WO2016199789A1

WO2016199789A1 - Method of manufacturing trifluoromethyl substituted semisquarate, method of manufacturing trifluoromethyl compound starting from trifluoromethyl substituted semisquarate, and trifluoromethyl group-containing compound

Info

Publication number: WO2016199789A1
Application number: PCT/JP2016/066988
Authority: WO
Inventors: 芳彦山本; 崇黒原; 正俊澁谷
Original assignee: 国立大学法人名古屋大学
Priority date: 2015-06-08
Filing date: 2016-06-08
Publication date: 2016-12-15
Also published as: JPWO2016199789A1

Abstract

The present invention addresses the problem of efficiently synthesizing a trifluoromethyl substituted semisquarate in a short process, in order to manufacture trifluoromethyl compounds with various functionalities. A method was developed of synthesizing a trifluoromethyl substituted semisquarate with squarate as a starting material, in the two steps of a trifluoromethylation reaction and an allyl alcohol transfer reaction. Furthermore, a method was established of manufacturing trifluoromethyl compounds with various functionalities starting from a trifluoromethyl substituted semisquarate.

Description

Method for producing trifluoromethyl-substituted semisquarate, method for producing trifluoromethyl compound starting from trifluoromethyl-substituted semisquarate, and compound containing trifluoromethyl group

The present invention relates to a novel method for synthesizing a trifluoromethyl-substituted semisquarate, a method for synthesizing various functional trifluoromethyl compounds starting from the compound, and a trifluoromethyl group-containing compound.

Fluorine-containing compounds are known to have high chemical stability due to the strong carbon-fluorine bond, and are used in fields such as pharmaceuticals, functional materials, and agricultural chemicals. Especially in pharmaceuticals, since it was found that Fludrocortisone has an anti-inflammatory action 10 times higher than Cortisone に in the 1950s (Non-Patent Documents 1 and 2), many compounds have been synthesized. The development of fluorine-containing drugs such as 5-fluorouracil, which is currently used for chemotherapy, is progressing (Non-patent Documents 3 and 4).

In pharmaceuticals, it is known that by introducing fluorine, an effect called a polar effect, a mimic effect, a block effect, or a hydrophobic enhancement effect is brought about (Non-Patent Documents 5 and 6). The polar effect is an effect of having resistance to an electrophilic reaction such as an oxidation reaction due to the influence of the strong electronegativity of fluorine and acquiring a stronger interaction with a protein. The mimic effect is an effect in which a fluorine atom is an atom having the next smallest radius after hydrogen, and thus shows a similar behavior without being distinguished in vivo. The blocking effect is an effect that stabilizes the suppression of substitution reaction, reduction, and oxidative metabolism in the living body because the spread of the electron orbit of fluorine is close to that of carbon and the carbon-fluorine bond becomes strong. In addition, the hydrophobicity enhancing effect is an effect of changing the absorption and transport in the living body by acquiring lipophilicity. Furthermore, the effect of sustained efficacy, the effect of enhancing drug absorption, and the improvement of selectivity as these combined effects are known as the effects of fluorine. Because of these high effects, the number of fluorine-containing pharmaceuticals has increased to 14% of those on the market.

Since fluorine-containing compounds have the effects as described above, synthesis of organic fluorine compounds has played a major role in the development of pharmaceuticals and the like. Among these, aromatic trifluoromethyl compounds (Ar—CF ₃ ) are used in many pharmaceuticals.

At present, the introduction of trifluoromethyl group is performed by two methods as shown in FIG. Building block method (Non-patent Documents 3, 4, 7 to 11) aiming at synthesis of target structure using compound having trifluoromethyl group such as trifluoroacetic acid and benzotrifluoride derivative, and trifluoromethyl unit This is a direct trifluoromethylation method in which is directly introduced into the molecular skeleton (Non-patent Documents 12 to 21, Patent Document 1).

U.S. Pat. No. 3,408,411

The building block method requires many steps to produce the target compound, and further requires separation and purification operations. Since the target compound is synthesized from a simple trifluoromethyl compound through many steps, the more complicated the target compound, the more complicated the synthesis route and the higher the cost. Also, the manufacturing method is poor in generality.

Therefore, in recent years, development of a direct trifluoromethylation method in which a trifluoromethyl group is directly introduced into a target compound skeleton has been developed. The direct trifluoromethylation method is a method in which a target skeleton is once constructed and a trifluoromethyl group is introduced at the final stage. However, in addition to the fact that the skeleton construction itself requires multiple steps, since trifluoromethylation is a special reaction, generally expensive reagents and harsh reaction conditions are required. Therefore, the generality is poor, and the applicable skeleton is limited.

Therefore, it has been desired to develop a method for producing a versatile trifluoromethyl compound without requiring an expensive reagent. There are also many trifluoromethyl compounds that cannot be synthesized by the above-mentioned known methods, such as trifluoromethylated heterocyclic compounds. The present invention provides a method for efficiently synthesizing a trifluoromethyl-substituted semisquarate using a commercially available squalate compound as a starting material in a short process, and a method for producing various functional trifluoromethyl compounds starting from the compound. Let it be an issue.

If it is possible to synthesize semisquarate substituted with a trifluoromethyl group, it will be possible to efficiently synthesize quinone or butenolide introduced with a trifluoromethyl group by using this as a synthesis element. . Therefore, if semisquarate substituted with a trifluoromethyl group can be synthesized, various functional trifluoromethyl compounds can be provided. The present invention not only synthesizes trifluoromethyl compounds efficiently, but also synthesizes and provides new compounds such as compounds in which a trifluoromethyl group is introduced into a heterocyclic compound that could not be synthesized by conventional methods. This is the issue.

The present invention is a method for producing a trifluoromethyl-substituted semisquarate shown below and a novel trifluoromethyl compound.
[1] A compound represented by the following general formula (1) as a starting material,

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
A method for producing a compound into which a trifluoromethyl group has been introduced by an addition reaction step and a ring expansion step.
[2] The production method according to [1], wherein the compound into which the trifluoromethyl group is introduced is a quinone compound.
[3] The production method according to [2], wherein the quinone compound into which the trifluoromethyl group is introduced is a compound represented by the following general formula (4) or (5).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl and sec-butyl. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, alkyl Selected from a group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, any two adjacent substituents of R ¹ to R ⁴ may form a condensed benzene, wherein alkyl The hydrocarbon moiety of the group, alkenyl group and alkoxy group may be any of C1 to C8 linear, branched or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group and sec-butyl group. R ⁵ and R ⁶ are each independently hydrogen, alkyl group, alkenyl group, (It is selected from an alkoxy group, a chloro group, and a fluoro group, wherein the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
[4] The production method of [1], wherein the compound into which the trifluoromethyl group is introduced is a heterocyclic condensed ring compound.
[5] The process according to [4], wherein the heterocyclic condensed ring compound into which the trifluoromethyl group is introduced is a compound represented by the following general formula (6) or (7).

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R ⁷ and R ⁸ are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R ⁷ and R ⁸ may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. X is CH═CH, S, NCH ₃ )
[6] The production method according to [1], wherein the compound into which the trifluoromethyl group is introduced is a hydroquinone compound.
[7] The production method of [6], wherein the hydroquinone compound having a trifluoromethyl group introduced therein is a compound represented by any one of the following general formulas (8) to (10).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl and sec-butyl. R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, Selected from an alkyl group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, and any two adjacent substituents of R ⁹ to R ¹² may form a condensed benzene, where (The hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R ¹³ and R ¹⁴ are each independently hydrogen, alkyl group, alkenyl group, (It is selected from an alkoxy group, a chloro group, and a fluoro group, wherein the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. R ¹⁵ and R ¹⁶ are each independently hydrogen, an alkyl group, an alkenyl group, Selected from an alkoxy group, a chloro group and a fluoro group, R ¹⁵ and R ¹⁶ may combine to form a condensed benzene, X is O, S or NP, and P is a carbamate or sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
[8] The production method according to [1], wherein the compound into which the trifluoromethyl group is introduced is a butenolide compound.
[9] The production method according to [8], wherein the butenolide compound into which the trifluoromethyl group is introduced is a compound represented by the following general formulas (10-1) and (10-2).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl, and sec-butyl. R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ are each independently hydrogen, Selected from an alkyl group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, and any two adjacent substituents of R ¹⁷ to R ²⁰ may form a condensed benzene, where (The hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R ²¹ and R ²² are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R ²¹ and R ²² may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
[10] The production method of [1], wherein the compound into which the trifluoromethyl group is introduced is a four-membered ring compound.
[11] The production method according to [10], wherein the four-membered ring compound into which the trifluoromethyl group is introduced is a compound represented by the following general formula (10-3c) or (10-3d).

