 2.812-2.860 (2H, m, C ₄ −
H ₂ ).

[0103]

Example 6 2-Fluoro-3-methyl-2-cyclo
penten-1-one (II-3f) and 2-fl
uuro-3-fluoromethyl-2-cyc
lopenten-1-one (II- 7) II-1f (480mg, 5mmol) in fluorotrichloromethane - chloroform (5: 4,225ml) was added, 3 equivalents of stirring at -78 ℃ 5% F ₂ / N ₂ gases (flow rate 180 ml / min) are conducted. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and concentrated, and the residue is subjected to medium pressure column chromatography. It is developed with pentane-ether (3: 1), and the obtained main product is subjected to medium pressure column chromatography again. Develop with dichloromethane, II-7 (36 mg, 5%), then II-3f (7
6 mg, 13%) as an oil.

II-7: Colorless oily substance. High-resolution MS m / z: (M
⁺⁾ _{Calculated: C 6 H 6 F 2 O} : 132.0586. Measured value:
132.0401. IR (CDCl ₃ ): 1730,1
680 cm ^-1 . ¹ H-NMR (300 MHz, CDC
l ₃ ) δ: 2.498-2.527 (2H, m, C ₅ -H
₂ ), 2.629-2.703 (2H, m, C ₄ −
H ₂ ), 5.303 (2H, br d, J = 47.0H
_{z, C 3 -CH 2 F)} . II-3f: colorless oil High-resolution MS m / z: (M
⁺ ) Calculated: C ₆ H ₇ FO: 114.0481. Measured value:
114.0481. IR (CHCl _3): 1720,1
675 cm ^-1 . ¹ H-NMR (300 MHz, CDC
l ₃ ) δ: 2.051 (3H, s, C ₃ -Me), 2.4
_{15-2.515 (4H, m, C 4} -H 2, C 5 -H 2).

[0105]

Example 7 2-Fluoro-2-cyclohexen-1-o
ne (I-4b) (A) Fluorinated with 3 equivalents of fluorine II-8a (192 mg, 2 mmol) fluorotrichloromethane-chloroform-ethanol (5: 4: 1).
To 100ml) solution, to conduct 3 equivalents of 5% F ₂ / N ₂ gas (flow rate 180 ml / min) with stirring at -78 ° C.. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer is dried over anhydrous magnesium sulfate and concentrated. Ether (5 ml) and triethylamine (300 mg, 3 mmol) are added to the residue, and the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ether and washed with 10% hydrochloric acid and saturated saline. The organic layer is dried over anhydrous magnesium sulfate and then concentrated, and the residue is subjected to PTLC. Develop with hexane-ethyl acetate (3: 1), and obtain the main product again with PTLC.
Attached to. Develop with dichloromethane, I-4b (27m
g, 12%) and II-8a (10 mg, 5%) are obtained as oils.

(B) Fluorination with 4 equivalents of fluorine II-8a (961 mg, 10 mmol) fluorotrichloromethane-chloroform-ethanol (5: 4:
1,250 ml) solution, while stirring at −78 ° C., 3 equivalents of 5% F ₂ / N ₂ gas (flow rate 590 ml / min) are passed. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer is dried over anhydrous magnesium sulfate and concentrated. Ether (25 ml) and triethylamine (1500 mg, 15 mmol) were added to the residue and the mixture was stirred at room temperature for 3
Stir for hours. The reaction solution is washed with 10% hydrochloric acid and saturated saline, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is subjected to silica gel column chromatography. The product is developed with dichloromethane and the obtained main product is subjected to medium pressure column chromatography. Developing with hexane-dichloromethane (2: 1), I-4b (188 mg,
17%) and II-8a (173 mg, 18%) are obtained as oils.

I-4b: colorless oil. The instrument data matched the data of I-4a obtained in [Synthesis 1].

