JP4617446B2 - NOVEL THIOPHENE COMPOUND, AND PROCESS FOR PRODUCING CAFE OFFRAN OR ITS ANALOGUE USING THE SAME - Google Patents

Description

  The present invention relates to a novel thiophene compound. In addition, the present invention relates to a method for producing caffeine offrans or analogs thereof (hereinafter collectively referred to as “cafeoffrans”) using the novel thiophene compound as an intermediate raw material. The novel thiophene compound of the present invention is useful as an intermediate for the synthesis of caffeofurans, which are aromatic component substances. Furthermore, the present invention relates to a novel thiophene compound (hereinafter also referred to as “aroma thiophene compound” in order to distinguish it from the thiophene compound), which itself has fragrance and can be effectively used as an odor component substance.

  Caffe offran (compound name: 2,3-dihydro-6-methylthieno [2,3-c] furan) was isolated by M. Stoll et al. In 1963 as a characteristic aroma component substance present in coffee. It is a compound (Non-patent Document 1). The structure was determined by G. Buchi et al., And was clarified to have the structure shown in the following formula, and was named caffeo-off run (Non-patent Document 2).

Conventional methods for synthesizing cafe-off run include the method by G. Buchi et al. (Non-Patent Document 2), the method by E. Brenna et al. (Non-Patent Documents 3 and 4), and the method by D. Rewicki et al. (Non-Patent Document 5). Although known, none of them are efficient. Specifically, the method of G. Buchi et al. Is a method of synthesizing caffeofuran in 3 steps using 4,5-dihydrothiophene-3 (2H) -one as a raw material. In addition to the problem that the yield of is low, there are other problems such as the formation of two types of products by the Grignard reaction in the second step. The method of E. Brenna et al. Requires as many as 10 steps from the raw material. In the method of D. Rewicki et al., Although the total yield is 12%, it is difficult to obtain 3,4-dibromofuran as a raw material. Thus, none of the conventional synthesis methods can be said to be efficient, and there is a problem as an industrial mass production method.
Helv.Chim.Acta, 50,628, (1967) J. Org. Chem., 36,199, (1971) J. Chem. Research (S), 74, (1998) J. Chem. Research (M), 551, (1998) Liebigs Ann.Chem., 625, (1986)

  The present invention has been made for the purpose of solving the conventional problems relating to the synthesis of the above-mentioned cafe-off-run. Specifically, an object of the present invention is to provide an efficient method for synthesizing caffeine offran or its analogs (cafeoffrans). It is another object of the present invention to provide a novel thiophene compound that can be effectively used as a raw material or a synthetic intermediate for efficiently synthesizing the caffeofranes. Furthermore, an object of the present invention is to provide a novel aromatic thiophene compound useful as an aromatic component substance produced using the thiophene compound as a raw material or a synthetic intermediate, and a method for producing the same.

  In view of the above-mentioned problems, the present inventors have conducted extensive research to develop a method for producing caffeofurans useful as an aroma component substance efficiently in a short process. It has been found that by reacting under a hydrogen atmosphere using a metal catalyst, cyclization occurs simultaneously with the reduction, and caffeofurans having a 2,3-dihydrothieno [2,3c] furan skeleton can be produced in one step. The present inventor has found that the thiophene compound is a novel compound that can be produced in a short process from an easily available raw material, and uses this novel reaction as a raw material or synthetic intermediate for the purpose of the present invention. It was confirmed that a certain cafe-off run could be produced efficiently. The present invention has been completed based on such findings.

That is, the present invention is a novel thiophene compound shown in the following item 1.
Item 1. A thiophene compound represented by the general formula (1):

[Wherein, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or an alcohol protecting group, R ³ is a hydrogen atom, —COR ⁴ group or —C (OH) R ⁵ group. (Wherein R ⁴ and R ⁵ are each a lower alkyl group having 1 to 4 carbon atoms). However, when R ² and R ³ are hydrogen atoms, R ¹ is neither a hydrogen atom, a methyl group, nor an n-propyl group. ].

Moreover, this invention is a manufacturing method of the caffeofran or its analog using the said novel thiophene compound shown to the following items 2-4:
Item 2. Production of a caffeophthalan represented by the general formula (3a) or an analog thereof having a step of reducing and cyclizing the thiophene compound represented by the general formula (2) in the presence of a transition metal catalyst in a hydrogen atmosphere. Method:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
Item 3. Item 3. The production method according to Item 2, wherein the transition metal catalyst is a rhodium catalyst.

Item 4. Steps A to D represented by the following formula:
Step A: Protect the hydroxyl group of compound (4) to obtain compound (5) Step B: Step of acylating compound (5) to obtain compound (6) Step C: Compound (6) above A step of deprotecting to obtain compound (7), and step D: a step of reducing and cyclizing compound (2) in the presence of a transition metal catalyst in a hydrogen atmosphere. A method for producing caffeine offran or its analog represented by:

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ^{2 ′} represents an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms).

The present invention also provides a novel café furan analog listed in Item 5:
Item 5. 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan, 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan, or 4-ethyl-2, 3-Dihydrothieno [2,3c] furan.

Furthermore, this inventor confirmed that the novel thiophene compound which has fragrance property can be manufactured by using the novel thiophene compound as described in said item 1 as a raw material. Based on this finding, the present invention further provides a novel thiophene compound (aromatic thiophene compound) useful as an aroma component substance, and a method for producing the same, as described in items 6 and 7 below:
Item 6. A thiophene compound represented by the following general formula (7):

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms).
Item 7. The manufacturing method of the thiophene compound (7) of claim | item 6 which has the process of cyclizing the compound (8) shown by the following Formula:

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms).

The above-mentioned cafe-off run and its analog (3a) and the novel thiophene compound (7) described in Item 6 above have fragrance and are useful as fragrance component substances. Accordingly, the present invention relates to the use of caffeofuran or an analog thereof, which is an aroma component substance, and the novel thiophene compound (7) as shown in the following items 8 and 9:
Item 8. Café off-run represented by the general formula (3) or an analog thereof:

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ^{4 ′} represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms),
And a fragrance composition comprising at least one compound selected from the group consisting of the thiophene compound (7) according to item 6 and a ratio of 10 ⁻² to 10 ⁶ ppb.
Item 9. Café off-run represented by the general formula (3) or an analog thereof:

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ^{4 ′} represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms),
And a food / beverage product comprising at least one compound selected from the group consisting of the thiophene compound (7) of Item 6 in a ratio of 10 ⁻³ to 10 ⁹ ppb.

  According to the present invention, it is possible to provide a novel thiophene compound and a method for producing caffeofuran or an analog thereof using the novel thiophene compound as an intermediate raw material. The novel thiophene compound of the present invention is useful as an intermediate for the synthesis of caffeofurans, which are aromatic component substances. Furthermore, according to the present invention, it is possible to provide a novel thiophene compound (fragrance thiophene compound) which itself has aroma and can be effectively used as an aroma component substance.

(1) Novel thiophene compound The present invention relates to a thiophene compound represented by the following general formula (1).

Here, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. Specifically, the lower alkyl group has 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t-butyl group. A lower alkyl group can be exemplified. Preferably, it is a hydrogen atom or a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group.

R ² represents a hydrogen atom or an alcohol protecting group. As the alcohol protecting group, a wide variety of known groups used in the art for protecting the hydroxyl group of alcohol can be used. Although not limited, specifically, tetrahydrofuranyl group (THF group), tetrahydropyranyl group (THP group), methoxymethyl group (MOM group), t-butyldimethylsilyl group (TBDMS group), acetyl group, ethoxy Examples thereof include a methyl group (EOM group) and a benzyloxymethyl group (BOM group). A tetrahydropyranyl group (THP group) and a methoxymethyl group (MOM group) are preferred.

R ³ is a hydrogen atom, a group represented by —COR ⁴ , or a group represented by —C (OH) R ⁵ . Here, R ⁴ and R ⁵ both represent a lower alkyl group having 1 to 4 carbon atoms. Specifically, the lower alkyl group has 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t-butyl group. A lower alkyl group can be exemplified. Preferably, it is a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group.

  The thiophene compound (1) provided by the present invention can be broadly classified into the following three groups [thiophene compounds (A) to (C)].

(I) Thiophene compound (A)

(Wherein R ^{2 ′} represents an alcohol protecting group.)
The thiophene compound (A) corresponds to the thiophene compound in the case where R ¹ and R ³ are both hydrogen atoms in the general formula (1). Here, as the alcohol protecting group, any of those mentioned above can be mentioned. Preferably, it is a tetrahydropyranyl group (THP group). As the thiophene compound (A) having such an alcohol protecting group, 2- (3-thienylmethyloxy) tetrahydro-2H-pyran described in Example 1 (1) is preferable. (Compound (b)).

  The thiophene compound (A) can be easily synthesized by protecting the hydroxyl group of thiophene-3-methanol with an alcohol protecting group according to a conventional method (Step A).

(Wherein R ^{2 ′} represents an alcohol protecting group.)
Specifically, as shown in Example 1, it can be carried out by reacting thiophene-3-methanol with an alcohol protecting agent. The reaction conditions are not particularly limited, and can be carried out, for example, under pH conditions corresponding to the alcohol protecting agent used. Specifically, neutral conditions can be suitably used when tetrahydrofuran, which will be described later, is used as the alcohol protecting agent, and acidic conditions when 3,4-dihydro-2H-pyran is used.

  As alcohol protectants, depending on the alcohol protecting group to be bonded, tetrahydrofuran (in the case of a THF group), 3,4-dihydro-2H-pyran (in the case of a THP group), chloromethyl methyl ether (in the case of a MOM group), Examples thereof include t-butyldimethylsilyl chloride (in the case of TBDMS group), acetic anhydride (in the case of acetyl group), chloromethyl ethyl ether (in the case of EOM group), and chloromethyl benzyl ether (in the case of BOM group). Preferred is 3,4-dihydro-2H-pyran or chloromethyl methyl ether.

  Such a reaction can be usually carried out under conditions of −10 ° C. to 80 ° C. using a solvent corresponding to the type of alcohol protective agent used, such as dichloromethane, tetrahydrofuran, ethyl acetate, ether, toluene, acetonitrile, pyridine and the like. .

  In addition, this reaction can be performed under an acidic catalyst by adding an acidic catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, or pyridium as necessary (for example, when the reaction is performed under acidic conditions). .

(Ii) Thiophene compound (B)

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
The thiophene compound (B) corresponds to the thiophene compound in the case where R ³ is —COR ⁴ in the general formula (1). The lower alkyl group is preferably a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group, in which either R ¹ or R ⁴ is selected. Examples of the alcohol protecting group include any of those described above, and a tetrahydropyranyl group (THP group) is preferable.

Specific examples of the compound included in the thiophene compound (B) include, as described in Examples 1 to 3, R ¹ is a hydrogen atom, R ² is an alcohol protecting group, and R ⁴ is a methyl group or an ethyl group. 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-ethanone (compound (c)) or 1 which is a lower alkyl group having 1 or 2 carbon atoms such as a group -{3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-propanone (compound (f)), and R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ⁴ 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d)) or 1- [3 is a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group And-(hydroxymethyl) -2-thienyl] -1-propanone (compound (g)). Also, as described in Examples 6, 9 and 10, R ¹ is a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group, R ² is an alcohol protecting group, and R ⁴ is a carbon such as a methyl group or an ethyl group. 1- {3-[(tetrahydro-2H-2-pyranyloxy) ethyl] -2-thienyl} -1-propanone (compound (D)), 1- {3- [ (Tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-ethanone (compound (U)), and 1- {3-[(tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-propanone (compound (X)) can be mentioned. The thiophene compound (B-1) (compounds (c) and (f)) in which R ¹ is a hydrogen atom and R ² is an alcohol protecting group is as described above in Examples 1 to 3. It can be synthesized by acylating the thiophene compound (A) according to a conventional method (step B).