(Wherein R ²³ and R ²⁴ are each independently selected from a C1-C6 linear, branched, cyclic alkyl group or a phenyl group.)

(Wherein R ²⁵ and R ²⁶ are each independently selected from a C1-C6 linear, branched, cyclic alkyl group or phenyl group.)
[12] The production method of [1], wherein the compound into which the trifluoromethyl group is introduced is a bicyclo ring compound.
[13] The production method according to [12], wherein the bicyclo ring compound into which the trifluoromethyl group is introduced is a compound represented by the following general formula (37-1).

(Wherein R ²⁷ and R ²⁸ are each independently selected from a C1-C6 linear, branched, or cyclic alkyl group or a phenyl group, and R ²⁷ or R ²⁸ may form a ring structure) .)
[14] The production method of [1], wherein the compound into which the trifluoromethyl group is introduced is an aminocyclopentenedione compound.
[15] The production method of [14], wherein the aminocyclopentenedione compound having a trifluoromethyl group introduced is a compound represented by the following general formula (10-4).

(Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl, sec-butyl, R ²⁹ is a C1-C8 alkyl group, linear, branched, cyclic) R ³⁰ is selected from a t-butyl group or a 1,1,3,3-tetramethylbutyl group.)
[16] A method for producing a trifluoromethyl-substituted semisquarate represented by the following general formula (1):

By the step of trifluoromethylating a squarate represented by the following general formula (3):

A compound represented by the following general formula (2) is produced,

A production method comprising synthesizing by a step of performing an allyl alcohol transfer reaction.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
[17] A method for producing a trifluoromethyl-substituted semisquarate represented by the following general formula (1):

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
A compound represented by the following general formula (2)

A production method comprising synthesizing by a step of performing an allyl alcohol transfer reaction.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
[18] The method for producing a trifluoromethyl-substituted semisquarate according to [16] or [17], wherein the allyl alcohol transfer reaction is a reaction using Re ₂ O ₇ or Ph ₃ SiReO ₃ as a catalyst. A manufacturing method characterized by being.
[19] A method for producing a compound represented by the following general formula (2),

The squarate represented by the following general formula (3)

A production method comprising synthesizing by a trifluoromethylation step.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
[20] The production method according to [16] or [19], wherein the trifluoromethylation step comprises a silyl trifluoromethylation reaction using CF ₃ Me ₃ Si as an organosilicon reagent; A production method comprising a desilylation step.
[21] A compound represented by the following general formula (1).

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
[22] A compound of the following general formula (2).

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
[23] Trifluoromethyl compounds represented by the following formulas (12) to (52), (17-1), (10-3a), and (10-3b).

Developed a versatile method for producing trifluoromethyl compounds without the need for expensive reagents, enabling efficient synthesis of trifluoromethyl compounds. Furthermore, it has become possible to produce trifluoromethyl compounds that have been difficult to produce.

The figure which shows the trifluoromethyl substituted semisquarate method typically. The figure which shows typically the introduction method of the conventional trifluoromethyl group.

FIG. 1 schematically shows the trifluoromethyl-substituted semisquarate method of the present invention. Using squalate of compound 3 as a starting material, trifluoromethyl-substituted semisquarate of compound 1 can be synthesized in a short process.

In FIG. 1, examples of R include isopropyl, n-propyl, t-butyl, isobutyl, and sec-butyl. The squarate of compound 3 and R of compound 2 can have the above functional groups, but the two Rs may be different groups or the same group. However, it is preferable that both are the same groups from the ease of synthesis.

Squaric acid ester is a useful molecule as a four-membered ring synthesis element because it can be converted into the target skeleton in a short process. Various molecules such as quinone and butenolide can be synthesized by ring expansion reaction of hydroxycyclobutenone obtained by adding an organometallic reagent. Therefore, if it is possible to synthesize semisquarates substituted with trifluoromethyl groups, it is possible to efficiently synthesize quinones and butenolides into which trifluoromethyl groups have been introduced by using them as synthesis elements. It becomes.

Examples of naphthoquinones and benzoquinones that can be synthesized from the trifluoromethyl-substituted semisquarate of the present invention include compounds represented by the following general formula (4) or (5).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl and sec-butyl. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, Selected from an alkyl group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, and any two adjacent substituents of R ¹ to R ⁴ may form a condensed benzene, where (The hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group and sec-butyl group. R ⁵ and R ⁶ are each independently hydrogen, alkyl group, alkenyl group, (It is selected from an alkoxy group, a chloro group, and a fluoro group, wherein the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

In addition, examples of the heterocyclic derivative that can be synthesized from trifluoromethyl-substituted semisquarate include compounds represented by the following general formulas (6) and (7).

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R ⁷ and R ⁸ are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R ⁷ and R ⁸ may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. X is CH═CH, S, NCH ₃ )

Also, hydroquinones corresponding to the quinones (4), (5) and (6) include (8), (9) and (10).

(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. R ¹⁵ and R ¹⁶ are each independently hydrogen, an alkyl group, an alkenyl group, Selected from an alkoxy group, a chloro group and a fluoro group, R ¹⁵ and R ¹⁶ may combine to form a condensed benzene, X is O, S or NP, and P is a carbamate or sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

In addition, examples of butenolides that can be synthesized from trifluoromethyl-substituted semisquarate include compounds represented by the following general formulas (10-1) and (10-2).

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R ²¹ and R ²² are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R ²¹ and R ²² may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

Furthermore, it has become possible to synthesize a bicyclo ring compound represented by the following formula (37) from trifluoromethyl-substituted semisquarate via intermediates (10-3a, 10-3b) which are novel compounds.

In addition, since a synthesis method for improving the yield of the compound represented by 10-3a could be developed, it became possible to synthesize a compound represented by the following general formula 10-3c. As a result, synthesis of a compound represented by the following general formula 10-3d and synthesis of a compound represented by the following general formula 37-1 became possible.

(Wherein R ²⁵ and R ²⁶ are each independently selected from a C1-C6 linear, branched, cyclic alkyl group or phenyl group.)

(Wherein R ²⁷ and R ²⁸ are each independently selected from a C1-C6 linear, branched, or cyclic alkyl group or a phenyl group, and R ²⁷ or R ²⁸ may form a ring structure) .)

In addition, aminocyclopentenedione represented by the general formula (10-4) can also be synthesized from trifluoromethyl-substituted semisquarate.

(Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl, sec-butyl, R ²⁹ is a C1-C8 alkyl group, linear, branched, cyclic) R ³⁰ is selected from a t-butyl group or a 1,1,3,3-tetramethylbutyl group.)

Furthermore, it has become possible to synthesize an unsaturated carboxylic acid which is a ring-opening compound represented by the following formula (48) from trifluoromethyl-substituted semisquarate.

Hereinafter, the present invention will be described more specifically with reference to embodiments, but the scope of the present invention is not limited to the following embodiments.

[Example 1]
≪Method for producing trifluoromethyl-substituted semisquarate (1) ≫
1.1 Trifluoromethylation step of squarate ester A method for producing a trifluoromethyl-substituted semisquarate by separately performing two steps of trifluoromethylation and allyl alcohol transfer is shown below.

First, the process of trifluoromethylating a squaric acid ester by applying the silyl trifluoromethylation method developed by Mukaiyama et al. A general experimental procedure for trifluoromethylation is shown by taking trifluoromethylation with respect to diisopropyl squarate shown in the following reaction formula as an example.