[0108]

Example 8 cis-2,3-Difluoro-2-methyl
cyclohexane-1-one (II- 9b) II-8b (220mg, 2mmol) in fluorotrichloromethane - chloroform (5: 4,90ml) was added, 3 equivalents of stirring at -78 ℃ 5% F ₂ / N ₂ gases (flow rate 180 ml / min) are conducted. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was mixed with P
Subject to TLC. It is developed with hexane-dichloromethane (1: 1), and the obtained main product is subjected to PTLC again. Developing with hexane-ethyl acetate (3: 1), cis-II-9
b (40 mg, 14%) is obtained as an oil.

Cis-II-9b: colorless oily substance. High-resolution MS m / z: (M
⁺⁾ _{Calculated: C 7 H 10 F 2 O} : 148.0700. Found: 148.0693. ¹ H-NMR (500 MHz,
CDCl ₃ ) δ: 1.547 (3H, d, J = 22.0)
Hz), 1.588-1.652 (1H, m , C 5 -H
_{axial), 2.024-2.130 (2H, m} , C 4 -H
_{axial, C 5 -H equatrial),} 2.242 (1H, d
t, J = 3.0, 8.5 Hz, C ₄ -H _equatrial ),
2.420 (1H, dt, J = 14.0, 7.0Hz,
C ₆ −H _axial ), 2.707 (1H, dt, J = 5.
5, 14.0 Hz, C ₆ -H _equatrial ), 4.545
(1H, dddd, J = 48.0, 17.0, 8.5,
3.0Hz, C ₃ -H).

[0110]

Example 9 2-Fluoro-3-methyl-2-cyclo
hexen-1-one (II-11) II-8c (275 mg, 2.5 mmol) fluorotrichloromethane-chloroform (5: 4, 112.5 m)
l) Add 3 equivalents of 5% F _{2 to the} solution with stirring at -78 ° C.
/ N ₂ gas (flow rate 180 ml / min) is conducted. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer is dried over anhydrous magnesium sulfate and concentrated. Ether (5 ml) and triethylamine (3
(00 mg, 3 mmol) and the mixture is stirred at room temperature for 6 hours.
The reaction solution is diluted with ether and washed with 10% hydrochloric acid and saturated saline. The organic layer is dried over anhydrous magnesium sulfate and then concentrated, and the residue is subjected to PTLC. Deploy with dichloromethane, II
-11 (43 mg, 13%) is obtained as an oil.

II-11: colorless oil. High-resolution MS m / z: (M
⁺ ) Calculated value: C ₇ H ₉ FO: 128.0638. Measured value:
1280619. IR (CHCl ₃ ): 1690,1
660 cm ^-1 . ¹ H-NMR (500 MHz, CDC
l ₃ ) δ: 1.934 (3H, d, J = 3.0 Hz, C ₃
-Me), 1.995 (2H, dt, J = 13.0,
_{6.0Hz, C 5 -H 2),} 2.427 (2H, q, J =
_{6.0Hz, C 6 -H 2),} 2.504 (2H, dt, J
_{= 2.5,6.0Hz, C 4 -H 2)} .

[0112]

Example 10 cis-2,3-Difluorocyclopentant
an-1,4-diol (III-2a) III-1a (500 mg, 5 mmol) fluorotrichloromethane-chloroform-ethanol (5: 4:
1,250 ml) solution and 3 equivalents of 5% F ₂ / N ₂ gas (flow rate 500 ml / min) are passed through while stirring at −78 ° C. After evaporating the solvent, the residue is subjected to medium pressure column chromatography. Development with hexane-ethyl acetate (1: 1), III-6a (30 mg, 4%), then III-2a
(114 mg, 16%) is obtained as an oil.

III-2a: colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.62
9 (1H, br dt, J = 15.0, 5.0Hz, C
_5- H), 2.042 (2H, brs, OH), 2.
677 (1H, br dt, J = 22.0, 7.5H
_{z, C 5 -H), 4.380-4.446} (2H, m,
_{C 1 -H, C 4 -H)} , 4.820-4.952 (2H,
_{m, C 2 -H, C 3} -H).