(In the formula, R ^{2 ′} represents an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
Specifically, as shown in Step B of Examples 1 to 3, this reaction can be performed by reacting the thiophene compound (A) with an alkyl metal reagent and then reacting with an acylating reagent. it can. Such a reaction is usually performed under conditions of −100 ° C. to 20 ° C. using a solvent corresponding to the type of acyl group to be bonded, such as tetrahydrofuran, dichloromethane or toluene.

  Here, examples of the alkyl metal reagent include, but are not limited to, n-butyllithium, sec-butyllithium, and t-butyllithium. Preferred is n-butyllithium. The ratio of the alkyl metal reagent used is not particularly limited, but is usually 1 to 1.5 mol, preferably 1 to 1.1 mol, relative to 1 mol of the thiophene compound (A).

  Examples of the acylating reagent include, but are not limited to, acetic anhydride, propionic anhydride, acetyl chloride, and propionyl chloride. Acetic anhydride and propionic anhydride are preferred. The ratio of the acylating reagent to be used is not particularly limited, but is usually 1 to 3 mol, preferably 1 to 1.2 mol, relative to 1 mol of the thiophene compound (A).

The thiophene compound (B-2) (compounds (d) and (g)) in which R ¹ and R ² are both hydrogen atoms is obtained by using the thiophene compound obtained above as shown in Examples 1 and ( B-1) The alcohol protecting group (where R ² is an alcohol protecting group) can be synthesized by deprotecting according to a standard method (Step C).

(In the formula, R ^{2 ′} represents an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
Specifically, as shown in Step C of Examples 1 and 3, the thiophene compound (B-1) is reacted with an organometallic reagent or by reacting with an alcohol in the presence of an acidic catalyst. can do. Such a reaction is usually performed at −30 ° C. to 80 ° C. using a solvent such as dichloromethane, methanol, ethanol, propanol, or toluene.

  Here, examples of the organometallic reagent include, but are not limited to, dimethylaluminum chloride and diethylaluminum chloride. Preferred is dimethylaluminum chloride. The ratio of the organometallic reagent to be used is not particularly limited, but is usually 1 to 3 mol, preferably 2 to 2.5 mol with respect to 1 mol of the thiophene compound (B-1).

  Moreover, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, pyridinium, etc. can be illustrated as an acidic catalyst. Furthermore, examples of alcohol include ethanol and methanol.

The thiophene compounds targeted by the present invention (B), both of R ¹ and R ⁴ are a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, a thiophene compound wherein R ² is a hydrogen atom (B-3) is included. Specifically, in 1- [3- (1-hydroxyethyl))-2-thienyl] -1-ethanone (compound (j)) described in Example 4 (2), Example 6 (4) 1- [3- (1-hydroxyethyl))-2-thienyl] -1-propanone (compound (E)), described in Example 9 (2), 1- [3- (1-hydroxy Propyl))-2-thienyl] -1-ethanone (compound (V)) and 1- [3- (1-hydroxypropyl))-2-thienyl] -1- described in Example 10 (2) An example is propanone (compound (Y)). Such a thiophene compound (B-3) (for example, the compound (j) described in Example 4) is prepared by, for example, converting thiophene-3-methanol into step A (protection of a hydroxyl group), as shown in Examples 1 to 3. Subject to Step B (acylation) and Step C (deprotection) to 2-acylthiophene-3-methanol [1- [2- (hydroxymethyl) -2-thienyl] -1-alkanone] (eg, compound ( c) or (g)), and then the obtained 2-acylthiophene-3-methanol is oxidized as shown by the following formula (step (i)) to give the aldehyde compound (2- Acyl-3-thiophenecarbaldehyde: can be synthesized by alkylating compound (i)) (step (ii)).

(In the formula, R ¹ and R ⁴ are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms.)
Specifically, in step (i), as shown in Example 4 (1), for example, 2-acylthiophene-3-methanol (for example, compound (d)) is converted to metal oxide such as manganese dioxide or magnesium oxide. Can be carried out by oxidation in the presence of. In addition, the oxidation reaction can also be carried out by a method of reacting oxalyl chloride, dicyclohexylcarbodiimide, acid anhydride, or chlorine in dimethyl sulfoxide, and a method of reacting dimethyl sulfide and N-chlorosuccinimide. Such a reaction is usually carried out using a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, ether, or dimethyl sulfoxide under the conditions of -30 ° C to 100 ° C.

  Further, step (ii) can be carried out by reacting the aldehyde compound obtained in step (i) above with an organometallic reagent as shown in Example 4 (2). Such a reaction is usually performed at −30 ° C. to 100 ° C. using a solvent such as tetrahydrofuran, dichloromethane, ether, or toluene. Here, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide, butylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, etc. can be used as the organometallic reagent.

Furthermore the thiophene compound a hydroxyl group of (B-3), by protecting an alcohol protecting agent according to a conventional method, none of R ¹ and R ⁴ are a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, A thiophene compound (B-4) in which R ^{2 ′} is an alcohol protecting group can be synthesized.

(In the formula, R ¹ and R ⁴ are the same or different, a lower alkyl group having 1 to 4 carbon atoms, and R ^{2 ′} represents an alcohol protecting group.)
(Iii) Thiophene compound (C)

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or an alcohol protecting group, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms.)
Such a thiophene compound (C) corresponds to the thiophene compound in the case where R ³ is —C (OH) R ⁵ in the general formula (1). The lower alkyl group is preferably a lower alkyl group having 1 or 2 carbon atoms, such as a methyl group or an ethyl group, in which either R ¹ or R ⁵ is selected. Examples of the alcohol protecting group include any of those described above, and a tetrahydropyranyl group (THP group) is preferable.

As a suitable compound contained in the thiophene compound (C), specifically, as described in Example 5, R ¹ and R ² are both hydrogen atoms, and R ⁵ is a carbon such as a methyl group or an ethyl group. 1- (3-hydroxymethyl-2-thienyl) -1-ethanol (compound (l)) or 1-{(3-hydroxymethyl) -2-thienyl}-which is a lower alkyl group of the number 1 or 2 Mention may be made of 1-propanol (compound (n)). The thiophene compound (C-1) in which R ¹ is a hydrogen atom, R ² is a hydrogen atom or an alcohol protecting group, and R ⁵ is a lower alkyl group is, as shown in Example 5, the thiophene compound described above It can be synthesized by reducing (B-1) or (B-2) according to a conventional method (step (iii)).

(In the formula, R ² represents a hydrogen atom or an alcohol protecting group, and R ⁴ and R ⁵ represent the same lower alkyl group having 1 to 4 carbon atoms.)
Further, the thiophene compound (C-2) in which R ¹ is a lower alkyl group, R ² is a hydrogen atom or an alcohol protecting group, and R ⁵ is a lower alkyl group can be prepared by the thiophene compound described above according to the method of Example 5. Compound (B-3) can be synthesized by reduction according to a conventional method (step (iii)).

(Wherein R ¹ represents a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or an alcohol protecting group, and R ⁴ and R ⁵ represent the same lower alkyl group having 1 to 4 carbon atoms.)
Although these reduction reactions are not limited, as shown in Example 5, the thiophene compound (B) (thiophene compound (B-1), (B-2) or (B-3)) is converted into, for example, aluminum hydride. It can be carried out by reacting with a metal hydride such as lithium or sodium borohydride. Such a reaction can be usually carried out at a temperature of -20 ° C to 50 ° C using a solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate, ether, or toluene.

  In the above-described method for producing each thiophene compound, the post-treatment operation after completion of each reaction is not particularly limited. For example, after completion of the reaction, the obtained reaction solution is concentrated under reduced pressure and then chromatographed using silica gel ( For example, it can be subjected to any purification operation such as silica gel collection thin layer chromatography, silica gel column chromatography, etc.), distillation, recrystallization and the like.

  The thiophene compound (1) thus obtained can be effectively used as a raw material or a synthetic intermediate for efficiently producing caffeofuran or an analog thereof useful as an aroma component substance, as will be described later.

(2) Method for producing cafe-off run or its analog
(2-1) The present invention provides a novel method for producing a caffeofloran represented by the general formula (3a) or an analog thereof (hereinafter also referred to as a caffeolane).

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
Here, the lower alkyl group represented by R ¹ or R ⁴ may be the same or different and includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and t. Examples thereof include lower alkyl groups having 1 to 4 carbon atoms such as -butyl group. Preferably, it is a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group. Caffeofuran (chemical name: 6-methyl-2,3-dihydrothieno [2,3c] furan) is a 2,3- (3-) compound in which R ¹ is a hydrogen atom and R ⁴ is a methyl group in the above general formula (3). This is a compound having a dihydrothieno [2,3c] furan skeleton (2,3-dihydrothieno [2,3c] furan compound). As an analog of such caffeosilane, it is preferable that in the general formula (3), R ¹ is a hydrogen atom and R ⁴ is an ethyl group [chemical name: 6-ethyl-2,3-dihydrothieno [2, [3c] furan] (compound (h)): dimethyl caffeophthalan [chemical name: 4,6-dimethyl-2,3-dihydrothieno [2,3c] furan] in which both R ¹ and R ⁴ are methyl groups ( Compound (k)): 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan (compound (F)) in which R ¹ is a methyl group and R ⁴ is an ethyl group (compound (F)): R ¹ is an ethyl group , ⁴ -ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan (compound (W)) in which R ⁴ is a methyl group: 4,6- in which both R ¹ and R ⁴ are ethyl groups Mention may be made of diethyl-2,3-dihydrothieno [2,3c] furan (compound (Z)).

  Such caffeine offlanes (3) can be synthesized by reducing and cyclizing the thiophene compound represented by the general formula (2) (step D). The thiophene compound (2) corresponds to the thiophene compound (B-2) or (B-3) described above.

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)
Specifically, the cafe-off-lanes (3a) are synthesized by reacting the thiophene compound (2) [(B-2) or (B-3)] described above using a transition metal catalyst in a hydrogen atmosphere. can do.

  Although it does not restrict | limit as a transition metal catalyst, For example, a rhodium catalyst and a palladium catalyst can be mentioned. A rhodium catalyst is preferred, and tris (triphenylphosphine) rhodium (I) chloride is more preferred. The amount of the transition metal catalyst to be used is not particularly limited, but it can be generally used in a ratio of 0.001 to 0.5 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of the thiophene compound (2).

  The hydrogen atmosphere is not particularly limited, but preferably a hydrogen gas atmosphere in which the gas pressure is in the range of 0.1 MPa to 5 MPa, more preferably a hydrogen gas atmosphere in which the gas pressure is in the range of 0.5 MPa to 2 MPa is exemplified. it can.

  The reaction conditions are not particularly limited, but usually, the transition metal catalyst and the solvent are added to the reaction vessel, and the thiophene compound (2) is dissolved in the solvent and added to about 50 to 150 ° C, preferably 80 to 120 ° C. It is carried out by heating and stirring at a temperature of 0 ° C. for 0.5 to 48 hours, preferably about 2 to 24 hours.

  The solvent used in the reaction here is not limited, but preferably includes a benzene solvent such as benzene, toluene and xylene, or a chlorine solvent such as methylene chloride.

  After completion of the above reaction, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then subjected to chromatography using silica gel (for example, silica gel collection thin layer chromatography, silica gel column chromatography, etc.), distillation, recrystallization, etc. The product may be subjected to any purification operation, and thus the caffeoflorans (3a) which are the target compound of the present invention can be obtained. The transition metal catalyst used in the method of the present invention can be recovered and reused by a known method.

  The thiophene compound (2) used as a raw material in the production of the above-mentioned cafe-off-lanes can be prepared according to the above-described method for producing the thiophene compound (B-2) or (B-3).

  The method for producing the café-off run (3a) of the present invention includes a method represented by the following formula.

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ^{2 ′} represents an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms).

  The said method can be implemented by following process AD.