A stirring bar was placed in a Schlenk tube and dried by heating under reduced pressure. Diisopropyl squarate (3- ⁱ Pr) (99.9 mg, 0.50 mmol), sodium acetate (NaOAc) (4.2 mg, 0.05 mmol), tetrabutylammonium chloride ^{_{(n Bu 4 NCl) (13.8mg}} , 0.05mmol), was added tetrahydrofuran (THF) (1mL). The mixture was stirred at 25 ° C. for 15 minutes, and trifluoromethyltrimethylsilane (Me ₃ SiCF ₃ ) (111 μL, 0.75 mmol) was added. After stirring for 20 minutes, disappearance of the raw materials was confirmed, and tetrabutylammonium fluoride (TBAF) 1M THF solution (1 mL, 1 mmol) was added to stop the reaction. Water (20 mL) was added and the mixture was extracted with Et ₂ O (20 mL × 3). The obtained organic layer was washed with saturated brine (10 mL), dried over MgSO ₄ and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain a white solid (92.4 mg, yield 69%). The analysis results of the obtained compound are shown below.

The analysis was performed by the following method. ^{For 1} H · ¹³ C · ¹⁹ FNMR measurement, ESC-400 (400 Hz) manufactured by JEOL Ltd. was used. CDCl ₃ was used as a measurement solvent, and NMR measurement was performed at 25 ° C. All chemical shifts of ¹ H · ¹³ C · ¹⁹ F NMR are expressed in δ values (ppm). ^In the case of ¹ H NMR measurement, a singlet (7.26 ppm) derived from CHCl ₃ is used as a reference peak, and in the case of ¹³ C NMR measurement, a triplet (77.0 ppm) derived from CHCl ₃ is used as a reference peak, and ¹⁹ F The chemical shift of NMR was based on the singlet signal (-63.7 ppm) of α, α, α-trifluorotoluene as an external standard. The chemical shift splitting pattern is defined as follows. s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sext: sextet, sept: septet, m: multiplet. Coupling constants are expressed in Hz. The infrared absorption spectrum (IR) was measured using FT / IR-230 manufactured by JASCO Corporation, and all characteristic absorptions were expressed in cm ⁻¹ . MPS100 made by SRS was used for the melting point measurement. For mass spectrometry, JMS-T100LP manufactured by JEOL Ltd. was used, and high-resolution mass spectrometry by DART or ESI was performed.

Here, although the method of trifluoromethylation using diisopropyl squarate as a starting material has been described in detail, trifluoromethylation can be carried out in the same manner using other squarate esters as shown below. Other trifluoromethylation can be carried out in the same manner using a Schlenk tube or a two-necked eggplant flask. Desilylation can be performed by adding TBAF (2 equivalents) or saturated aqueous potassium fluoride (1 mL).

Trifluoromethylation was performed using dipropyl squarate as a starting material, and a compound of the following formula (2-1): 4-hydroxy-2,3-dipropyoxy-4- (trifluoromethyl) cyclobut-2-enone (2- ⁿ Pr) Was synthesized. The yield was 40%. The analysis results of the obtained compound are shown below.

The squaric acid diisobutyl performed trifluoromethyl into the starting material, the following formula (2-2) compound of, 4-hydroxy-2,3-diisobutoxy -4- (trifluoromethyl) cyclobut-2-enone (2- i Bu) Was synthesized. The yield was 40%. The analysis results of the obtained compound are shown below.

Trifluoromethylation was performed using disec-butyl squarate as a starting material, and a compound of the following formula (2-3), 2,3-di-sec-butyl-4-hydroxy-4- (trifluoromethyl) cyclobut-2- Oneone (2- ^s Bu) was synthesized. The yield was 65%. The analysis results of the obtained compound are shown below.

Tritert-butyl squarate is used as a starting material, and trifluoromethylation is carried out to obtain a compound of the following formula (2-4): 2,3-di-tert-butyl-4-hydroxy-4- (trifluoromethyl) cyclobut-2- en-1-one (2- ^t Bu) was synthesized. The yield was 90%. The analysis results of the obtained compound are shown below.

1.2 Allyl alcohol transfer reaction step Next, an allyl alcohol transfer reaction represented by the following reaction formula is performed. A general experimental procedure for hydroxyl group transfer reaction will be described by taking as an example the synthesis of 1- ⁱ Pr (11) by hydroxyl group transfer reaction using a Re ₂ O ₇ catalyst.

A stirring bar was placed in the Schlenk tube, and after heating and drying under reduced pressure, the atmosphere was replaced with argon. 2- ⁱ Pr (128.5 mg, 0.48 mmol) and Re ₂ O ₇ (7.8 mg, 0.016 mmol) were added, and argon substitution was performed again. Dichloromethane (25 mL) was added and stirred at 25 ° C. for 10 hours. After completion of the reaction, the mixture was filtered through alumina under an argon stream, and the filtrate was concentrated to obtain a yellow liquid (99.2 mg, 99%). The obtained liquid was solidified by standing for a long time or cooling. The analysis result of the obtained compound is shown.

Here, the method for synthesizing a trifluoromethyl-substituted semisquarate by 2- ⁱ Pr allylic alcohol transfer reaction has been described in detail. However, as shown below, other hydroxycyclobutenones can be used to form allyl alcohol. Alcohol transfer reactions can be performed. Other allyl alcohol transfer reactions can be performed in the same manner using a Schlenk tube or a two-necked eggplant flask.

The ^2-n Pr performed allyl alcohol rearrangement reaction starting materials, compounds of formula (11-1), 3-propoxy- 4- (trifluoromethyl) were synthesized cyclobut-3-ene-1,2- dione. Purification was carried out by a short column using Al ₂ O ₃ as a filler (developing solvent was dichloromethane), and the yield was 62%. The analysis results of the obtained compound are shown below.

The ^2-i Bu performed allyl alcohol rearrangement reaction starting materials, compounds of formula (11-2), 3-isobutoxy- 4- (trifluoromethyl) were synthesized cyclobut-3-ene-1,2- dione. Purification was performed by a short column (developing solvent was dichloromethane) using Al ₂ O ₃ as a filler, and the yield was 50%. The analysis results of the obtained compound are shown below.

It performed allyl alcohol rearrangement reaction of ^2-s Bu starting materials, compounds of formula (11-3) was synthesized 3-sec-butoxy-4- ( trifluoromethyl) cyclobut-3-ene-1,2-dione . Purification was performed by a short column using Al ₂ O ₃ as a filler (developing solvent was dichloromethane), and the yield was 34%. The analysis results of the obtained compound are shown below.

Performed allyl alcohol rearrangement reaction of ^2-t Bu in the starting materials, compounds of formula (2-4), was synthesized 3-tert-butoxy-4- ( trifluoromethyl) cyclobut-3-ene-1,2-dione . The yield was 78%. However, it was extremely unstable, and purification was carried out under a short column (developing solvent was dichloromethane) with Al ₂ O ₃ / K ₂ CO ₃ as a filler, and concentration was also carried out under argon. The analysis results of the obtained compound are shown below.

[Example 2]
≪Method for producing trifluoromethyl-substituted semisquarate (2) ≫
It is also possible to produce a trifluoromethyl-substituted semisquarate continuously by the following method. Purification is only the distillation operation in the last step, and the reaction can be performed more simply and efficiently.

A trifluoromethyl-substituted semisquarate (Compound 1- ⁱ Pr) was synthesized from 3 g of commercially available diisopropyl squalate (Compound 3- ⁱ Pr) by continuously performing the two steps shown in the following reaction formula. The yield was 84%. Hereinafter, the synthesis method will be described in detail.

A Schlenk tube was charged with a stirring bar and dried under reduced pressure. Diisopropyl squarate (2.98 g, 15 mmol), sodium acetate (61.0 mg, 0.74 mmol), tetrabutylammonium chloride (206.2 mg, 0.74 mmol), THF (15 mL) was added. The mixture was stirred at 25 ° C for 20 minutes, and trifluoromethyltrimethylsilane (3.1 mL, 21 mmol) was added. After stirring for 90 minutes, disappearance of the raw materials was confirmed, tetrabutylammonium fluoride 1M THF solution (21 mL, 21 mmol) was added, and the mixture was stirred for 15 minutes. Water (30 mL) was added and extracted with Et ₂ O (30 mL × 3). The obtained organic layer was washed with saturated brine (30 mL) and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Got.