[0114]

[Embodiment 11] cis-4-Acetoxy-2,3-difluor
ocyclopentan-1-ol [(-)-III-
3] To a solution of III-2a (97 mg, 0.7 mmol) in vinyl acetate (10 ml) was added lipase AY (97 mg),
Stir at 24 ° C. for 9 hours. The reaction solution is filtered through Celite, the solvent is evaporated, and the residue is subjected to medium pressure column chromatography. Developing with hexane-ethyl acetate (3: 1), III-
3 (60 mg, 48%) is obtained as crystals.

(-)-III-3: colorless prism crystals (pentane-ether) having an mp of 61 ° C.

High-resolution MS
m / z: (M ⁺⁾ _{Calculated: C 7 H 10 F 2 O} 3: 180.05
98. Found: 180.0579. IR (CHC
l ₃ ): 3610, 1730 cm ⁻¹ . ¹ H-NMR (50
0 MHz, CDCl ₃ ) δ: 1.600 (1H, dt,
_{J = 15.0,5.0Hz, C 5 -H)} , 2.099
(3H, s, OAc), 2.840 (1H, br d
_{t, J = 15.0Hz, C 5} -H), 4.408-4.
475 (1H, m, C ₁ -H), 4.829 (1H, d
dd, J = 51.0, 12.0, 4.0 Hz, C ₃ −
H), 5.042 (1H, ddd, J = 50.0, 1
3.5,4.0Hz, C ₂ -H), 5.152-5.2
_{28 (1H, m, C 4} -H).

[Equation 2]

[0117]

Example 12 (−)-III-3 MTPA ester (III-13)
And (+)-III-3 MTPA ester (III-
13 ′) (±) -III-3 (3 mg, 0.02 mmol) and (R) -MTPA (13 mg, 0.05 mmol) in dichloromethane solution was added to DMAP (3.5 mg, 0.03 m).
mol), then DCC (12 mg, 0.06 mmo
1) is added and the mixture is stirred at room temperature. Water is added to the reaction solution, and the mixture is stirred, extracted with ether, and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is subjected to PTLC. Hexane-
Developing with ethyl acetate (5: 1), III-13 and III-
13 '(6 mg, 80%) is obtained as an oil in the ratio 22: 1.

III-13: colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.74
0 (1H, dt, J = 16.0, 5.0Hz, C ₅ −
H), 2.049 (3H, s, OAc), 3.016
(1H, dt, J = 15.5, 8.0 Hz, C ₅ −
H), 3.532 (3H, s, OMe), 4.934.
(1H, ddt, J = 50.0, 11.0, 4.0H
_{z, C 3 -H), 4.988} (1H, ddt, J = 5
0.0,14.0,4.0Hz, C ₂ -H), 5.20
_{8-5.273 (1H, m, C 1} -H), 5.468-
_{5.533 (1H, m, C 4} -H), 7.400-7.
500 (5H, m, Ph). III-13 ': colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.60
8 (1H, dt, J = 16.0, 4.0 Hz, C ₅ −
H), 1.993 (3H, s, OAc), 2.721.
(1H, dt, J = 15.0, 7.0Hz, C ₅ −
H), 3.553 (3H, s, OMe), 5.100-
_{5.300 (2H, m, C 2} -H, C 3 -H), 5.20
_{8-5.273 (1H, m, C 1} -H), 5.468-
_{5.533 (1H, m, C 4} -H), 7.400-7.
500 (5H, m, Ph).

[0119]

Example 13 (+)-III-14 MTPA ester (III-1)
5) and (-)-III-14 MTPA ester
(III-15 ′) (±) -III-14 (28 mg, 0.2 mmol) and (R) -MTPA (117 mg, 0.5 mmol) in dichloromethane (1 ml) solution in DMAP (5 mg, 0.
04 mmol), then DCC (103 mg, 0.5 m
(mol) and stirred at room temperature for 24 hours. Water is added to the reaction solution, and the mixture is stirred, extracted with ether, and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is subjected to PTLC.
Development with hexane-ethyl acetate (8: 1), III-15
And III-15 '(64.8 mg, 87%) 4: 1.
As an oil.