Step A : A hydroxyl group of a compound represented by the chemical formula (4) [thiophene-3-methanol (when R ¹ is a hydrogen atom) or 3- (1-hydroxyalkyl) thiophene (when R ¹ is a lower alkyl group)] It is a process of protecting. Specifically, this step involves alcohol protection of the compound (4) [thiophene-3-methanol, 3- (1-hydroxyalkyl) thiophene] in the presence of an acidic catalyst or under neutral or basic conditions. It can be carried out by reacting with an agent. Alcohol protecting agents include tetrahydrofuran, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, t-butyldimethylsilyl chloride, acetic anhydride, chloromethyl ethyl ether, chloromethyl benzyl, depending on the alcohol protecting group to be bound. Mention may be made of ethers. Preferred is 3,4-dihydro-2H-pyran.

  Such a reaction can be usually carried out under conditions of −10 ° C. to 80 ° C. using a solvent according to the type of alcohol protecting agent used, such as dichloromethane, tetrahydrofuran, ethyl acetate, ether, toluene, acetonitrile or pyridine. . In addition, this reaction can be performed in the presence of an acidic catalyst by adding an acidic catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, pyridium, if necessary. Thus, the compound represented by the chemical formula (5) can be obtained.

Step B : Compound (5) obtained in Step A above [for example, when 3,4-dihydro-2H-pyran is used as an alcohol protecting agent, 2- (3-thienylmethyloxy) tetrahydro-2H-pyran (R ¹ (when ¹ is a hydrogen atom) or 2- (1-alkyl-1- (3-thienyl) methyloxy) tetrahydro-2H-pyran (when R ¹ is a lower alkyl group)].

  Specifically, this step can be carried out by reacting compound (5) with an alkyl metal reagent and then with an acylating reagent. Such a reaction can be carried out usually at −100 ° C. to 20 ° C. using a solvent such as tetrahydrofuran, dichloromethane or toluene.

  Here, examples of the alkyl metal reagent include, but are not limited to, n-butyllithium, sec-butyllithium, and t-butyllithium. Preferred is n-butyllithium. The ratio of the alkyl metal reagent to be used is not particularly limited, but can be usually 1 to 1.5 mol, preferably 1 to 1.1 mol, relative to 1 mol of compound (5).

  Examples of the acylating reagent include, but are not limited to, acetic anhydride, propionic anhydride, acetyl chloride, and propionyl chloride. Acetic anhydride and propionic anhydride are preferred. The ratio of the acylating reagent to be used is not particularly limited, but can be usually 1 to 3 mol, preferably 1 to 1.2 mol, relative to 1 mol of compound (5). Thus, the compound represented by the chemical formula (6) can be obtained.

Step C : a step of removing (deprotecting) the alcohol protecting group of the compound (6) obtained in Step B.

  Specifically, such a step can be carried out by reacting compound (6) with an organometallic reagent or by reacting with an alcohol in the presence of an acidic catalyst. Such a reaction can be usually carried out under a condition of −30 ° C. to 80 ° C. using a solvent such as dichloromethane, methanol, ethanol, propanol or toluene.

  Here, examples of the organometallic reagent include, but are not limited to, dimethylaluminum chloride and diethylaluminum chloride. Preferred is dimethylaluminum chloride. The ratio of the organometallic reagent to be used is not particularly limited, but is usually 1 to 3 mol, preferably 2 to 2.5 mol, relative to 1 mol of compound (6). Examples of the acidic catalyst include sulfuric acid, hydrochloric acid, (±) -camphorsulfonic acid, pyridinium p-toluenesulfonate, and the like. Furthermore, ethanol, methanol, etc. can be illustrated as alcohol. Thus, the compound represented by the chemical formula (2) can be obtained.

Step D : A step of reducing and cyclizing the compound (2) obtained in Step C. Such a step can be carried out by reacting compound (2) with a transition metal catalyst in a hydrogen atmosphere. The specific method, the type of transition metal catalyst and the ratio thereof are as described above.

Thus, the café-off-lan has the compound (4) [thiophene-3-methanol (when R ¹ is a hydrogen atom) or 3- (1-hydroxyalkyl) thiophene (when R ¹ is a lower alkyl group)]. It can be efficiently synthesized as a starting material. Therefore, according to such a method, it is possible to industrially mass-produce café-off run in a short process.

  The thus obtained cafe-off-lanes (3a) (2,3-dihydrothieno [2,3c] furan compound) has a unique aroma depending on the type of the compound and is useful as an aroma component substance. For example, when a 0.000005% by weight dilute aqueous solution is used, caffeine offran exhibits a roasted nut-like aroma, a vegetable-like green aroma, or a caramel-like sweet aroma. In addition, ethyl caffeofloran has a sweet, roasted scent when it is used as a 0.000005% by weight diluted aqueous solution, and dimethyl caffeofran has a bluish green bean-like shape when used as a 0.000005% by weight diluted aqueous solution. A scent, or a green scent of vegetables, or a fresh scent.

Further, as caffeolanes (3a), 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan (compound (F)) in which R ¹ is a methyl group and R ⁴ is an ethyl group (Example (F)) 6): 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan (compound (W)) (Example 9) in which R ¹ is an ethyl group and R ⁴ is a methyl group A novel compound in the literature, Compound (F) has a nut-like scent and Compound (W) has a spicy scent. In addition, 4,6-diethyl-2,3-dihydrothieno [2,3c] furan (compound (Z)) (Example 10) in which R ¹ and R ⁴ are both ethyl groups has a dry nut-like fragrance. Have.

  (2-2) The present invention also provides a method for producing an analog of caffeofloran represented by the general formula (3b) (hereinafter also referred to as caffeofrancs (3b)).

(In the formula, R ¹ represents a lower alkyl group having 1 to 4 carbon atoms.)
As the caffeofran analog (3b), 4-methyl-2,3-dihydrothieno [2,3c] furan (compound (L)) in which R ¹ is a methyl group in the general formula (3b) is preferable: 4-ethyl-2,3-dihydrothieno [2,3c] furan (compound (T)) in which R ¹ is an ethyl group can be given. The latter 4-ethyl-2,3-dihydrothieno [2,3c] furan is a novel document.

  Such caffeine offlanes (3b) can be synthesized by reducing and cyclizing the compound represented by the following formula (9) (Step J).

(In the formula, R ¹ represents a lower alkyl group having 1 to 4 carbon atoms.)
Specifically, the caffeofurans (3b) can be synthesized by reacting the compound (9) with a transition metal catalyst in a hydrogen atmosphere. Although it does not restrict | limit as a transition metal catalyst, For example, a rhodium catalyst and a palladium catalyst can be mentioned. A rhodium catalyst is preferred, and tris (triphenylphosphine) rhodium (I) chloride is more preferred. Although the amount of the transition metal catalyst used is not particularly limited, it can be used usually in a proportion of 0.001 to 0.5 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of the compound (9).

  The hydrogen atmosphere is not particularly limited, but preferably a hydrogen gas atmosphere in which the gas pressure is in the range of 0.1 MPa to 5 MPa, more preferably a hydrogen gas atmosphere in which the gas pressure is in the range of 0.5 MPa to 2 MPa is exemplified. it can.

  Although there is no particular limitation on the reaction conditions, usually, the transition metal catalyst and the solvent are added to the reaction vessel, and the compound (9) is dissolved in the solvent and added to about 50 to 150 ° C, preferably 80 to 120 ° C. At a temperature of 0.5 to 48 hours, preferably 2 to 24 hours. The solvent used in the reaction here is not limited, but preferably includes a benzene solvent such as benzene, toluene and xylene, or a chlorine solvent such as methylene chloride.

  After completion of the above reaction, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then subjected to chromatography using silica gel (for example, silica gel collection thin layer chromatography, silica gel column chromatography, etc.), distillation, recrystallization, etc. The product may be subjected to any purification operation, and thus the caffeofranes (3b), which is the target compound of the present invention, can be obtained. The transition metal catalyst used in the method of the present invention can be recovered and reused by a known method.

  The method for producing cafe-off-runs (3b) of the present invention includes a method represented by the following formula.

(Wherein R ¹ represents a lower alkyl group having 1 to 4 carbon atoms, and R ^{2 ′} represents an alcohol protecting group).

  The said method can be implemented by performing process EJ following process A mentioned above.

Step E : Compound (5) obtained in Step A [For example, when 3,4-dihydro-2H-pyran is used as an alcohol protecting agent, 2- (1-alkyl-1- (3-thienyl) methyloxy) Tetrahydro-2H-pyran] is hydroxymethylated.

  Specifically, this step can be carried out by reacting compound (5) with an alkyl metal reagent and then reacting with an aldehyde. Such a reaction can be carried out usually under conditions of −100 ° C. to 50 ° C. using a solvent such as tetrahydrofuran, dichloromethane or toluene.

  Here, examples of the alkyl metal reagent include, but are not limited to, n-butyllithium, sec-butyllithium, and t-butyllithium. Preferred is n-butyllithium. The ratio of the alkyl metal reagent to be used is not particularly limited, but can be usually 1 to 1.5 mol, preferably 1 to 1.1 mol, relative to 1 mol of compound (5).

  Examples of aldehydes include, but are not limited to, paraformaldehyde and formaldehyde dimethyl acetal. Paraformaldehyde is preferred. The ratio of aldehydes to be used is not particularly limited, but can be usually 1 to 3 mol, preferably 1 to 1.2 mol, relative to 1 mol of compound (5). Thus, the compound represented by the chemical formula (10) can be obtained.

Process F : It is a process of acetylating the compound (10) obtained by the said process E.

  Specifically, this step can be carried out by reacting compound (10) with an alkyl metal reagent and then with an acetylating reagent. Such a reaction can be carried out usually at −100 ° C. to 20 ° C. using a solvent such as tetrahydrofuran, dichloromethane or toluene. Here, examples of the alkyl metal reagent include those described above. Examples of the acetylating reagent include acetic anhydride. The ratio of the acetylating reagent to be used is not particularly limited, but can be usually 1 to 3 mol, preferably 1 to 1.2 mol, relative to 1 mol of compound (10). Thus, the compound represented by the chemical formula (11) can be obtained.

Step G: A step of eliminating (deprotecting) the alcohol protecting group of the compound (11) obtained in Step F.

  Specifically, this step can be carried out by reacting compound (11) with an organometallic reagent or by reacting with an alcohol in the presence of an acidic catalyst. Such a reaction can be usually carried out under a condition of −30 ° C. to 80 ° C. using a solvent such as dichloromethane, methanol, ethanol, propanol or toluene. Here, examples of the organometallic reagent include, but are not limited to, dimethylaluminum chloride and diethylaluminum chloride. Preferred is dimethylaluminum chloride. The ratio of the organometallic reagent to be used is not particularly limited, but can be usually 1 to 3 mol, preferably 2 to 2.5 mol, relative to 1 mol of compound (11). Moreover, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, pyridinium, etc. can be illustrated as an acidic catalyst. Furthermore, ethanol, methanol, etc. can be illustrated as alcohol. Thus, the compound represented by the chemical formula (12) can be obtained.

Step H : Step for oxidizing the hydroxyl group of the compound (12) obtained in Step G. This step can be performed by reacting compound (12) with an oxidizing reagent. Such a reaction is not particularly limited, but can be performed, for example, using dimethyl sulfoxide and oxalyl chloride, magnesium oxide, chromium oxide, pyridinium chlorochromate, pyridinium dichromate and the like, usually at a temperature of -30 to 50 ° C. . Thus, the compound represented by the chemical formula (13) can be obtained.

Step I : A step of deprotecting the acetyl group of the compound (13) obtained in Step H. Specifically, this step can be performed by hydrolyzing the compound (13) under acidic or basic conditions, or by reacting with an alcohol in the presence of a basic catalyst. Such a reaction can be usually carried out under a condition of −30 ° C. to 80 ° C. using a solvent such as dichloromethane, methanol, ethanol, propanol or toluene. Thus, the compound represented by the chemical formula (9) can be obtained.