Next, an allyl alcohol transfer reaction is performed. The crude product was transferred to a 100 mL two-necked flask, dried under reduced pressure for 2 hours, and purged with argon. Re ₂ O ₇ (218 mg, 0.45 mmol, 3 mol%) was added in the glove bag, diluted with dehydrated dichloromethane (35 mL) and stirred for 10 hours. After confirming the disappearance of the raw materials, after concentration, purification was performed using a Kugelrohr distiller (3 hPa, 70 ° C.) to obtain a yellow solid (2.61 g, yield 84%). A compound similar to Example 1 could be obtained.

[Example 3]
≪Synthesis of physiologically active substance analogues (1) ≫
A method for synthesizing a physiologically active substance analog starting from the compound of the general formula (1) synthesized by the method of Example 1 or 2 is described below.

A quinone having a trifluoromethyl group introduced therein is synthesized by an addition reaction step, a ring expansion reaction and an oxidation reaction step. The production method will be described in detail by taking as an example the production of 2-isopropoxy-3- (trifluoromethyl) naphthalene-1,4-dione (12). The following reaction formula is an outline of the production method.

First, a Grignard reagent solution is prepared. PhMgBr (manufactured by Aldrich) (910 μL of 1.1 M THF solution or 333 μL of 3.0 M Et ₂ O solution; 1 mmol) was added to a container heated and dried under reduced pressure, diluted with dry ether, stirred for 30 minutes, 0.1 M Et ₂ O solution.

Next, an addition reaction is performed. A stir bar, 1- ⁱ Pr (104.2 mg, 0.5 mmol) and diethyl ether (2 mL) were added to a 50 mL two-necked eggplant flask heated and dried under reduced pressure, and cooled to -90 ° C. The temperature in the system was measured with a thermometer, and the prepared Grignard reagent solution was added dropwise at a rate of 20 mL / h over 30 minutes using a syringe pump while taking care not to reach a temperature of −90 ° C. or higher. After further stirring for 30 minutes, disappearance of the raw material was confirmed by NMR, and the reaction was stopped by adding a saturated aqueous ammonium chloride solution (2 mL) while maintaining at −90 ° C., and the temperature was returned to room temperature. The mixture was extracted with Et ₂ O (10 mL × 3), washed with saturated brine (10 mL), dried over sodium sulfate, and p-xylene (10 mL) was added.

Ring expansion reaction and oxidation reaction are performed as follows. Et ₂ O was removed with a rotary evaporator to obtain a p-xylene solution (about 10 mL). The resulting solution was purged with argon and stirred at 140 ° C. for 10 minutes. After confirming the disappearance of 4-hydroxycyclobutenone as an intermediate product, the mixture was cooled to room temperature. Phthalocyanine iron (II) complex [Fe (pc)] (8.4 mg, 0.015 mmol) and acetic acid (0.5 mL) were added and stirred for 1 hour in an oxygen atmosphere. After confirming the disappearance of hydroquinone, cerite filtration and concentration were performed to obtain a crude product.

Purification was performed by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain a yellow liquid (103.8 mg, yield 73%). The analysis results of the obtained compound, 2-isopropoxy-3- (trifluoromethyl) naphthalene-1,4-dione, are shown below.

[Example 4]
≪Synthesis of physiologically active substance analogues (2) ≫
2-isopropoxy-6-methyl-3- (trifluoromethyl) naphthalene-1,4-dione, whose structural formula is shown in the following formula (13), is obtained by using 4-methylmagnesium bromide (non-non-crystalline) as a Grignard reagent with aryl bromide and magnesium metal. It was manufactured in the same manner as in Example 3 except that Patent Documents 23 and 24) were prepared and used.

The yield was 58%. The analysis results of the obtained compound are shown below.

[Example 5]
≪Synthesis of physiologically active substance analogues (3) ≫
2-isopropoxy-6-methoxy-3- (trifluoromethyl) naphthalene-1,4-dione, whose structural formula is shown in the following (14), is obtained by using 4-methoxyphenymagnesium bromide (manufactured by Aldrich) as a Grignard reagent. Was produced in the same manner as in Example 3.

The yield was 63%. The analysis results of the obtained compound are shown below.

[Example 6]
≪Synthesis of bioactive substance analogues (4) ≫
2-isopropoxy-5-methoxy-3- (trifluoromethyl) naphthalene-1,4-dione, whose structural formula is shown in (15) below, is obtained by using 2-methoxyphenymagnesium bromide (manufactured by Aldrich) as a Grignard reagent. Was produced in the same manner as in Example 3.

The yield was 49%. The analysis results of the obtained compound are shown below.

[Example 7]
≪Synthesis of physiologically active substance analogues (5) ≫
6-chloro-2-isopropyoxy-3- (trifluoromethyl) naphthalene-1,4-dione, whose structural formula is represented by the following formula (16), is obtained by using 4-chlorophenylmagnesium bromide (manufactured by Aldrich) as a Grignard reagent. Was produced in the same manner as in Example 3.

The yield was 65%. The analysis results of the obtained compound are shown below.

[Example 8]
≪Synthesis of physiologically active substance analogues (6) ≫
6-fluoro-2-isopropoxy-3- (trifluoromethyl) naphthalene-1,4-dione, whose structural formula is represented by the following formula (17), used 4-fluorophenylmagnesium bromide (manufactured by Aldrich) as a Grignard reagent. Others were produced in the same manner as in Example 3.

[Example 9]
≪Synthesis of bioactive substance analogues (7) ≫
Ethyl 6-isopropoxy-5,8-dioxo-7- (trifluoromethyl) -5,8-dihydroxynaphthalene-2-carboxylate having the structural formula shown in the following formula (17-1) is p-ethoxycarbonylphenylmagnesium chloride as a Grignard reagent. It was manufactured in the same manner as in Example 3 except that (Non-patent Document 25) was used.

[Example 10]
≪Synthesis of physiologically active substance analogues (8) ≫
3-isopropoxy-2- (trifluoromethyl) phenanthrene-1,4-dione, whose structural formula is represented by the following formula (18), was used in Examples except that 1-naphthylmagnesium bromide (manufactured by Aldrich) was used as a Grignard reagent. 3 was produced in the same manner as in No. 3.

The yield was 32%. The analysis results of the obtained compound are shown below.

[Example 11]
≪Synthesis of bioactive substance analogues (9) ≫
2-isopropoxy-3- (trifluoromethyl) phenanthrene-1,4-dione, which has the structural formula shown in the following formula (19), is 2-naphthylmagnesium bromide prepared by using aryl bromide and magnesium metal as a Grignard reagent (non-patent literature) 23 and 24) were used in the same manner as in Example 3.

The yield was 62%. The analysis results of the obtained compound are shown below.

[Example 12]
≪Synthesis of physiologically active substance analogues (10) ≫
6-isopropoxy-5- (trifluoromethyl) benzofuran-4,7-dione, which has the structural formula shown in the following formula (20), is 2-furylmagnesium bromide prepared from an organolithium reagent using MgBr ₂ as a Grignard reagent. It was manufactured in the same manner as in Example 3 except that Patent Documents 26 and 27) were used.

The yield was 69%. The analysis results of the obtained compound are shown below.

[Example 13]
≪Synthesis of bioactive substance analogues (11) ≫
6-isopropoxy-5- (trifluoromethyl) benzo [b] thiophene-4,7-dione, whose structural formula is shown in the following formula (21), was prepared from an organolithium reagent using MgBr ₂ as a Grignard reagent. It was manufactured in the same manner as in Example 3 except that thienylmagnesium bromide (Non-patent Documents 26 and 27) was used.

The yield was 78%. The analysis results of the obtained compound are shown below.

[Example 14]
≪Synthesis of bioactive substance analogues (12) ≫
3-isopropoxy-2- (trifluoromethyl) dibenzo [b, d] furan-1,4-dione, whose structural formula is shown in the following formula (22), was prepared from an organolithium reagent using MgBr ₂ as a Grignard reagent. The product was prepared in the same manner as in Example 3 except that 2-benzofurylmagnesium bromide (Non-patent Documents 26 and 27) was used.

The yield was 73%. The analysis results of the obtained compound are shown below.