III-15: colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.79
0 (1H, dt, J = 15.0, 3.5Hz, C ₅ −
H), 2.000 (3H, s, OAc), 2.878
(1H, dt, J = 15.0, 7.5Hz, C ₅ −
H), 3.562 (3H, s, OMe), 5.547.
(1H, dd, J = 7.5,3.5Hz , C 1 -H),
5.761 (1H, dd, J = 7.5, 3.5Hz, C
_{4 -H), 6.178 (2H,} s, C 2 -H, C 3 -
H), 7.402-7.413 (5H, m, Ph). III-15 ': colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.87
2 (1H, dt, J = 15.0, 3.5Hz, C ₅ −
H), 2.023 (3H, s, OAc), 2.931
(1H, dt, J = 15.0, 7.5Hz, C ₅ −
H), 3.554 (3H, s, OMe), 5.547.
(1H, dd, J = 7.5,3.5Hz , C 1 -H),
5.761 (1H, dd, J = 7.5, 3.5Hz, C
_4- H), 6.101 (1H, d, J = 6.0 Hz, C ₂
-H), 6.160 (1H, d, J = 6.0 Hz, C ₂
-H), 7.521-7.537 (5H, m, Ph).

[0121]

Example 14 (R) -4-Acetoxy-2-fluoro-2-
cyclopentan-1-one [(+) III-
5] III-3 (54 mg, 0.3 mmol) was added to acetic acid (1 m
l), and added thereto chromium (VI) oxide (60 mg,
0.6 mmol) aqueous solution (0.1 ml) is added and the mixture is stirred under ice cooling for 4 hours. The reaction mixture is diluted with water, extracted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and then concentrated, and ether (0.5 ml) and triethylamine (60 mg, 0.6 mmol) are added to the residue and the mixture is stirred at room temperature for 2 hours. The solvent is distilled off and the residue is subjected to PTLC. Developing with hexane-ethyl acetate (2: 1), (+)-III-5
(7 mg, 21%) is obtained as an oil.

(+)-III-5: colorless oily substance. High-resolution MS m / z: (M
⁺⁾ _{Calculated: C 7 H 7 FO 3:} 158.0379. Measured value:
158.0379. IR (CHCl ₃ ): 1745, 1
660 cm ^-1 . ¹ H-NMR (500 MHz, CDC
l ₃ ) δ: 2.113 (3H, s, OAc), 2.45
5 (1H, dt, J = 19.0, 1.0 Hz, C ₅ −
H), 2.943 (1H, dd, J = 19.0, 6.0)
_{Hz, C 5 -H), 5.750-5.785} (1H,
m, C ₄ -H), 6.930 (1H, d, J = 3.0H
z, C ₃ -H).

[Equation 3] _{(C = 0.89, CHCl 3)} .

[0123]

Example 15 7a-Fluoro-7-methoxy-5-tri
methylsiloxy-3a, 4,7,7a-
tetrahydro-1-indanone ( IV-
2) 2-Fluoro-2-cyclopenten-1-one (40 m
g, 0.4 mmol) in xylene (2 ml) solution.
nishefsky diene (346 mg, 2 mmol)
Is added and the mixture is heated under reflux for 4 hours. After distilling off the solvent, distillation under reduced pressure (0.2 mmHg / 147 ° C.) was performed to obtain 7a-fluoro-7.
-Methoxy-5-trimethylsilyloxy-3a, 4
7,7a-Tetrahydro-1-indanone (127m
g, quantitative) as an oil.