Step J : A step of reducing and cyclizing the compound (9) obtained in Step I. Such a step can be carried out by reacting compound (9) with a transition metal catalyst in a hydrogen atmosphere. The specific method, the type of transition metal catalyst and the ratio thereof are as described above.

  Thus, the caffeolanes (3b) can be efficiently synthesized using 3- (1-hydroxyalkyl) -thiophene as a starting material. Therefore, according to this method, it is possible to industrially mass-produce the café-off run (3b) in a short process.

The caffeoflorans (3b) (2,3-dihydrothieno [2,3c] furan compound) thus obtained has a unique aroma depending on the type of the compound, similar to the caffeolanes (3). It is useful as an aroma component substance. For example, 4-methyl-2,3-dihydrothieno [2,3c] furan (compound (L)) (Example 7), in which R ¹ is a methyl group, is a roasted sesame-like scent as caffeine offrans (3b) 4-ethyl-2,3-dihydrothieno [2,3c] furan (compound (T)) (Example 8) in which R ¹ is an ethyl group has a cooked potato-like aroma.

  As described above, since the café-off runs [(3a), (3b)] (hereinafter collectively referred to as the café-off runs (3)) are useful as a component of the fragrance, the present invention provides such café-off runs (3 ) As a main component of the fragrance.

Proportion of Kafeo furans to be blended in the perfume composition (3) it depends on the type and purpose of Kafeo furans used (3), for example, perfume composition 100 wt% in the 10 ^-9 to 10 ^{- A} proportion of ¹ wt% (10 ⁻² to 10 ⁶ ppb), preferably 10 ⁻⁵ to 10 ⁻² wt% (10 ² to 10 ⁵ ppb) can be exemplified.

  Specifically, since both café-off run and ethyl café-off run have a roasted fragrance, the fragrance composition containing these includes sesame, coffee, cocoa, chocolate, maple, caramel, tea, nuts, vanilla, beef It is useful as a fruit flavor such as meat, buttermilk, cream, cheese, grape, raspberry and black currant. Furthermore, since dimethyl caffeine offran has a green odor and a green fragrance of vegetables, the perfume composition containing dimethyl caffeine offran is green fruits such as green beans, kiwi, melon, watermelon, apple, banana; tomato, cabbage, cucumber It is useful as a vegetable flavor such as;

Furthermore, this invention relates to the food / beverage products containing this fragrance | flavor composition. Although the ratio of the cafe-off run (3) mix | blended with this food / beverage is different with the kind of cafe-off run (3) and the kind of food / beverage to be used, it is 10 <-12> ^{-10 in} 100 weight% of food-drinks compositions. ^A ratio of ⁻⁴ wt% (10 ⁻³ to 10 ⁹ ppb), preferably 10 ⁻⁶ to 10 ⁻¹ wt% (1 to 10 ⁵ ppb) can be exemplified.

  Food / beverage products that can contain cafe-off-runs (3) as a fragrance ingredient are not limited, but for example, frozen confectionery such as ice cream, ice milk, lacto ice, sherbet, ice confectionery; milk beverage, lactic acid bacteria beverage, soft drink ( (Including fruit juice), carbonated beverages, fruit juice beverages, vegetable beverages, vegetable and fruit beverages, sports beverages, powdered beverages such as powdered beverages; alcoholic beverages such as liqueurs; tea beverages such as coffee beverages and tea beverages; Soups such as potage soup; puddings such as custard pudding, milk pudding, pudding with fruit juice, desserts such as jelly, bavaroa and yogurt; gums such as chewing gum and bubble gum (plate gum, sugar-coated grain gum); marble In addition to coated chocolate such as chocolate, strawberry chocolate, blueberry cho Chocolates such as chocolate with flavor such as rate and melon chocolate; hard candy (including bonbon, butterball, marble, etc.), soft candy (including caramel, nougat, gummy candy, marshmallow, etc.), drop, toffee, etc. Caramels; baked confectionery such as hard biscuits, cookies, rice crackers, rice crackers; sauces such as separate dressing, non-oil dressing, ketchup, sauce, sauce; jams such as strawberry jam, blueberry jam, apple jam, prazabu; And processed meat products such as sausage and grilled pork; fish paste products such as fish ham, fish sausage, fish meat surimi and salmon; and dairy products such as cheese.

(3) Aromatic thiophene compound and method for producing the same Further, the present invention provides a thiophene compound (aromatic thiophene compound) represented by the following general formula (7).

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms).

Since the thiophene compound itself has aroma, it can be effectively used as a component of a fragrance (fragrance component substance). Here, the lower alkyl group represented by R ¹ or R ⁵ is the same or different, and is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t. Examples thereof include lower alkyl groups having 1 to 4 carbon atoms such as -butyl group. Preferably, it is a lower alkyl group having 1 or 2 carbon atoms such as a methyl group or an ethyl group.

A preferred aromatic thiophene compound is 6-methyl-4,6-dihydrothieno [2,3c] furan in which R ¹ is a hydrogen atom and R ⁵ is a methyl group.

  The aromatic thiophene compound can be produced by reducing compound (2) and then cyclizing the resulting compound (8) as shown in the following formula:

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ⁴ and R ⁵ represent the same lower alkyl group having 1 to 4 carbon atoms).

  Specifically, as shown in Example 5 (1), the reduction reaction can be performed by reacting the compound (2) with a metal hydride such as lithium aluminum hydride or sodium borohydride. . Such a reaction can be usually carried out at a temperature of -20 to 50 ° C. using a solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate, ether, or toluene.

  Specifically, the cyclization reaction of the compound (8) thus obtained is carried out by using, for example, an alkyl metal reagent (for example, n-butyllithium, sec-butyllithium or t-butyl) as shown in Example 5 (2). In the presence of lithium, etc.) by reacting with a reagent such as p-toluenesulfonyl chloride, methanesulfonyl chloride or trifluoromethanesulfonyl chloride. Such a reaction can be carried out usually at a temperature of −30 ° C. to 60 ° C. using a solvent such as dichloromethane, THF, toluene and the like.

After completion of the above reaction, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then subjected to chromatography using silica gel (for example, silica gel collection thin layer chromatography, silica gel column chromatography, etc.), distillation, recrystallization, etc. You may use for arbitrary refinement | purification operations, Therefore The aromatic thiophene compound (7) which is the target compound of this invention can be obtained.
Thus, the aromatic thiophene compound (7) can be efficiently synthesized using the compound (2) as a raw material, and the synthesis yield is adjusted to about 30% or more by adjusting the reaction conditions. be able to. Therefore, according to this method, the aromatic thiophene compound (7) can be industrially mass-produced in a short process.

  The aromatic thiophene compound (7) thus obtained has a unique aroma depending on the type of compound and is useful as an aroma component substance. For example, 6-methyl-4,6-dihydrothieno [2,3c] furan, which is a kind of aromatic thiophene compound (7), has a fruity sweetness, green flavor, or 0.0035% by weight diluted aqueous solution, or Play a coffee-like aroma.

  Thus, since aromatic thiophene compound (7) is useful as a component of a fragrance | flavor, this invention provides the fragrance | flavor composition which contains this aromatic thiophene compound (7) as a main component of a fragrance | flavor.

Proportion of fragrant thiophene compounds contained in the perfume composition (7) depends on the type and purpose of fragrant thiophene compound used (7), the perfume composition 100 wt%, ^{10-9 - A} proportion of ¹ wt% (10 ⁻² to 10 ⁶ ppb), preferably 10 ⁻⁵ to 10 ⁻² wt% (10 ² to 10 ⁵ ppb) can be exemplified.

  Specifically, since 6-methyl-4,6-dihydrothieno [2,3c] furan has a fruity sweetness, a green scent, a coffee-like aroma and the like, 6-methyl-4,6-dihydrothieno [ A perfume composition comprising 2,3c] furan is useful as a perfume for coffee or cocoa, or a perfume for melon or watermelon.

Furthermore, this invention relates to the food / beverage products containing this fragrance | flavor composition. The ratio of the aromatic thiophene compound (7) to be blended in such a food or drink varies depending on the type of the aromatic thiophene compound (7) used or the kind of the food or drink, but 10 ^{−12 in} 100% by weight of the food or drink composition. A ratio of ˜10 ⁻³ wt% (10 ⁻⁵ to 10 ⁴ ppb), preferably 10 ⁻⁸ to 10 ⁻⁴ wt% (10 ⁻¹ to 10 ³ ppb) can be exemplified.

  Examples of the food and drink that can contain the fragrant thiophene compound (7) as a fragrance component include those described above in the same manner as the cafe-off run (3).

  EXAMPLES Hereinafter, although this invention is demonstrated concretely using an Example, this invention is not limited to these at all.

Example 1 Synthesis of Caffe Offran (Method 1)
Caffeofuran (compound (e)) was produced from thiophene-3-methanol (compound (a)) according to the following formula. In the formula, THP means a tetrahydropyranyl group.

(1) Step A: Protection of hydroxyl group of thiophene-3-methanol
Synthesis of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran (compound (b )) To 4.56 g (40 mmol) of thiophene-3-methanol (compound (a)), 3,4-dihydro-2H-pyran 3.36 g (40 mmol) and 80 ml of dichloromethane solution were added, followed by 0.25 g (1 mmol) of pyridinium p-toluenesulfonic acid. The mixture was stirred at room temperature for 30 minutes, and the solution was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 2- (3-thienylmethyloxy) as a colorless oily substance in which the hydroxyl group of thiophene-3-methanol was protected. ) Tetrahydro-2H-pyran (compound (b), 7.92 g, yield 100%) was obtained. The physical properties of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 7.30 (dd, J = 3.2, 4.8 Hz, 1H), 7.25 (dd, J = 3.2, 1.2 Hz, 1H), 7.09 (dd, J = 1.2, 4.8 Hz, 1H), 4.77 (d, J = 12.4 Hz, 2H), 4.70 (t, J = 4 Hz, 1H), 4.54 (d, J = 12.4 Hz, 2H), 3.91 (m, 1H), 1.88- 1.51 (m, 6H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 139.25, 127.35, 125.74, 122.67, 97.43, 66.99, 62.02, 30.44, 25.42, 19.25;
MS (m / e) 198 (M ⁺ );
IR (neat) n _max 2945, 2872, 2247, 1466, 1454, 1440, 1120, 1030, 908, 736 cm ⁻¹ .

(2) Step B: Acylation
Synthesis of 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-ethanone (compound (c)) 2- (3 -thienylmethyloxy) tetrahydro- obtained above 0.792 g (4 mmol) of 2H-pyran (compound (b)) was dissolved in 80 ml of tetrahydrofuran (THF) solution. To this, 2.5 ml of n-butyllithium (1.6 M hexane solution, 4 mmol) was added dropwise under an argon atmosphere under cooling at −78 ° C. After 30 minutes, 0.408 g (4 mmol) of acetic anhydride was added to the solution and stirred for 30 minutes, and then the temperature was returned to room temperature and stirring was continued for another 30 minutes. The solution was then washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2 as a colorless oily substance. -Thienyl} -1-ethanone (compound (c), 0.653 g, yield 68%) was obtained. The physical properties of 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-ethanone are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 7.47 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 5.07 (d, J = 15.2 Hz, 2H), 4.91 (d, J = 15.2 Hz, 2H), 4.74 (t, J = 4 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 1H), 2.52 (s, 3H), 1.90-1.52 (m, 6H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 190.68, 147.40, 129.99, 129.53, 98.52, 65.29, 62.21, 30.50, 29.17, 25.23, 22.88, 19.41;
MS (m / e) 240 (M ⁺ );
IR (neat) n _max 2943, 2870, 2249, 1660 1525, 1415, 1122,1068, 910, 731 cm ⁻¹ .