[Example 15]
≪Synthesis of bioactive substance analogues (13) ≫
3-isopropoxy-2- (trifluoromethyl) dibenzo [b, d] thiophene-1,4-dione, whose structural formula is shown in (23) below, was prepared from an organolithium reagent using MgBr ₂ as a Grignard reagent. It was manufactured in the same manner as in Example 3 except that thienylmagnesium bromide (Non-patent Documents 26 and 27) was used.

The yield was 74%. The analysis results of the obtained compound are shown below.

[Example 16]
≪Synthesis of bioactive substance analogues (14) ≫
Tert-butyl 2-isopropoxy-1,4-dioxo-3- (trifluoromethyl) -1,4-dihydro-9H-carbazole-9-carboxylate, which has the structural formula shown in the following formula (24), and a structure shown in the following (25) The tert-butyl 2- (3-isopropoxy-5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl) -1H-indole-1-carboxylate having the formula is used as a Grignard reagent as 2-iodo By using N-Boc-2-indole magnesium bromide (Non-patent Document 28) prepared from indole, it can be obtained simultaneously by carrying out the production in the same manner as in Example 3.

The yield of tert-butyl 2-isopropoxy-1,4-dioxo-3- (trifluoromethyl) -1,4-dihydro-9H-carbazole-9-carboxylate (compound represented by the structural formula (24)) is 24%. Met. The analysis results of the obtained compound are shown below.

tert-butyl 2- (3-isopropoxy-5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl) -1H-indole-1-carboxylate (compound represented by structural formula (25)) The yield of was 23%. The analysis results of the obtained compound are shown below.

[Example 17]
≪Synthesis of bioactive substance analogues (15) ≫
The tert-butyl 3-isopropoxy-1,4-dioxo-2- (trifluoromethyl) -1,4-dihydro-9H-carbazole-9-carboxylate having the structural formula shown in the following (26) is a 3-iodo as a Grignard reagent. This was prepared in the same manner as in Example 3 except that N-Boc-3-indole magnesium bromide (Non-patent Document 29) prepared from an indole derivative was used.

The yield was 70%. The analysis results of the obtained compound are shown below.

[Example 18]
≪Synthesis of physiologically active substance analogues (16) ≫
2-isopropoxy-5,6-dimethyl-3- (trifluoromethyl) cyclohexa-2,5-diene-1,4-dione having the structural formula shown in the following formula (27) is 1-methyl-1- Production was carried out in the same manner as in Example 3 except that propenyl magnesium bromide (manufactured by Aldrich) was used.

The yield was 42%. The analysis results of the obtained compound are shown below.

[Example 19]
≪Synthesis of bioactive substance analogues (17) ≫
3-isopropoxy-2- (trifluoromethyl) dibenzo [b, d] thiophene-1,4-diyl diacetate, whose structural formula is shown in the following formula (28), was prepared from an organolithium reagent using MgBr ₂ as a Grignard reagent An addition reaction was performed using benzothienylmagnesium bromide (Non-patent Documents 26 and 27). The p-xylene solution (about 10 ml) obtained after the addition reaction was transferred to a two-necked eggplant flask. The atmosphere was replaced with argon and heated at 140 ° C. for 10 minutes. The disappearance of the raw material was confirmed by TLC analysis and cooled to room temperature.

Acetic anhydride (472 μL, 5 mmol) and pyridine (403 μL, 5 mmol) were added with a syringe, and N, N-dimethylaminopyridine (6.3 mg, 0.05 mmol) was further added under an argon stream to perform acetylation. After stirring for 5 minutes, disappearance of hydroquinone was confirmed by TLC analysis. The solvent was removed under reduced pressure to give the crude product. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain a pale yellow solid (160.3 mg, 75%).

The analysis results of the obtained compound are shown below.

[Example 20]
≪Synthesis of bioactive substance analogues (18) ≫
2-isopropoxy-4-oxo-3- (trifluoromethyl) -4H-quinolizin-1-yl acetate represented by the following formula (29) is an organolithium reagent prepared from 2-bromopyridine, 2-pyridyllithium ( After performing an addition reaction using Non-Patent Document 30), acetic anhydride (2.2 equivalents) was added to stop the reaction. The p-xylene solution (about 10 ml) obtained after the addition reaction was transferred to a two-necked eggplant flask. The atmosphere was replaced with argon and heated at 100 ° C. for 30 minutes. The disappearance of the raw material was confirmed by TLC analysis and cooled to room temperature. The solvent was removed under reduced pressure to give the crude product. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain a brown liquid (88.1 mg, 54%).

The analysis results of the obtained compound are shown below.

[Example 21]
≪Synthesis of bioactive substance analogues (19) ≫
7-isopropoxy-5-oxo-6- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-8-yl acetate represented by the following formula (30) is an organolithium reagent prepared from thiazole, It was produced in the same manner as in Example 20 except that 2-thiazolyl lithium (Non-patent Document 30) was used.

The yield was 48%. The analysis results of the obtained compound are shown below.

[Example 22]
≪Synthesis of physiologically active substance analogues (20) ≫
7-isopropoxy-1-methyl-5-oxo-6- (trifluoromethyl) -1,5-dihydroimidazo [1,2-a] pyridin-8-yl acetate represented by the following formula (31) is N- This was prepared in the same manner as in Example 20 except that the organolithium reagent prepared from methylimidazole (1-methyl-1H-imidazol-2-yl) lithium (Non-patent Document 30) was used.

The yield was 55%. The analysis results of the obtained compound are shown below.

[Example 23]
≪Synthesis of bioactive substance analogues (21) ≫
Butenolides can be synthesized by the following method. The method for synthesizing butenolides is described in detail by taking 3-isopropoxy-5-oxo-2-phenyl-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl acetate as a structural formula shown in the following formula (32) as an example. To do.

A PhMgBr 3.0 M ether solution (Aldrich, 415 μL, 1.25 mmol) was diluted with dehydrated diethyl ether (12.1 mL), adjusted to a concentration of about 0.1 M and used.

To a dried eggplant flask under an argon atmosphere, trifluoromethyl-substituted semisquarate (1- ⁱ Pr) (104.3 mg, 0.5 mmol) and dehydrated diethyl ether (2 mL) were added and cooled to -90 ° C. The prepared 0.1M PhMgBr ether solution (10 mL, 1.0 mmol) was maintained at −90 ° C. or lower with a thermometer and added dropwise at a rate of 20 mL / h. After completion of the dropwise addition, the mixture was further stirred for 30 minutes, and a saturated ammonium chloride aqueous solution (10 mL) was added under a condition of −90 ° C. to stop the reaction, and then the temperature was raised to room temperature. Extraction was performed with Et ₂ O (10 mL × 3), and the obtained organic layer was washed with saturated brine (10 mL), dried over Na ₂ SO ₄ and concentrated to obtain a crude product.

Pb (OAc) ₄ (445.2 mg, 1.0 mmol) and dehydrated toluene (2 mL) were added to a Schlenk tube dried and placed in an argon atmosphere, and stirred for 10 minutes. To this solution, a dehydrated toluene (1 mL) solution of the above crude product was added using a cannula. Stirring was continued at room temperature for 1 hour, the reaction was stopped by adding water (10 mL), and the brown precipitate formed at this time was filtered through celite with dichloromethane to obtain a two-phase solution. The aqueous layer was extracted with dichloromethane (10 mL × 3), and the obtained organic layer was washed with saturated brine (10 mL) and dried over Na ₂ SO ₄ . The crude product obtained by concentration was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain a colorless liquid (131.9 mg, 77%). The analysis results are shown below.

[Example 24]
≪Synthesis of bioactive substance analogues (22) ≫
3-isopropoxy-2- (4-methoxyphenyl) -5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl acetate, which has the structural formula shown in the following formula (33), is replaced with PhMgBr. This was prepared in the same manner as in Example 23 except that -MeOC ₆ H ₄ MgBr was used. The yield was 74%. The analysis results are shown below.

[Example 25]
≪Synthesis of physiologically active substance analogues (23) ≫
In the following formula (34), ethyl 4- (2-acetoxy-3-isopropoxy-5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl) benzoate is substituted for PhMgBr. It was produced in the same manner as in Example 23 except that p-EtO ₂ CC ₆ H ₄ MgBr was used. The yield was 65%. The analysis results are shown below.