IV-2: Colorless oily product High-resolution MS m / z: (M
⁺ ) Calculated value: C ₁₃ H ₂₁ FO ₃ Si: 272.1244. Found: 272.1239. IR (CHCl ₃ ): 176
0.1665 cm ^-1 . ¹ H-NMR (500 MHz, C
_{DCl 3) δ: 1.958-2.585 (7H} , m, C
_{2 -H 2, C 3 -H 2} , C 3a -H, C 4 -H 2), 3.2
_{44 (3H, s, C 7} -OMe), 3.996 (1H,
dd, J = 17.5, 5.0 Hz, C ₇ -H), 5.1
02 (1H, d, J = 5.0Hz, C 6 -H).

[0125]

Example 16 7a-Fluoro-7-methoxy-3a, 4
5,6,7,7a-hexahydroindan-
1,5-dione (IV-3) 7a-fluoro-7-methoxy-5-trimethylsilyloxy-3a, 4,7,7a-tetrahydrooxy-1
A solution of indanone (127 mg, 0.45 mmol) in tetrahydrofuran (1 ml) with potassium fluoride (26
(mg, 0.45 mmol) and stirred at room temperature for 4 hours. The reaction solution is diluted with water and ether and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated,
a-fluoro-7-methoxy-3a, 4,5,6,7,
7a-Hexahydroindane-1,5-dione (66m
g, 83%) as crystals.

IV-3: colorless needle crystals at mp 100-101 ° C. MS m / z: 200 (M ⁺ ). Anal. Calculated value: C
_{10 H 13 FO 3: C,} 59.99; H, 6.54. Found: C, 59.78; H, 6.38. IR (CHC
l ₃ ): 1765, 1720 cm ⁻¹ . ¹ H-NMR
(500 MHz, CDCl ₃ ) δ: 1.928 (1H,
_{tt, J = 12.0,9.0Hz, C 3} -H), 2.0
_{56-2.128 (1H, m, C 3} -H), 2.369
(1H, dt, J = 19.5, 9.5Hz, C ₂ −
H), 2.419-2.483 (2H, m , C 2 -H,
C _4- H), 2.699 (1H, dt, J = 15.5,
_{2.5Hz, C 6 -H), 2.764} (1H, br
d, J = 15.5 Hz, C ₆ -H), 2.790 (1
H, dd, J = 16.0, 8.0 Hz, C ₄ -H),
_{2.844-2.961 (1H, m, C 3} -H), 3.
_{257 (3H, s, C 7} -OMe), 4.062 (1
H, dq, J = 10.0,2.5Hz, C 7 -H).

[0127]

Example 17 Light of 2-fluoro-2-cyclopenten-1-one [2
+2] addition reaction 2-fluoro-2-cyclopenten-1-one (20 m
g, 0.2 mmol) and 2,3-dimethyl-2-butene (336 mg, 4 mmol) in pentane (15 ml).
And is irradiated with 350 nm light for 2 hours. The solvent is distilled off and the residue is subjected to PTLC. Development with hexane-ethyl acetate (5: 1) gives less polar (IV-7) and more polar (IV-8) as oils.

(IV-7): colorless oil (IV-8): colorless oil

[0129]

Example 18 IV-6 2-Fluoro-2-cyclohexan-1-one (57 m
g, 0.5 mmol) in xylene (2 ml) solution.
nishefsky diene (432 mg, 2.5 mmo
1) is added and the mixture is heated under reflux for 13 hours. The solvent is evaporated, the residue is added to a solution of tetrahydrofuran (1 ml) with potassium fluoride (58 mg, 1 mmol), and the mixture is stirred at room temperature for 12 hours. The reaction solution is diluted with water and ether and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated, IV
-6 (32 mg, 30%) was obtained as crystals.