(3) Step C: Deprotection
1- {3-[(Tetrahydro-2H-2-pyranyloxy) methyl] -2 prepared in synthesis step B of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d)) -Thienyl} -1-ethanone (compound (c), 1.44 g (6 mmol)) was dissolved in dichloromethane, and 12 ml (12 mmol) of a 1M hexane solution of dimethylaluminum chloride was added dropwise to 60 ml of this solution while stirring at -25 ° C. did. After completion of the dropwise addition, the solution was returned to room temperature and further stirred for 1 hour. Subsequently, saturated sodium hydrogencarbonate aqueous solution was added to this solution, reaction was complete | finished, and cerite filtration was performed. The separated organic layer was washed with saturated brine, dried by adding magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d ), 0.767 g, yield 82%). The physical properties of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 7.49 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 4.74 (d, J = 5.6 Hz, 2H), 4.24 (t, J = 5.6 Hz, OH, 1H), 2.58 (s, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 192.43, 149.98, 136.57, 130.91, 130.51, 59.98, 29.09;
MS (m / e) 156 (M ⁺ );
IR (neat) n _max 3441, 2253, 1651, 1518, 1413, 1263, 1032, 908, 733 cm ⁻¹ .

(4) Step D: Cyclization reaction involving reduction
Synthesis of Caffeolane (Compound (e)) Compound (d) (312 mg (2 mmol)) prepared in Step C above was dissolved in 10 ml of benzene solution, and then 92 mg (0.1 mmol) of tris (triphenylphosphine) rhodium (I) Chloride was added. The solution was stirred while heating at 100 ° C. for 24 hours under a hydrogen atmosphere of 1 MPa. The residue obtained by concentrating the solution was purified by silica gel column chromatography (pentane: ether = 100: 1) to give 142 mg of 6-methyl-2,3-dihydrothieno [2,3c] furan as a colorless oil ( Café off-run, compound (e), yield 51%) was obtained. 6-Methyl-2,3-dihydrothieno [2,3c] furan is shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 6.98 (t, J = 1.6 Hz, 1H), 3.62 (t, J = 7.2 Hz, 2H), 2.87 (dt, J = 1.6 7.2 Hz, 2H), 2.20 (s, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 140.22, 131.61, 128.27, 122.11, 41.99, 26.70, 12.53;
MS (m / e) 140 (M);
IR (neat) n _max 2982, 2916, 1631, 1577, 1433, 1265, 1103, 920, 733 cm ⁻¹ .

Example 2 Synthesis of Caffe Offran (Method 2)
Caffeofuran (compound (e)) was produced from thiophene-3-methanol (compound (a)) according to the following formula.

(1) Step A: Protection of hydroxyl group of thiophene-3-methanol
Synthesis of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran (compound (b)) According to Step A described in Example 1, thiophene-3-methanol (compound (a)) to 2- (3-thienyl) Methyloxy) tetrahydro-2H-pyran (compound (b)) was synthesized.

(2) Step B: Acylation
Synthesis of 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-ethanone (Compound (c)) According to Step B described in Example 1, 2- (3-thienyl 1- {3-[(Tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-ethanone (compound (c)) was synthesized from methyloxy) tetrahydro-2H-pyran (compound (b)). .

(3) Step C ′: Deprotection
Synthesis of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d)) 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2- prepared above Thienyl} -1-ethanone ((compound (c), 2.4 g, 10 mmol) was dissolved in methanol and (±) -camphorsulfonic acid was added at room temperature while stirring.After stirring for 15 minutes, 1.38 g ( 10 mmol) of potassium carbonate was added to terminate the reaction, the reaction solution was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). By purification, 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d), 1.38 g, yield 88%) was obtained as a colorless oily substance. (Hydroxymethyl) -2-thienyl] -1-ethanone is shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 7.49 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 4.74 (d, J = 5.6 Hz, 2H), 4.24 (t, J = 5.6 Hz, OH, 1H), 2.58 (s, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 192.43, 149.98, 136.57, 130.91, 130.51, 59.98, 29.09;
MS (m / e) 156 (M ⁺ );
IR (neat) n _max 3441, 2253, 1651, 1518, 1413, 1263, 1032, 908, 733 cm ⁻¹ .

(4) Step D: Reduction reaction with cyclization
Synthesis of Caffeolane (Compound (e)) The compound (d) prepared in Step C ′ above was subjected to reduction and cyclization reaction according to the method of Step D described in Example 1 to give 6-methyl- 142 mg of 2,3-dihydrothieno [2,3c] furan (cafe off run, compound (e), yield 51%) was obtained. The physical properties of 6-methyl-2,3-dihydrothieno [2,3c] furan (cafe off run) are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 6.98 (t, J = 1.6 Hz, 1H), 3.62 (t, J = 7.2 Hz, 2H), 2.87 (dt, J = 1.6 7.2 Hz, 2H), 2.20 (s, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 140.22, 131.61, 128.27, 122.11, 41.99, 26.70, 12.53;
MS (m / e) 140 (M);
IR (neat) n _max 2982, 2916, 1631, 1577, 1433, 1265, 1103, 920, 733 cm ⁻¹ .

Example 3 Synthesis of 6-ethyl-2,3-dihydrothieno [2,3c] furan According to the following formula, thiophene-3-methanol (compound (a)) to 6-ethyl-2,3-dihydrothieno [2,3c] Furan (compound (h)) was prepared.

(1) Step A: Protection of hydroxyl group of thiophene-3-methanol
Synthesis of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran (compound (b)) According to step A of Example 1, thiophene-3-methanol (compound (a)) from 4.56 g (40 mmol) to 2- ( 3-Thienylmethyloxy) tetrahydro-2H-pyran (compound (b)) was prepared.

(2) Step B: Acylation
Synthesis of 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-propanone (compound (f)) 2- (3 -thienylmethyloxy) tetrahydro-2H prepared above 1- {3-[(Tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1 according to Step B of Example 2 using 0.792 g (4 mmol) of pyran (compound (b)) -Propanone (compound (f), 0.686 g, yield 65%) was obtained. The physical properties of 1- {3-[(tetrahydro-2H-2-pyranyloxy) methyl] -2-thienyl} -1-propanone are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm): 7.45 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 5.10 (d, J = 14.8 Hz, 2H), 4.95 (d, J = 15.2 Hz, 2H), 4.74 (t, J = 4 Hz, 1H), 3.92 (m, 1H), 3.537 (m, 1H), 2.89 (q, J = 7.2 Hz, 2H), 1.91 -1.53 (m, 6H), 1.21 (t, J = 7.2 Hz, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 193.91, 147.41, 129.46, 129.29, 121.71, 98.51, 65.46, 62.22, 34.62, 30.48, 25.37, 19.42, 8.28;
MS (m / e) 254 (M ⁺ );
IR (neat) n _max 2943, 2874, 2251, 1662, 1525, 1417, 1203, 1122, 1068, 1035, 910, 733 cm ⁻¹ .

(3) Step C: Deprotection
1- {3-[(Tetrahydro-2H-2-pyranyloxy) methyl] -2 prepared in synthesis step B of 1- [3- (hydroxymethyl) -2-thienyl] -1-propanone (compound (g)) -Thienyl} -1-propanone (compound (f), 1.44 g (6 mmol)) was dissolved in dichloromethane, and 60 ml of this solution was stirred at -25 ° C with 12 ml (12 mmol) of 1M hexane solution of dimethylaluminum chloride. It was dripped. After completion of the dropwise addition, the solution was returned to room temperature and further stirred for 1 hour. Subsequently, saturated sodium hydrogencarbonate aqueous solution was added to this solution, reaction was complete | finished, and cerite filtration was performed. The separated organic layer was washed with saturated brine, dried by adding magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1- [3- (hydroxymethyl) -2-thienyl] -1-propanone (compound (g ), 0.595 g, yield 88%). The physical properties are shown below.

¹ H NMR (CDCl ₃ , 400MHz, d ppm) 7.45 (d, J = 4.8 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 4.72 (d, J = 7.6 Hz, 2H), 4.26 ( t, J = 7.6 Hz, OH, 1H), 2.92 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 195.40, 149.80, 137.25, 130.55, 130.39, 60.01, 34.71, 8.43;
MS (m / e) 170 (M ⁺ );
IR (neat) n _max 3410, 2254, 1653, 1518, 1413, 1217, 1028, 908, 734 cm ⁻¹ .

(4) Step D: Reduction reaction with cyclization
Synthesis of 6-ethyl-2,3-dihydrothieno [2,3c] furan (Compound (h)) The compound (g) prepared in Step C above was reduced and cyclized according to the method of Step D described in Example 1. Reaction was performed to obtain 6-ethyl-2,3-dihydrothieno [2,3c] furan (compound (h), yield 54%) as a colorless oily substance. The physical properties are shown below.

¹ H NMR (CDCl ₃ , 400MHz, d ppm) 6.980 (t, J = 1.6 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 2.86 (dt, J = 1.6 7.2 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 145.30, 131.44, 126.56, 120.98, 41.76, 25.26, 20.17, 11.40;
MS (m / e) 154 (M ⁺ );
IR (neat) n _max 2972, 2935, 2849, 1627, 1573, 1460, 1265, 1109, 949, 754 cm ⁻¹ .

Example 4 Synthesis of 4,6-dimethyl-2,3-dihydrothieno [2,3c] furan 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone [2-acetyl-thiophene] 4,6-Dimethyl-2,3-dihydrothieno [2,3c] furan (compound (k)) was prepared from -3-methanol (compound (d)). In addition, 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone (compound (d)) can be prepared in Example 1 (3) or Example 2 (3).

(1) Synthesis of 2-acetyl-3-thiophenecarbaldehyde (compound (i))
Magnesium oxide (100 ml) was added to 100 ml of a dichloromethane solution containing 1.106 g (7 mmol) of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone [2-acetyl-thiophene-3-methanol (compound (d))]. IV) 69.5 g was added and stirred vigorously for 20 minutes at room temperature. The filtrate obtained by filtering the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (pentane: ether = 2: 1) to give 1.066 g of 2-acetyl-3-thiophenecarbaldehyde (compound (i), yield 99) as a pale yellow oily substance. %). The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm); 10.56 (s, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 2.65 (s, 3H) ;
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 187.20, 184.60, 129.60, 129.54, 128.54, 124.20, 29.69;
MS (m / e) 154 (M ⁺ );
IR (neat) n _max 3099, 3086, 1672, 1514, 1423, 1242, 1014, 839, 756 cm ⁻¹ .

(2) Synthesis of 1- [3- (1-hydroxyethyl) -2-thienyl] -1-ethanone (Compound (j)) 2-Acetyl-3-thiophenecarbaldehyde (Compound (i)) obtained above ) 3 ml (3 mmol) of a 1MTHF solution of methylmagnesium bromide was added dropwise to 30 ml of a THF solution containing 0.462 g (3 mmol) while cooling to -78 ° C. The solution was returned to room temperature and stirred for an additional 30 minutes. After adding 30 ml of ether, the solution was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to 0.286 g of 1- [3- (1-hydroxyethyl) -2-thienyl] -1-ethanone (compound ( j), yield 56%) was obtained as a colorless oil. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 400 MHz, d ppm); 7.49 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 5.15 (m, J = 6.4 Hz, 1H), 4.65 (d, J = 6.4 Hz, OH, 1H), 2.59 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 192.51, 154.51, 136.64, 130.90, 129.06, 65.25, 29.40, 22.38;
MS (m / e) 170 (M ⁺ );
IR (neat) n _max 3427, 2982, 2251, 1649, 1514, 1410, 1244, 1113, 910, 734 cm ⁻¹ .

(3) Reduction reaction with cyclization
Synthesis of 4,6-dimethyl-2,3-dihydrothieno [2,3c] furan (compound (k)) 1- [3- (1-hydroxyethyl) -2-thienyl] -1 prepared in (2) above -Ethanone (compound (j)) is reduced and cyclized according to the method of Step D described in Example 1 to give 4,6-dimethyl-2,3-dihydrothieno [2,3c] furan as a colorless oil. (Compound (k), yield 58%) was obtained. The physical properties of this compound are shown below:
¹ H NMR (CDCl ₃ , 400MHz, d ppm) 3.58 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 7.2 Hz, 2H), 2.15 (s, 6H);
¹³ C NMR (CDCl ₃ , 100MHz, d ppm) 140.53, 138.16, 126.64, 117.47, 42.05, 25.51, 12.71, 12.61;
MS (m / e) 154 (M ⁺ );
IR (neat) n _max 2918, 2878, 2247, 1660, 1558, 1435, 1217, 1113, 1074, 908, 733 cm ⁻¹ .