[Example 26]
≪Synthesis of bioactive substance analogues (24) ≫
In the following formula (35), 2- (benzofuran-2-yl) -3-isopropoxy-5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl acetate is used instead of PhMgBr. This was prepared in the same manner as in Example 23 except that 2-benzofurylMgBr was used. The yield was 62%. The analysis results are shown below.

[Example 27]
≪Synthesis of physiologically active substance analogues (25) ≫
2- (benzo [b] thiophen-2-yl) -3-isopropoxy-5-oxo-4- (trifluoromethyl) -2,5-dihydrofuran-2-yl acetate, which is represented by the following formula (36), is: Production was carried out in the same manner as in Example 23 except that 2-benzothienylMgBr was used instead of PhMgBr. The yield was 68%. The analysis results are shown below.

[Example 28]
≪Synthesis of physiologically active substance analogues (26) ≫
Bicyclo ring compounds can be synthesized by the following method. 2-isopropoxy-7-oxo-1- (trifluoromethyl) bicycle [3.2.0] hept-2-en-3-yl acetate, which is a bicyclo ring compound having the structural formula shown in the following formula (37), is a novel compound. The precursors 10-3a and 10-3b were produced as follows.

Allylmagnesium chloride 2.0 M THF solution (Aldrich, 625 μL, 1.25 mmol) was diluted in dehydrated diethyl ether (11.9 mL) and used as an approximately 0.1 M solution.

1- ⁱ Pr (104.3 mg, 0.5 mmol) was added to a 50 mL eggplant flask that had been heat-dried and purged with argon, and dehydrated ether (2 mL) was added. The solution was cooled to −90 ° C., and the prepared about 0.1 M allylmagnesium chloride Et ₂ O solution (12.5 mL, 1.25 mmol) was added dropwise at a rate of 20 mL / h. After the addition, the mixture was further stirred for 1 hour. . The reaction was quenched with saturated aqueous ammonium chloride (10 ml) and allowed to warm to room temperature. Extraction was performed with diethyl ether (10 mL × 3), and the obtained organic layer was washed with saturated brine (10 mL) and then dried over Na ₂ SO ₄ . The crude product obtained by concentration was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain a pale yellow solid (10-3a, 51.6 mg, 41%).

A precursor compound (196 mg, 0.78 mmol) having a structural formula represented by the formula (10-3a) was added to 30 mL double necked eggplant and diluted with dehydrated diethyl ether (8 mL). To this solution were added acetyl chloride (110 μL, 1.56 mmol) and triethylamine (216 μL, 1.56 mmol), and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction was quenched with H ₂ O (20 mL) and extracted with ether (20 mL × 3). The crude product obtained by concentration was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain a colorless liquid (10-3b, 177.7 mg, 78%).

A precursor compound (73.1 mg, 0.25 mmol) having the structural formula shown in Formula (10-3b) was dissolved in p-xylene (5 mL). This solution was stirred at 120 ° C. for 1 hour. The crude product obtained by cooling to room temperature and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: chloroform = 1: 2), and the compound represented by the structural formula in formula (37) was purified as a colorless liquid ( 64.4 mg, 88%). The yield of the final product represented by Formula 37 was 88%. The analysis results are shown below.

The analysis results of the intermediate compounds 10-3a and 10-3b were as follows.

[Example 29]
≪Synthesis of bioactive substance analogues (27) ≫
When the synthesis was carried out using an allyl Grignard reagent, the yield of the intermediate compound 10-3a was low. Therefore, the compound 2-isopropoxy-7-oxo-1- (trifluoromethyl) bicycle described in Example 28 was used. 3.2.0] Synthesis was limited to hept-2-en-3-yl acetate. Therefore, by developing the following method using an allyl silicon compound, the yield of the compound represented by 10-3a was successfully improved.

The heat-dried Schlenk tube was filled with argon, 1- ⁱ Pr (52.4 mg, 0.25 mmol) was added, and the mixture was diluted with dehydrated dichloromethane (1.5 mL). This solution was cooled to −78 ° C., a 1.0 M solution of tin tetrachloride in dichloromethane (250 μL, 0.25 mmol) was added, and allylsilane (manufactured by TCI, 60 μL, 0.375 mmol) was added, and the mixture was added at −78 ° C. for 10 minutes. After stirring, the mixture was stirred for 1 hour in an ice bath. Purified water (10 mL) was added to stop the reaction, and the temperature was raised to room temperature, followed by extraction with dichloromethane (10 mL × 3). The obtained organic layer was washed with saturated brine (10 mL) and then Na ₂ SO _4. And dried. Neutral silica gel (500 mg) and dichloromethane (0.5 mL) were added to the crude product obtained by concentration, and the mixture was stirred at room temperature for 30 minutes to remove the silyl group. When the disappearance of the silyl ether intermediate was confirmed by TLC analysis, the mixture was concentrated by a rotary evaporator, and the obtained crude product was subjected to silica gel column chromatography (developing solvent used hexane / ethyl acetate = 4: 1). To give a pale yellow solid (10-3a, 59.6 mg, 95%).

[Example 30]
≪Synthesis of bioactive substance analogues (28) ≫
As described above, since the yield of the compound represented by 10-3a was improved, it was possible to synthesize the following compounds. 4-hydroxy-3-isopropyoxy-4- (2-phenylallyl) -2- (trifluoromethyl) cyclobut-2-enone represented by the following formula (38) is trimethyl (2-phenylallyl) silane instead of allylsilane. This was manufactured in the same manner as in Example 29 except that (Non-patent Document 31) was used. The yield was 94%. The analysis results are shown below.

[Example 31]
≪Synthesis of bioactive substance analogues (29) ≫
2-isopropoxy-4-oxo-1- (2-phenylallyl) -3- (trifluoromethyl) cyclobut-2-ethyl acetate is represented by the following structural formula (39) in the same manner as compound 10-3b of Example 28. Manufactured. The yield was 93%. The analysis results are shown below.

[Example 32]
≪Synthesis of bioactive substance analogues (30) ≫
2-isopropoxy-7-oxo-5-phenyl-1- (trifluoromethyl) bicyclo [3.2.0] hept-2-en-3-yl acetate is shown in Example 28. It was manufactured by heating for 1 hour in the same manner. The yield was 96%. The analysis results are shown below.

[Example 33]
≪Synthesis of bioactive substance analogues (31) ≫
4-hydroxy-3-isopropoxy-4- (2-methylenoxyl) -2- (trifluoromethyl) cyclobut-2-enone, which has the structural formula shown in the following formula (41), is trimethyl (2-methylenecylyl) instead of allylsilane. This was manufactured in the same manner as in Example 29 except that (Non-patent Document 31) was used. The yield was 97%. The analysis results are shown below.

[Example 34]
≪Synthesis of physiologically active substance analogues (32) ≫
2-isopropoxy-1- (2-methylenoxyl) -4-oxo-3- (trifluoromethyl) cyclobut-2-ethyl acetate represented by the following structural formula (42) is the same as compound 10-3b of Example 28. Manufactured. The yield was 98%. The analysis results are shown below.

[Example 35]
≪Synthesis of physiologically active substance analogues (33) ≫
5-hexyl-2-isopropyoxy-7-oxo-1- (trifluoromethyl) bicycle [3.2.0] hept-2-en-3-yl acetate, which is represented by the following formula (43), is obtained in Example 28. It was manufactured by heating for 1 hour in the same manner. The yield was 95%. The analysis results are shown below.

[Example 36]
≪Synthesis of physiologically active substance analogues (34) ≫
2-isopropoxy-4-oxo-1- (1-phenylallyl) -3- (trifluoromethyl) cyclobut-2-ethyl acetate is represented by the following formula (44) in the same manner as in Example 29. Instead, titanium tetrachloride was allylated at −40 ° C. using cinnamethyltrimethylsilane (Non-patent Document 32) instead of allylsilane, and then the same as compound 10-3b of Example 28 without isolating the resulting alcohol. To be directly acylated. Obtained as a 7: 3 diastereomeric mixture, the yield was 38% in two steps. The analysis results are shown below.