IV-6: colorless plate crystals with mp 112-113 ° C. MS m / z: 214 (M ⁺ ). Elemental analysis: Calculated value: C
₁₁ H ₁₅ FO ₃ : C, 61.67; H, 7.06. Found: C, 61.71; H, 7.03. IR (CHC
l ₃ ): 1725 cm ⁻¹ . ¹ H-NMR (500 MH
z, CDCl ₃ ) δ: 1.672-1.768 and
1.983-2.050 (2H and 1H, m, C
_{2 -H axial, C 3 -H 2} ), 2.122 (1H, dq, J
_{= 4.0,13.0Hz, C 4 -H axial)} , 2.296
(1H, dt, J = 14.5,2.0Hz , C 2 -H
_equatrial ), 2.603-2.702 (3H, m, C _{4
-H equatri al, C 5 -H 2} ), 2.760-2.883
_{(3H, m, C 4a -H} , C 7 -H 2), 3.327 (1
_{H, s, C 8 -OMe)} , 3.894-3.928 (1
_{H, m, C 8 -H)} .

[0131]

EFFECTS OF THE INVENTION According to the method of the present invention, 2-fluorocycloalkenones which can be widely applied to fluorine-containing organic synthesis reaction as a fluorine-containing synthetic block, that is, a synthetic intermediate can be efficiently synthesized.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 67/297

Claims (17)

[Claims] 1. The following formula: Wherein 2-fluoroalkene-1-ol represented by the formula (wherein n represents 1 or 2) is added with molecular fluorine diluted with an inert gas. (In the formula, n represents the same meaning as described above). 2. The following formula: 2-cycloalkene-1-ol represented by the formula (wherein n represents 1 or 2) is added with molecular fluorine diluted with an inert gas to give the following formula: (Wherein n has the same meaning as above), the compound is oxidized with an oxidizing agent and further reacted with a base. (In the formula, n represents the same meaning as described above) A method for producing 2-fluoro-2-cycloalkene-1-one. 3. The production method according to claim 1, wherein the concentration of molecular fluorine diluted with an inert gas is 1-10%. 4. Nitrogen is used as the inert gas.
-3. The manufacturing method according to any one of 3. 5. The method according to claim 1, wherein the oxidizing agent is chromium trioxide.
4. The manufacturing method according to any one of 4 above. 6. The base is triethylamine.
-5. The manufacturing method according to any one of item 5. 7. The following formula: (In the formula, R and R ′ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)
The following formula characterized by adding molecular fluorine diluted with an inert gas to 2-cycloalkene-1-one represented by (In the formula, R, R ′ and n have the same meanings as described above). 8. The following formula: (In the formula, R and R ′ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)
By adding molecular fluorine diluted with an inert gas to 2-cycloalkene-1-one represented by the following formula: (Wherein R, R ′ and n have the same meanings as described above), and when R is a hydrogen atom, this compound is reacted with a base. 10] (In the formula, R, R ′, and n have the same meanings as described above.) A method for producing 2-fluoro-2-cycloalkene-1-one. 9. The method according to claim 7, wherein the concentration of molecular fluorine diluted with an inert gas is 1-10%. 10. The manufacturing method according to claim 7, wherein nitrogen is used as the inert gas. 11. The production method according to claim 7, wherein the base is triethylamine. 12. The following formula: The following formula characterized by adding molecular fluorine diluted with an inert gas to cis-2-cyclopentene-1,4-diol represented by The manufacturing method of the compound shown by these. 13. The following formula: By adding molecular fluorine diluted with an inert gas to cis-2-cyclopentene-1,4-diol represented by the following formula: A compound represented by the following formula is obtained, and this compound is then catalyzed by lipase. (Wherein Ac represents an acyl group) is reacted with a compound represented by the following formula: (Wherein Ac represents the same meaning as described above), and then the compound is oxidized with an oxidizing agent and then reacted with a base. (Wherein Ac represents the same meaning as described above) 4-
Acyloxy-2-fluoro-2-cyclopentene-1
-On manufacturing method. 14. The method according to claim 12, wherein the concentration of molecular fluorine diluted with an inert gas is 1-10%. 15. The manufacturing method according to claim 12, wherein nitrogen is used as the inert gas. 16. The oxidizing agent is chromium trioxide.
The manufacturing method according to any one of 2 to 15. 17. The production method according to claim 12, wherein the base is triethylamine.