Example 5 (A) Synthesis of 6-methyl-4,6-dihydrothieno [2,3c] furan According to the following formula, 6-methyl-4,6-dihydrothieno [2,3c] furan was synthesized.

(1) Reduction reaction 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone [2-acetyl-thiophene-3-methanol (compound (d))] in 20 ml of THF solution of 0.624 g (4 mmol) To the solution, 0.152 g (4 mmol) of lithium aluminum hydride was added dropwise with stirring at 0 ° C. After further stirring for 10 minutes, ethyl acetate was added dropwise to the solution to terminate the reaction, followed by celite filtration. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. By purifying the obtained residue by column chromatography (hexane: ethyl acetate = 1: 1), 0.62 g of 1- {3- (hydroxymethyl) -2-thienyl} -1-ethanol (compound (l), Yield 98%) was obtained as a colorless oil. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 400MHz, δppm) 7.15 (d, J = 4.8 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 5.20 (q, J = 6.4 Hz, 1H), 4.67 (d , J = 8.4 Hz, 1H), 4.61 (d, J = 8.4 Hz, 1H), 3.34 (w, OH, 1H), 2.88 (w, OH, 1H), 1.61 (d, J = 6.4 Hz, 3H) ;
¹³ C NMR (CDCl ₃ , 100MHz, δppm) 145.80, 132.23, 128.83, 122.96, 63.48, 57.68, 24.06;
MS (m / e) 158 (M ⁺ );
IR (neat) n _max 3339, 2974, 1437, 1068, 995, 910, 734 cm ⁻¹ .

(2) Cyclization reaction
1.25 ml of n-butyllithium at 0 ° C. in 20 ml of THF solution containing 0.316 g of 1- {3- (hydroxymethyl) -2-thienyl} -1-ethanol (compound (l), 2 mmol) (1.6 M in hexane, 2 mmol) was added dropwise. After 5 minutes, 0.38 g of p-toluenesulfonyl chloride (2 mmol) was added to the solution, and then returned to room temperature and stirred for 1 hour. The solution was cooled again to 0 ° C., and 1.25 ml (1.6 M in hexane, 2 mmol) of n-butyllithium was added dropwise. After the addition, the solution was stirred at room temperature for 18 hours. The solution was washed with saturated brine, dried over magnesium sulfate and concentrated. By purifying the obtained residue by silica gel column chromatography (pentane: ether = 100: 1), 0.089 g of 6-methyl-4,6-dihydrothieno [2,3c] furan (compound (m), yield) 32%) was obtained as a colorless oil. The physical properties of this compound are shown below.
¹ H NMR (CDCl ₃ , 400MHz, δppm) 7.28 (d, J = 5.2 Hz, 1H), 6.78 (d, J = 5.2 Hz, 1H), 5.40 (m, J = 4, 2.8, 6 Hz, 1H) , 5.02 (dd, J = 4, 7.2 Hz, 1H), 4.92 (dd, J = 2.8, 7.2 Hz, 1H), 1.50 (d, J = 6 Hz, 3H);
¹³ C NMR (CDCl ₃ , 100MHz, δppm) 143.28, 142.96, 129.68, 119.18, 77.77, 70.01, 22.91;
MS (m / e) 140 (M ⁺ );
IR (neat) n _max 2976, 2864, 2247, 1655, 1446, 1342, 1224, 1095, 1059, 976, 910, 839, 731 cm ⁻¹ .

(B) Synthesis of 6-ethyl-4,6-dihydrothieno [2,3c] furan 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanone [2-acetyl-thiophene-3- Instead of methanol (compound (d))], 1- [3- (hydroxymethyl) -2-thienyl] -1-propanone (compound (g)) obtained in Example 3 (3) was used. According to the method, 6-ethyl-4,6-dihydrothieno [2,3c] furan (compound (o)) is prepared by performing (1) reduction reaction and (2) cyclization reaction as shown in the following formula. be able to.

Example 6 Synthesis of 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan From thiophene-3-carbaldehyde (compound (A)) to 4-methyl-6-ethyl-2 according to the following formula , 3-Dihydrothieno [2,3c] furan (compound (E)) was prepared. In the formula, THP means a tetradropyranyl group.

(1) Step 0: Grignard reaction
Synthesis of 3- (1-hydroxyethyl) thiophene (compound (B))
To 150 ml of a THF solution containing 5.0 g (44.58 mmol) of thiophene-3-carbaldehyde (compound (A)), 16.35 ml (49.04 mmol) of a 3MTHF solution of methylmagnesium bromide was added dropwise while cooling to 0 ° C. The solution was returned to room temperature and stirred for another 2 hours. After adding 30 ml of diethyl ether, the solution was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 3.30 g of 3- (1-hydroxyethyl) thiophene as a colorless oil (compound (B), yield 99% ) The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.29 (dd, J = 4.8, 2.8 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H) , 4.95 (q, J = 6.2 Hz, 1H), 1.96 (brd, 1H), 1.51 (d, J = 6.2 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 147.41, 126.24, 125.74, 120.26, 66.62, 24.55.

(2) Step A: Protection of hydroxyl group of 3- (1-hydroxyethyl) thiophene
Synthesis of 2- (3-thienylethyl-1-oxy) tetrahydro-2H-pyran (compound (C )) 6.3 g (49.15 mmol) of 3- (1-hydroxyethyl) thiophene (compound (B)) obtained above ) Was added 3,4-dihydro-2H-pyran 50 ml and p-toluenesulfonic acid 0.3 g (1.2 mmol). The mixture was stirred at room temperature for 30 minutes, 100 ml of diethyl ether was added, the solution was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Was distilled off. The solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to give 3- (1-hydroxyethyl) thiophene hydroxyl group as a colorless oily substance. -Thienylethyl-1-oxy) tetrahydro-2H-pyran (compound (C), 9.5 g, yield 91%) was obtained. The physical properties of 2- (3-thienylethyl-1-oxy) tetrahydro-2H-pyran are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.27 (dd, J = 4.8, 2.8 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H) , 4.95 (q, J = 6.9 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.48 (m, 1H), 1.85 (m, 1H), 1.64 (m, 1H), 1.49 ( d, J = 6.9 Hz, 3H), 1.56-1.44 (m, 4H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 144.88, 126.02, 125.99, 121.58, 96.09, 69.27, 62.75, 30.89, 25.60, 23.57 , 19.89;
¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.25 (dd, J = 4.9, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H) , 4.92 (q, J = 6.9 Hz, 1H), 4.85 (t, J = 3.4 Hz, 1H), 3.78 (m, 1H), 3.44 (m, 1H), 1.85 (m, 1H), 1.73 (m, 1H), 1.63 (m, 1H), 1.56-1.44 (m, 3H), 1.46 (d, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 145.65, 126.46, 125.51, 120.49 , 96.09, 69.36, 62.25, 30.99, 25.60, 20.92, 19.47.

(3) Step B: acylation
1- {3- [1- (Tetrahydro-2H-2-pyranyloxy) ethyl] -2-thienyl} -1-propanone (compound (D)) 2- (3-thienylethyl- 4.0 g (18.84 mmol) of 1-oxy) tetrahydro-2H-pyran (compound (C)) was dissolved in 300 ml of tetrahydrofuran (THF) solution. To this, 17.28 ml of sec-butyllithium (1.2 M hexane solution, 20.73 mmol) was added dropwise under an argon atmosphere under cooling at −78 ° C. One hour later, 3.06 g (23.55 mmol) of propionic anhydride was added to the solution and stirred for 30 minutes, and then returned to room temperature and further stirred for 1 hour. The solution was then washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] as a colorless oily substance. -2-thienyl} -1-propanone (compound (D), 2.1 g, yield 43%) was obtained. The physical properties of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] -2-thienyl} -1-propanone are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.40 (d, J = 5.5 Hz, 1H), 7.25 (d, J = 6.2 Hz, 1H), 5.69 (q, J = 6.9 Hz, 1H), 4.40 (dd, J = 4.7, 2.8 Hz, 1H), 3.91 (m, 1H), 3.46 (m, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.87-1.42 (m, 6H), 1.45 ( d, J = 6.9 Hz, 3H), 1.18 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 193.94, 153.11, 135.31, 129.78, 128.40, 96.81, 69.42, 62.62, 30.91, 25.53, 22.94, 19.77, 14.28, 8.39;
¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.38 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 6.2 Hz, 1H), 5.60 (q, J = 6.2 Hz, 1H), 4.75 (dd, J = 4.7, 2.8 Hz, 1H), 3.63 (m, 1H), 3.32 (m, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.87-1.42 (m, 6H), 1.39 ( d, J = 6.2 Hz, 3H), 1.24 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 194.01, 153.59, 133.40, 129.42, 129.10, 97.83, 70.55, 62.87, 31.17, 25.46, 21.96, 19.98, 14.21, 8.44.

(4) Process C: Deprotection
1- {3- [1- (tetrahydro-2H-2-pyranyloxy) prepared in synthesis step B of 1- [3- (1-hydroxyethyl) -2-thienyl] -1-propanone (compound (E) ) Ethyl] -2-thienyl} -1-propanone (compound (D), 2.1 g (7.83 mmol)) was dissolved in methanol, and (±) -camphorsulfonic acid was added to 150 ml of this solution at room temperature while stirring. It was. After stirring for 15 minutes, 1.08 g (7.83 mmol) of sodium carbonate was added to terminate the reaction. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 1- [3 as a colorless oily substance. -(1-Hydroxyethyl) -2-thienyl] -1-propanone (compound (E), 1.27 g, yield 88%) was obtained. The physical properties of 1- [3- (1-hydroxyethyl) -2-thienyl] -1-propanone are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm); 7.49 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 5.5 Hz, 1H), 5.14 (m, 1H), 2.82 (q, J = 6.9 Hz, 2H), 1.53 (d, J = 6.2 Hz, 3H), 1.24 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 193.61, 154.21, 134.60, 130.16, 129.16, 65.21, 30.40, 22.30, 21.18.

(5) Step D: Reduction reaction with cyclization
Synthesis of 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan (Compound (F)) Compound (E) (1.27 g (6.90 mmol)) prepared in the above Step C was added to 20 ml of a toluene solution. Dissolved and then 92 mg (0.16 mmol) of tris (triphenylphosphine) rhodium (I) chloride was added thereto. The solution was stirred while heating at 100 ° C. for 24 hours under a hydrogen atmosphere of 1 MPa. The residue obtained by concentrating the solution was purified by silica gel column chromatography (pentane: diethyl ether = 100: 1) to give 4-methyl-6-ethyl-2,3-dihydrothieno [2, as a colorless oily substance. 3c] furan 670 mg (compound (F), yield 58%) was obtained. The physical properties of 4-methyl-6-ethyl-2,3-dihydrothieno [2,3c] furan are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 3.57 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.53 (q, J = 7.6 Hz, 2H), 2.15 (s, 3H), 1.19 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 143.56, 140.48, 126.81, 120.92, 42.04, 25.23, 20.96, 12.75, 12.01.

Example 7 Synthesis of 4-methyl-2,3-dihydrothieno [2,3c] furan 4-Methyl-2,3-dihydrothieno [2,3c] furan was synthesized according to the following formula.