[Example 37]
≪Synthesis of physiologically active substance analogues (35) ≫
2-isopropoxy-7-oxo-4-phenyl-1- (trifluoromethyl) bicycle [3.2.0] hept-2-en-3-yl acetate represented by the following structural formula (45) is obtained in Example 28. It was manufactured by heating in the same manner for 3 hours. The yield was 75%. The analysis results are shown below.

[Example 38]
≪Synthesis of physiologically active substance analogues (36) ≫
4-acetoxy-3-isopropoxy-4a, 5,6,7-tetrahydro-2a- (trifluoromethyl) -1H-cyclobuta [c] pentapentalen-2 (2aH) -one, which has the structural formula shown in the following formula (46), In the same manner as in Example I, allylation was carried out using trimethylsilane (Non-patent Document 31) instead of allylsilane. The product was acetylated in the same manner as Compound 10-3b of Example 28 without isolating the alcohol, and the resulting ester was prepared by heating for 2 hours in the same manner as in Example 28 without isolation. The yield was 42% in three stages. The analysis results are shown below.

[Example 39]
≪Synthesis of physiologically active substance analogues (37) ≫
Aminocyclopentenedione can be synthesized by the following method. 2-Butyl-2- (tert-butylamino) -4-isopropoxy-5- (trifluoromethyl) cyclo-4-ene-1,3-dione, which is an aminocyclopentenedione whose structural formula is shown in the following formula (47), is as follows: It manufactured as follows.

The imidoyllithium reagent was prepared based on the method of Liebeskid et al. (Non-patent Document 33). Tert-butyl isocyanide (85 μL, 0.75 mmol) was dissolved in diethyl ether (2.02 mL) and cooled to −15 ° C. ⁿ BuLi (15 w / w%, 480 μL) was added and stirring was continued at −15 ° C. for 30 minutes. The resulting solution was cooled to −78 ° C. for use in subsequent addition reactions.

A solution of 1- ⁱ Pr (104.3 mg, 0.5 mmol) in dehydrated diethyl ether (10 mL) was cooled to -78 ° C. To this solution was added approximately 0.3 M imidoyllithium reagent (1.7 mL, 0.5 mmol) pre-cooled to −78 ° C. with a syringe and stirring was continued for 30 minutes. The reaction was quenched with a saturated aqueous ammonium chloride solution (10 mL), and then the temperature was raised to room temperature. Extraction was performed with diethyl ether (10 mL × 3), and the obtained organic layer was washed with saturated brine (10 mL) and then dried over Na ₂ SO ₄ . The crude product obtained by concentration was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain a dark red solid (87.2 mg, 50%). The yield was 50%. The analysis results are shown below.

[Example 40]
≪Synthesis of bioactive substance analogues (38) ≫
The unsaturated carboxylic acid which is a ring-opening compound can be synthesized by the following method. (Z) -4-acetoxy-3-isopropyoxy-6-phenyl-2- (trifluoromethyl) hex-3-en-5-ynoic acid represented by the structural formula of the following formula (48) was produced as follows. .

In a dried Schlenk tube, phenylacetylene (120 μL, 1.1 mmol) was dissolved in dehydrated diethyl ether (2.0 mL) and cooled to −78 ° C. ⁿ BuLi (15 w / w%, 640 μL) was added and stirred at room temperature for 2 hours until the solution became cloudy. Thereafter, dehydrated diethyl ether (1.36 mL) was added to give a 0.25 M solution (pale yellow).

1- ⁱ Pr (104.2 mg, 0.5 mmol) and dehydrated diethyl ether (2 mL) were added to a 50 mL two-necked eggplant flask and cooled to -90 ° C. Lithium phenylacetylide 0.25 M ether solution (2.0 mL, 0.5 mmol) was added dropwise at a rate of 10 mL / h. After dropping, the mixture was stirred for 1 hour, acetic anhydride (105 μL, 1.11 mmol) was added, and stirring was further continued for 30 minutes. The reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL) and the temperature was raised to room temperature. Extraction was performed with diethyl ether (20 mL), and the resulting aqueous layer was neutralized with 10% aqueous HCl. The neutralized aqueous layer was extracted with diethyl ether (20 mL × 3), and the combined organic layer was washed with saturated brine (20 mL) and dried over Na ₂ SO ₄ . The crude product obtained by concentration was purified by sulfuric acid silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a yellow liquid (132.1 mg, 71%). The analysis results are shown below.

[Example 41]
≪Synthesis of physiologically active substance analogues (39) ≫
4-hydroxy-3-isopropyoxy-4- (2-oxo-2-phenylethyl) -2- (trifluoromethyl) cyclobut-2-enone, whose structural formula is shown in the following formula (49), was synthesized as follows. .

The heat-dried Schlenk tube was filled with argon, 1- ⁱ Pr (62.4 mg, 0.30 mmol) was added, and the mixture was diluted with dehydrated dichloromethane (2.0 mL). The solution was cooled to −78 ° C., a 1.0 M solution of tin tetrachloride in dichloromethane (300 μL, 0.30 mmol) was added, and the mixture was stirred for 10 minutes. Trimethyl (1-phenylvinyloxy) silane (184 μL, 0.90 mmol) separately prepared (Non-patent Document 34) was added to this solution, and the mixture was stirred at −78 ° C. for 2 hours. Purified water (10 mL) was added to stop the reaction, and the temperature was raised to room temperature, followed by extraction with dichloromethane (10 mL × 3). The obtained organic layer was washed with saturated brine (10 mL) and then Na ₂ SO _4. And dried. The organic layer was concentrated by a rotary evaporator, and the resulting crude product was purified by silica gel column chromatography (developing solvent was hexane / ethyl acetate = 4: 1), and a pale yellow liquid (84.7 mg, 86 %). The analysis results of the obtained compound are shown below.

[Example 42]
≪Synthesis of bioactive substance analogues (40) ≫
Benzyl 2- (1-hydroxy-2-isopropyoxy-4-oxo-3- (trifluoromethyl) cyclobut-2-enyl) acetate having the structural formula shown in the following formula (50) is tin tetrachloride in the same manner as in Example 41. Instead of trimethyl (1-phenylvinyloxy) silane, (1- (benzoyloxy) vinyloxy) trimethylsilane (Non-patent Document 35) was used instead of trimethyl (1-phenylvinyloxy) silane. The yield was 86%. The analysis results are shown below.

[Example 43]
≪Synthesis of bioactive substance analogues (41) ≫
4-isopropoxy-5- (2-oxo-2-phenylethylidene) -3- (trifluoromethyl) furan-2 (5H) -one, whose structural formula is shown in the following formula (51), was synthesized as follows.

The heat-dried Schlenk tube was filled with argon, and Pb (OAc) ₄ (348.6 mg, 0.79 mmol), heat-dried molecular sieves 4A powder (400.2 mg), and dehydrated toluene (4.0 mL) were added. To this suspension was added 4-hydroxy-3-isopropoxy-4- (2-oxo-2-phenylethyl) -2- (trifluoromethyl) cyclobut-2-enone (129.0 mg, 0.39 mmol) at room temperature. Stir for 1 hour. Purified water (10 mL) was added to this solution to stop the reaction, and insoluble matters were filtered. The filtrate was extracted with ethyl acetate (10 mL × 3), and the obtained organic layer was washed with saturated NaHCO ₃ (10 mL) and dried over Na ₂ SO ₄ . The crude product obtained by concentrating the organic layer with a rotary evaporator was diluted in THF (8 mL), N-methyl morpholine (48 μL, 0.43 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated with an evaporator, and the resulting crude product was purified by silica gel column chromatography (developing solvent used was hexane / ethyl acetate = 6: 1) to give a yellow solid (97.1 mg, 76%). Got. The analysis results of the obtained compound are shown below.

[Example 44]
≪Synthesis of bioactive substance analogues (42) ≫
Benzyl 2- (3-isopropoxy-5-oxo-4- (trifluoromethyl) furan-2 (5H) -ylidene) acetate having the structural formula shown in the following formula (52) was produced in the same manner as in Example 43. The yield was 84%. The analysis results are shown below.