(1) Process F: Hydroxymethylation
Synthesis of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] -2-thienyl} -1-methanol (compound (G)) 2- (3-thienylethyl-1-oxy) tetrahydro- To 40 ml of THF solution of 2H-pyran 500 mg (2.36 mmol), 2.93 ml of sec-butyllithium (1.2 M hexane solution, 3.52 mmol) was added dropwise with stirring at -78 ° C. One hour later, 225 mg (7.04 mmol) of paraformaldehyde was added to the solution and stirred for 30 minutes, and then the temperature was returned to room temperature and stirring was continued for another hour. The solution was then washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] as a colorless oily substance. 2-Thienyl} -1-methanol (301 mg, yield 53%, compound (G)) was obtained. The physical properties of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] -2-thienyl} -1-methanol are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.20 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 4.93 (q, J = 6.9 Hz, 1H), 4.76 (d, J = 13.2 Hz, 1H), 4.75 (d, J = 13.2 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.48 (m, 1H), 1.83-1.49 (m, 6H), 1.46 (d, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 155.28, 129.69, 125.28, 123.68, 97.33, 64.43, 62.82, 62.39, 30.83, 25.79, 23.67, 19.41
¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.22 (d, J = 4.8 Hz, 1H), 6.99 (d, J = 4.8 Hz, 1H), 4.95 (q, J = 6.9 Hz, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.81 (d, J = 13.2 Hz, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.43 (m, 1H), 1.83-1.49 (m, 6H), 1.40 (d, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 155.01, 129.99, 124.96, 123.03, 98.01, 64.68, 62.79, 62.55, 30.32, 25.50, 23.63, 19.87 .

(2) Process G: Acetylation
1- {3- [1- (Tetrahydro-2H-2 -pyranyloxy) ethyl] -2-tenyl acetate (compound (H)) 1- {3- [1- (tetrahydro-2H-2 -pyranyloxy) ethyl] prepared in Synthesis Step F of 3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] ) Ethyl] -2-thienyl} -1-methanol (263 mg, 2.58 mmol) was added to 500 mg (2.06 mmol) of pyridine in 6.0 ml. After stirring at room temperature for 2 hours, 20 ml of diethyl ether was added, and a saturated aqueous potassium hydrogen sulfate solution was further added to the solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 10: 1) to give 0.62 g of 3- [1- (tetrahydro-2H-2-pyranyloxy) ethyl] -2-thenyl acetate (compound ( H), yield 98%) was obtained as a colorless oil. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.21 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 5.34 (d, J = 13.2 Hz, 1H), 5.23 (d, J = 13.2 Hz, 1H), 4.95 (q, J = 6.9 Hz, 1H), 4.40 (m, 1H), 3.89 (m, 1H), 3.40 (m, 1H), 2.87 (s, 3H) , 1.83-1.49 (m, 6H), 1.46 (d, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 174.56, 143.41, 128.67, 123.29, 122.52, 97.33, 64.63, 62.82, 61.78, 31.97, 25.11, 24.69, 21.32, 19.76
¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.23 (d, J = 4.8 Hz, 1H), 6.98 (d, J = 4.8 Hz, 1H), 5.33 (d, J = 13.2 Hz, 1H), 5.20 (d, J = 13.2 Hz, 1H), 4.91 (q, J = 6.9 Hz, 1H), 4.37 (m, 1H), 3.86 (m, 1H), 3.44 (m, 1H), 2.84 (s, 3H) , 1.83-1.49 (m, 6H), 1.41 (d, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 174.22, 142.99, 128.48, 123.78, 122.46, 97.31, 64.78, 62.77, 61.65, 32.10, 24.96, 24.73, 21.46, 19.78.

(3) Step H: Deprotection of THP group
3- [1- (Tetrahydro-2H-2-pyranyloxy) ethyl]-prepared in synthesis step G of 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanol (compound (I)) 2-Tenyl acetate (Compound (H), 498 mg (1.75 mmol)) was dissolved in methanol, and (±) -camphorsulfonic acid was added to 40 ml of this solution at room temperature with stirring. After stirring for 15 minutes, the solution was evaporated under reduced pressure, and 20 ml of diethyl ether was added to the resulting residue, followed by extraction with a saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. By purifying the obtained residue by column chromatography (hexane: ethyl acetate = 3: 1), 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanol 250 mg (yield 71%) Compound (I)) was prepared. 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanol physical properties are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm); 7.26 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.36 (d, J = 13.6 Hz, 1H), 5.21 (d, J = 13.6 Hz, 1H), 5.11 (q, J = 6.2 Hz, 1H), 2.41 (brd, 1H), 2.06 (s, 3H), 1.50 (d, J = 6.2 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz, d ppm) 171.02, 145.57, 132.35, 126.13, 126.07, 64.30, 58.40, 24.11, 21.09.

(4) Step I: hydroxyl group oxidation
Synthesis of 1- {2- [1-acetoxymethyl] -3-thienyl} -1 -ethanone (compound (J)) 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanol (compound (I), 1.18 g (14.98 mmol) of pyridine and 0.748 g (7.49 mmol) of chromium (VI) oxide were added to 15 ml of a dichloromethane solution of 250 mg (1.25 mmol)), and the mixture was stirred for 15 minutes. -{2- [1-acetoxymethyl] -3-thienyl} -1-ethanol was added and stirred for 10 minutes. The solution was filtered, neutralized with dilute hydrochloric acid, and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanone 225 mg (yield 91%, Compound (J)) was prepared. The physical properties of 1- {2- [1-acetoxymethyl] -3-thienyl} -1-ethanone are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.38 (d, J = 5.5 Hz, 1H), 7.21 (d, J = 5.5 Hz, 1H), 5.60 (s, 2H), 2.51 (s, 3H) , 2.13 (s, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 193.74, 170.33, 148.20, 136.40, 128.78, 123.98, 62.01, 29.47, 20.87.

(5) Process J: Deprotection of acetyl group
1- {2- [1-Acetoxymethyl] -3-thienyl} -1- prepared in Synthesis Step I of 1- [2- (hydroxymethyl) -3-thienyl] -1-ethanone (Compound (K)) Ethanon
To 35 ml of methanol solution of 735 mg (3.71 mmol), 3.5 ml of 2N sodium hydroxide aqueous solution was added and stirred for 15 minutes. 100 ml of diethyl ether was added to the solution, neutralized with dilute hydrochloric acid, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) 1- [2- (hydroxymethyl) -3-thienyl] -1-ethanone 470 mg (compound (K), yield) 81%). The physical properties of 1- [2- (hydroxymethyl) -3-thienyl] -1-ethanone are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.42 (d, J = 5.5 Hz, 1H), 7.17 (d, J = 5.5 Hz, 1H), 4.83 (s, 2H), 2.56 (s, 3H) ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 195.68, 153.00, 137.09, 129.54, 123.26, 59.10, 29.42.

(6) Step K: Reduction reaction with cyclization
Synthesis of 4-methyl-2,3-dihydrothieno [2,3c] furan (compound (L)) Compound (K) (580 mg (3.71 mmol)) prepared in Step J above was dissolved in 20 ml of toluene solution, 343 mg (0.371 mmol) of tris (triphenylphosphine) rhodium (I) chloride was added. The solution was stirred while heating at 100 ° C. for 32 hours under a hydrogen atmosphere of 1 MPa. The residue obtained by concentrating the solution was purified by silica gel column chromatography (pentane: diethyl ether = 100: 1) to give 236 mg of 4-methyl-2,3-dihydrothieno [2,3c] furan as a colorless oily substance. (Compound (L), yield 44%) was obtained. 4-Methyl-2,3-dihydrothieno [2,3c] furan is shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 6.88 (s, 1H), 3.63 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 2.19 (s, 3H) ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 142.89, 129.84, 128.55, 126.75, 42.17, 25.09, 12.82.

Example 8 Synthesis of 4-ethyl-2,3-dihydrothieno [2,3c] furan From thiophene-3-carbaldehyde (compound (A))] according to the following formula, 4-ethyl-2,3-dihydrothieno [2, 3c] furan (compound (T)) was prepared.

(1) Synthesis of 3- (1-hydroxypropyl) thiophene (Compound (M)) According to Step A of Example 6, from 10.0 g (89.17 mmol) of thiophene-3-carbaldehyde (Compound (A)) to 3- ( 12.45 g (98% yield) of 1-hydroxypropyl) thiophene (compound (M)) was produced. The physical properties of 3- (1-hydroxypropyl) thiophene are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.29 (dd, J = 4.8, 2.8 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H) , 4.68 (t, J = 6.2 Hz, 1H), 1.92 (brd, 1H), 1.80 (qd, J = 7.6, 6.2 Hz, 2H), 0.92 (t, J = 6.2 Hz, 3H); ¹³ C NMR ( CDCl ₃ , 150 MHz, d ppm) 146.22, 126.11, 125.77, 120.84, 72.11, 31.34, 10.11.

(2) Synthesis of 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N)) According to Step B of Example 6, 3- (1-hydroxypropyl) thiophene (compound (M) ) 17.89 g (90% yield) of 2- (3-thienylethyl-1-oxy) tetrahydro-2H-pyran (compound (N)) was prepared from 10.0 g (89.17 mmol). The physical properties of 2- (3-thienylethyl-1-oxy) tetrahydro-2H-pyran are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): (7.27 (dd, J = 4.8, 2.8 Hz), 7.25 (dd, J = 5.5, 3.4
Hz), 1H), (7.18 (d, J = 3.4 Hz), 7.13 (d, J = 1.7 Hz), 1H), (7.08 (d, J = 4.8 Hz), 7.03 (d, J = 4.8 Hz) , 1H), (4.81 (t, J = 3.7 Hz), 4.69 (t, J = 7.0 Hz), 1H), 4.65 (t, J = 6.2 Hz), 4.44 (t, J = 3.7 Hz), 1H) , (3.93 (m), 3.65 (m), 1H), (3.49 (m), 3.35 (m), 1H), 1.91-1.44 (m, 8H), (0.91 (t, J = 7.6 Hz), 0.84 (t, J = 7.6 Hz), 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) (144.46, 143.65), (126.49, 126.18), (125.86, 125.25), (123.00, 121.00), (97.72 95.26), (75.92, 74.49), (62.43, 62.19), (30.84, 30.82), (30.42, 28.76), (25.65, 25.56), (19.68, 19.43), (10.54, 9.65).

(3) Synthesis of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-methanol (Compound (O)) According to Step F of Example 7, 7.70 g ( 18.84 mmol) 2- (3-thienylethyl-1-oxy) tetrahydro-2H-pyran (compound (N)) to 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2- 3.99 g (yield 46%) of thienyl} -1-methanol (compound (O)) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): (7.22 (d, J = 4.8 Hz), 7.20 (d, J = 4.8 Hz), 1H), (7.03 (d, J = 4.8 Hz), 7.00 ( d, J = 4.8 Hz), 1H), 4.96 (m, 1H), 4.74 (m, 1H), 4.72 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.45 (m, 1H), 1.87-1.47 (m, 6H), 0.98 (m, 2H), (0.89 (t, J = 6.9 Hz), 0.84 (t, J = 6.9 Hz), 3H); ¹³ C NMR (CDCl ₃ , (150MHz, d ppm) (155.28, 155.02), (129.69, 129.44), (125.28, 125.01), (123.68, 123.55), (97.33, 96.98), (64.43, 64.39), (62.82, 62.55), (62.39, 62.11), (30.83, 30.57), (25.79, 25.66), (23.67, 23.60), (19.41, 19.02), (10.23, 10.09).

(4) Synthesis of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-hydroxymethyl acetate (compound (P)) According to Step G of Example 7, 3.99 g (16.60 mmol) of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-methanol (compound (O)) to 3- [1- (tetrahydro-2H 2-pyranyloxy) ethyl] -2-thenyl acetate (compound (P)) (4.55 g, yield 97%) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.40 (d, J = 5.5 Hz), 7.37 (d, J = 5.5 Hz), 1H), 7.25 (d, J = 6.2 Hz), 7.22 (d, J = 6.2 Hz), 1H), 5.69 (m, 1H), 4.75 (m, 1H), 4.56 (m, 1H), 4.23 (m, 1H), 3.91 (m, 1H), 3.46 (m, 1H) , (2.87 (s), 2.85 (s), 3H), 1.87-1.42 (m, 6H), 1.45 (m, 2H), 1.18 (t, J = 6.9 Hz), 1.16 (t, J = 6.9 Hz) ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 193.94, 153.11, 135.31, 129.78, 128.40, 96.81, 69.42, 62.62, 59.33, 30.91, 25.53, 22.94, 19.77, 14.28, 8.39.