≪Applicability of trifluoromethyl-substituted semisquarate≫
If the method for synthesizing a trifluoromethyl-substituted semisquarate of the present invention is used, application to the following compounds having known physiological activities can be expected.

≪Applicability (1) ≫
The compound having the structure represented by the above formula (13), 2-isopropoxy-6-methyl-3- (trifluoromethyl) naphthalene-1,4-dione, is an analog of the compound Paravaquinon exhibiting cell division inhibitory activity. Paravaquinone has been reported to exhibit cell division inhibitory activity in fertilized eggs of the sea urchin. Furthermore, it has been reported that its analog 3-ethyl-2-hydroxy-6-methylnaphthalene-1,4-dione exhibits similar activity (Non-patent Document 36). The trifluoromethyl-substituted naphthoquinone of the compound represented by the formula (13) synthesized in Example 4 is considered to have the same physiological activity.

≪Applicability (2) ≫
Furaquinocins exhibit a wide range of physiological activities such as in vitro cytotoxicity and platelet coagulation inhibitory activity against HeLaS3 and B16 melanoma cells. Among them, Fraquinocin A, B, and E shown below are synthesized using semisquarate 40 of the reaction formula shown below (Non-patent Document 37). Therefore, the use of trifluoromethyl-substituted semisquarate 1- ⁱ Pr makes it possible to synthesize trifluoromethyl analogues of Furaquinocins.

≪Applicability (3) ≫
The antimalarial active substance (−)-Elisapterosin B has also been achieved in total synthesis from semisquarate 41 shown in the following reaction formula (Non-patent Document 38). Therefore, if trifluoromethyl-substituted semisquarate is used, application to a trifluoromethyl-substituted antimalarial compound can be considered.

≪Possibility of application (4) ≫
Carbazomycins show antifungal activity and antibacterial activity, and recently, synthesis of Carbazimycin G using semisquarate 1 has been reported (Non-patent Document 39). The compound represented by the formula (26) synthesized in Example 17 is a trifluoromethyl compound as a precursor when synthesizing Carbazimycin G. Therefore, it is possible to synthesize a trifluoromethyl substituted Carbazimycin G analog using the precursor compound.

As described above, a trifluoromethyl group can be introduced into various compounds by the production method of the present invention.

According to the synthesis method of the present invention, various trifluoromethyl compounds that have been difficult to synthesize can be efficiently obtained.

Claims

Starting from a compound represented by the following general formula (1),

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
Addition reaction process,
And a method for producing a compound into which a trifluoromethyl group has been introduced by a ring expansion step.
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a quinone compound.
A quinone compound in which a trifluoromethyl group is introduced,
The production method according to claim 2, which is a compound represented by the following general formula (4) or (5).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl and sec-butyl. R 1 , R 2 , R 3 and R 4 are each independently hydrogen, alkyl Selected from a group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, any two adjacent substituents of R 1 to R 4 may form a condensed benzene, wherein alkyl The hydrocarbon moiety of the group, alkenyl group and alkoxy group may be any of C1 to C8 linear, branched or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group and sec-butyl group. R 5 and R 6 are each independently hydrogen, alkyl group, alkenyl group, (It is selected from an alkoxy group, a chloro group, and a fluoro group, wherein the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a heterocyclic condensed ring compound.
A heterocyclic condensed ring compound into which a trifluoromethyl group is introduced is
The production method according to claim 4, which is a compound represented by the following general formula (6) or (7).

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R 7 and R 8 are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R 7 and R 8 may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. X is CH═CH, S, NCH 3 )
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a hydroquinone compound.
A hydroquinone compound having a trifluoromethyl group introduced,
The production method according to claim 6, which is a compound represented by any one of the following general formulas (8) to (10).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl and sec-butyl. R 9 , R 10 , R 11 and R 12 are each independently hydrogen, Selected from an alkyl group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, and any two adjacent substituents of R 9 to R 12 may form a condensed benzene, where (The hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R 13 and R 14 are each independently hydrogen, alkyl group, alkenyl group, (It is selected from an alkoxy group, a chloro group, and a fluoro group, wherein the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, and a sec-butyl group. R 15 and R 16 are each independently hydrogen, an alkyl group, an alkenyl group, Selected from an alkoxy group, a chloro group and a fluoro group, R 15 and R 16 may combine to form a condensed benzene, X is O, S or NP, and P is a carbamate or sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a butenolide compound.
Butenolide compounds into which a trifluoromethyl group has been introduced
The production method according to claim 8, which is a compound represented by the following general formula (10-1) or (10-2).

Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl, and sec-butyl. R 17 , R 18 , R 19 , and R 20 are each independently hydrogen, Selected from an alkyl group, an alkenyl group, an alkoxy group, a chloro group, a fluoro group, and an ester group, and any two adjacent substituents of R 17 to R 20 may form a condensed benzene, where (The hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)

(Wherein R is selected from isopropyl group, n-propyl group, t-butyl group, isobutyl group, sec-butyl group. R 21 and R 22 are each independently hydrogen, alkyl group, alkenyl group, Selected from an alkoxy group, a chloro group, and a fluoro group, R 21 and R 22 may combine to form a condensed benzene, X is O, S, NP, and P is a carbamate, sulfonamide. Here, the hydrocarbon moiety of the alkyl group, alkenyl group, or alkoxy group may be any of C1 to C8 linear, branched, or cyclic.)
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a four-membered ring compound.
A four-membered ring compound into which a trifluoromethyl group is introduced is
The production method according to claim 10, which is a compound represented by the following general formula (10-3c) or (10-3d).

(Wherein R 23 and R 24 are each independently selected from a C1-C6 linear, branched, cyclic alkyl group or a phenyl group.)

(Wherein R 25 and R 26 are each independently selected from a C1-C6 linear, branched, cyclic alkyl group or phenyl group.)
The compound into which the trifluoromethyl group is introduced is
The production method according to claim 1, which is a bicyclo ring compound.
A bicyclo ring compound introduced with a trifluoromethyl group is
The production method according to claim 12, which is a compound represented by the following general formula (37-1).

(Wherein R 27 and R 28 are each independently selected from a C1-C6 linear, branched, or cyclic alkyl group or a phenyl group, and R 27 or R 28 may form a ring structure) .)
The compound into which the trifluoromethyl group is introduced is
The process according to claim 1, which is an aminocyclopentenedione compound.
An aminocyclopentenedione compound into which a trifluoromethyl group is introduced is
The production method according to claim 14, which is a compound represented by the following general formula (10-4).

(Wherein R is selected from isopropyl, n-propyl, t-butyl, isobutyl, sec-butyl, R 29 is a C1-C8 alkyl group, linear, branched, cyclic) R 30 is selected from a t-butyl group or a 1,1,3,3-tetramethylbutyl group.)
A method for producing a trifluoromethyl-substituted semisquarate represented by the following general formula (1):

By the step of trifluoromethylating a squarate represented by the following general formula (3):

A compound represented by the following general formula (2) is produced,

A production method comprising synthesizing by a step of performing an allyl alcohol transfer reaction.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
A method for producing a trifluoromethyl-substituted semisquarate represented by the following general formula (1):

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
A compound represented by the following general formula (2)

A production method comprising synthesizing by a step of performing an allyl alcohol transfer reaction.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
A method for producing a trifluoromethyl-substituted semisquarate according to claim 16 or 17,
The step of carrying out the allyl alcohol transfer reaction
A production method, which is a reaction using Re 2 O 7 or Ph 3 SiReO 3 as a catalyst.
A method for producing a compound represented by the following general formula (2),

The squarate represented by the following general formula (3)

A production method comprising synthesizing by a trifluoromethylation step.
(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
The manufacturing method according to claim 16 or 19,
The trifluoromethylation step comprises:
Performing a silyl trifluoromethylation reaction using CF 3 Me 3 Si as an organosilicon reagent;
A production method comprising a desilylation step.
A compound represented by the following general formula (1).

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group.)
A compound of the following general formula (2).

(In the formula, R is an isopropyl group, an n-propyl group, a t-butyl group, an isobutyl group, or a sec-butyl group, which may be different groups or the same group.)
Trifluoromethyl compounds represented by the following formulas (12) to (52), (17-1), (10-3a), and (10-3b).