(5) Synthesis of 1- {2- [1-acetoxymethyl] -3-thienyl} -1-propanol (Compound (Q)) According to Step 7 of Example 7, 4.55 g (16.11 mmol) of 3- [1 -(Tetrahydro-2H-2-pyranyloxy) ethyl] -3-thenyl acetate (compound (P)) to 1- {2- [1-acetoxymethyl] -3-thienyl} -1-propanol (compound (Q)) 2.66 g (yield 77%) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.26 (d, J = 5.5 Hz, 1H), 7.03 (d, J = 5.5 Hz, 1H), 5.34 (d, J = 13.1 Hz, 1H), 5.20 (q, J = 13.1 Hz, 1H), 4.80 (t, J = 6.2 Hz 1H), 2.05 (s, 3H), 1.87-1.73 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 170.98, 144.46, 132.93, 126.30, 126.08, 69.81, 58.41, 30.99, 21.08, 10.33.

(6) Synthesis of 1- {2- [1-acetoxymethyl] -3-thienyl} -1-propanone (Compound (R)) According to Step I of Example 7, 2.66 g (12.41 mmol) of 1- {2 -[1-acetoxymethyl] -3-thienyl} -1-propanol (compound (Q)) to 1- {2- [1-acetoxymethyl] -3-thienyl} -1-propanone (compound (R)) 2.30 g (87% yield) was prepared. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.38 (d, J = 5.5 Hz, 1H), 7.21 (d, J = 5.5 Hz, 1H), 5.60 (s, 2H), 2.51 (s, 3H) , 2.26 (q, J = 6.9 Hz, 2H), 1.09 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 193.63, 168.63, 149.21, 135.22, 126.50, 123.20, 61.78 , 28.40, 20.45, 14.69.

(7) Synthesis of 1- [2- (hydroxymethyl) -3-thienyl] -1-propanone (Compound (S)) According to Step J of Example 7, 2.30 g (10.84 mmol) of 1- {2- [ 1-acetoxymethyl] -3-thienyl} -1-propanone (compound (R)) to 1- [2- (hydroxymethyl) -3-thienyl] -1-propanone (compound (S)) 1.60 g (yield) 87%). The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.41 (d, J = 5.5 Hz, 1H), 7.18 (d, J = 5.5 Hz, 1H), 4.83 (s, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 196.60, 153.21, 137.33, 129.80, 123.39, 59.12, 29.42, 12.46.

(8) Synthesis of 4-ethyl-2,3-dihydrothieno [2,3c] furan (Compound (T)) According to Step K of Example 7, 1.60 g (9.40 mmol) of 1- [2- (hydroxymethyl) 4-ethyl-2,3-dihydrothieno [2,3c] furan (compound (T)) 0.44 g (yield 30%) was produced from -3-thienyl] -1-propanone (compound (S)). The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 6.89 (s, 1H), 3.62 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 2.50 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 144.70, 129.30, 128.81, 127.02, 42.19, 25.09, 12.86, 12.31.

Example 9 Synthesis of 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan According to the following formula, 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N) 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan (compound (W)). Note that 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N)) is prepared by steps A and B of Example 6.

(1) Synthesis of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-ethanone (Compound (U)) According to Step C of Example 6, 5.00 g ( 22.09 mmol) of 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N)) to 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2- 2.77 g (yield 47%) of thienyl} -1-ethanone (compound (U)) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): (7.41 (d, J = 5.5 Hz), 7.39 (d, J = 4.8 Hz), 1H), 7.26 (m, 1H), 5.93 (m, 1H) , 4.72 (m, 1H), 3.91 (m, 1H), 3.48 (m, 1H), (2.88 (s), 2.86 (s), 3H), 1.89-1.41 (m, 6H), 1.13 (m, 2H ), (0.94 (t, J = 6.9 Hz) 0.90 (t, J = 6.9 Hz), 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) (195.36, 194.96), (156.54, 151.11), ( 135.31, 131.46), (130.79, 129.40), (129.26, 128.05), (97.80, 96.03), (70.69, 68.89), (62.99, 62.37), (30.75, 30.10), (25.57, 25.01), (23.58, 20.91), (20.11, 19.60), (14.32, 14.09), (8.41, 8.26).

(2) Synthesis of 1- [3- (1-hydroxypropyl) -2-thienyl] -1-ethanone (Compound (V)) According to Step D of Example 1, 2.77 g (10.32 mmol) of 1- {3 -[1- (Tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-ethanone (compound (U)) to 1- [3- (1-hydroxypropyl) -2-thienyl] -1- 1.58 g (yield 83%) of ethanone (compound (V)) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 7.48 (d, J = 5.5 Hz, 1H), 7.14 (d, J = 5.5 Hz, 1H), 4.86 (dd, J = 7.6, 2.1 Hz, 1H) , 2.58 (s, 3H), 1.85-1.73 (m, 2H), 0.96 (t, J = 7.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) 192.71, 154.00, 135.78, 131.04, 130.08 71.52, 29.96, 29.70, 10.74.

(3) Synthesis of 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan (compound (W)) According to Step E of Example 1, 1.58 g (8.57 mmol) of 1- [3- From (1-hydroxypropyl) -2-thienyl] -1-ethanone (compound (V)) to 1.08 g of 4-ethyl-6-methyl-2,3-dihydrothieno [2,3c] furan (compound (W)) Yield 75%). The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 3.58 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.52 (q, J = 7.6 Hz, 2H), 2.15 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 145.99, 138.07, 125.75, 122.07, 42.17, 25.83, 21.04, 12.85, 12.26.

Example 10 Synthesis of 4,6-diethyl-2,3-dihydrothieno [2,3c] furan From 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N)) according to the following formula 4,6-Diethyl-2,3-dihydrothieno [2,3c] furan (compound (Z)) was prepared.

(1) Synthesis of 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-propanone (Compound (X)) According to Step C of Example 6, 5.00 g ( 22.09 mmol) of 2- (3-thienylpropyl-1-oxy) tetrahydro-2H-pyran (compound (N)) to 1- {3- [1- (tetrahydro-2H-2-pyranyloxy) propyl] -2- 2.95 g (yield 49%) of thienyl} -1-propanone (compound (X)) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): (7.41 (d, J = 5.5 Hz), 7.39 (d, J = 4.8 Hz), 1H), 7.26 (m, 1H), 5.67 (m, 1H) , (4.72 (dd, J = 4.7, 2.8 Hz), 4.42 (dd, J = 4.7, 2.8 Hz), 1H), (3.91 (m), 3.67 (m), 1H), (3.48 (m), 3.31 (m), 1H), 2.86 (m, 3H), 1.89-1.41 (m, 10H), (1.23 (t, J = 6.9 Hz), 1.19 (t, J = 6.9 Hz), 3H); ¹³ C NMR (CDCl ₃ , 150MHz, d ppm) (194.01, 193.94), (153.59, 153.11), (135.31, 133.40), (129.78, 129.42), (129.10, 128.40), (97.83, 96.81), (70.55, 69.42) , (62.87, 62.62), (31.17, 30.91), (25.53, 25.46), (22.94, 21.96), (19.98, 19.77), (14.29, 14.26), (10.43, 10.30), (8.44, 8.39).

(2) Synthesis of 1- [3- (1-hydroxypropyl) -2-thienyl] -1-propanone (Compound (Y)) According to Step D of Example 6, 2.95 g (10.45 mmol) of 1- {3 -[1- (Tetrahydro-2H-2-pyranyloxy) propyl] -2-thienyl} -1-propanone (compound (X)) to 1- [3- (1-hydroxypropyl) -2-thienyl] -1- 1.63 g (yield 79%) of propanone (compound (Y)) was produced. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm); 7.50 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 5.5 Hz, 1H), 5.16 (m, 1H), 2.82 (q, J = 6.9 Hz, 2H), 1.79 (m, 2H), 0.96 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 193.86, 155.00, 134.16, 131.53, 129.99, 67.61, 30.62 , 22.35, 21.06, 11.74.

(3) Synthesis of 4,6-diethyl-2,3-dihydrothieno [2,3c] furan (compound (Z)) According to Step 6 of Example 6, 1.63 g (8.22 mmol) of 1- [3- (1 -Hydroxypropyl) -2-thienyl] -1-propanone (compound (Y)) to 4.6-diethyl-2,3-dihydrothieno [2,3c] furan (compound (Z)) 1.38 g (92% yield) ) Was manufactured. The physical properties of this compound are shown below.

¹ H NMR (CDCl ₃ , 600 MHz, d ppm): 3.58 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.54 (q, J = 7.6 Hz, 2H), 2.53 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 150 MHz, d ppm) 145.78, 143.31 , 125.78, 120.98, 42.02, 25.42, 21.04, 20.96, 12.25, 11.95.

Example 11
A coffee fragrance was prepared by adding 1 ppm of cafe-off run to the coffee fragrance composition having the following composition.
Ingredient name Weight part vanillin 1
Cycloten 5
Maltol 5
Diacetyl 1
5-methylfurfural 1
Furfuryl alcohol 10
Furfuryl mercaptan (10% sol) 2
Furaneol 5
Coffee extract 250
Ethanol 320
Water 400
Total 1000.

Example 12
10 ppm of cafe-off run was added to 100 parts by weight of coffee flavor obtained by distilling coffee beans. When 0.1 part by weight of this was added to 100 parts by weight of coffee extract obtained from medium roasted coffee beans with an L value of 23, a more aromatic scented coffee was obtained.

Example 13
When 10 ppm of 6-ethyl-2,3-dihydrothieno [2,3c] furan is added to 100 parts by weight of a coffee extract obtained from medium roasted coffee beans with L value of 23, a more sweet roasted feeling No coffee.

Claims (8)

Thiophene compound represented by the general formula (1):

[Wherein R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a tetrahydrofuranyl group, a tetrahydropyranyl group, a methoxymethyl group, a t-butyldimethylsilyl group, an acetyl group, an ethoxy group, Any alcohol protecting group selected from the group consisting of a methyl group and a benzyloxymethyl group, R ³ is —COR ⁴ group (where R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms) Show.) However, when R ² is a hydrogen atom, R ¹ is not a hydrogen atom, a methyl group, or an n-propyl group. ]. A process for producing a caffeophthalan represented by the general formula (3a) or an analog thereof, comprising a step of reducing and cyclizing the thiophene compound represented by the general formula (2) in the presence of a transition metal catalyst:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms.)   The production method according to claim 2, wherein the transition metal catalyst is a rhodium catalyst. Steps A to D represented by the following formula:
Step A: Step of protecting the hydroxyl group of the compound (4) Step B: Step of reacting the compound (5) obtained in Step A with an alkyl metal reagent followed by reaction with an acylating reagent Step C: A step of deprotecting the compound (6) obtained in the step B; and a step D: a step of reducing and cyclizing the compound (2) obtained in the step C in the presence of a transition metal catalyst. Method for producing caffeine offran or its analog represented by 3a):

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ^{2 ′} represents an alcohol protecting group, and R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms). A thiophene compound represented by the following general formula (7):

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms). 6. The method according to claim 5 , comprising a step of cyclizing the compound (8) represented by the following formula by reacting with p-toluenesulfonyl chloride, methanesulfonyl chloride or trifluoromethanesulfonyl chloride in the presence of an alkyl metal reagent. To produce thiophene compound (7):

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms). Perfume composition characterized in that it comprises 請 Motomeko 5, wherein the thiophene compound (7) in a proportion of 1 ^{0 -2} ~10 6 ppb. 請 Motomeko 5, wherein the thiophene compound (7) a food or beverage, characterized in that it comprises a proportion of 1 ^{0 -3} ~10 9 ppb.