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"Method For Manufacturing Spilanthol And Intermediate Manufacturing Product Therefor"

Abstract: Provided is an amide ester that is useful as an intermediate manufacturing product for an aroma compound such as spilanthol or the like. Also provided is a spilanthol manufacturing method using said amide ester. High-purity spilanthol can be manufactured by reacting an amide ester represented by general formula (1) with a basic compound. (In the formula, R1 represents a phenyl group that may be substituted with a C1-6 alkyl group and either a C1-4 alkyl group, a C1-4 alkoxy group, or a halogen atom; R2 represents a C1-8 hydrocarbon group; and the wavy lines represent cis configurations, trans configurations, or a mixture of the two configurations.)

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Patent Information

Application #
Filing Date
13 January 2012
Publication Number
22/2015
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

TAKASAGO INTERNATIONAL CORPORATION
37-1, KAMATA 5-CHOME, OHTA-KU, TOKYO 1448721 JAPAN

Inventors

1. SHIGERU TANAKA
C/O CORPORATE RESEARCH & DEVELOPMENT DIVISION, TAKASAGO INTERNATIONAL CORPORATION, 4-11, NISHIYAWATA 1-CHOME, HIRATSUKA-SHI, KANAGAWA 2540073 JAPAN
2. KENYA ISHIDA
C/O CORPORATE RESEARCH & DEVELOPMENT DIVISION, TAKASAGO INTERNATIONAL CORPORATION, 4-11, NISHIYAWATA 1-CHOME, HIRATSUKA-SHI, KANAGAWA 2540073 JAPAN
3. KENJI YAGI
C/O CORPORATE RESEARCH & DEVELOPMENT DIVISION, TAKASAGO INTERNATIONAL CORPORATION, 4-11, NISHIYAWATA 1-CHOME, HIRATSUKA-SHI, KANAGAWA 2540073 JAPAN
4. HIDEO UJIHARA
C/O CORPORATE RESEARCH & DEVELOPMENT DIVISION, TAKASAGO INTERNATIONAL CORPORATION, 4-11, NISHIYAWATA 1-CHOME, HIRATSUKA-SHI, KANAGAWA 2540073 JAPAN

Specification

Description Title of Invention: METHOD FOR MANUFACTURING SPILANTHOL AND INTERMEDIATE MANUFACTURING PRODUCT THEREFOR Technical Field The present invention relates to a manufacturing method enabling manufacturing of spilanthol which is useful as flavors and fragrances in an aromatically favorable state, and a novel intermediate used in the method. Background Art Spilanthol (N-isobutyl-2,6,8-decatrienamide) is known to cause a smarting or numbing stimulus and/or a piercing stimulative feeling, and used as spices and/or herb spices in foods and beverages. Particularly, a (2E, 6Z, 8E) isomer is known to be a main component of Spilanthes oleracea, and as an effective component having strong numbing and astringent actions. The (2E, 6Z, 8E) isomer is useful as a sense stimulus component in a wide range of products such as foods, beverages, fragrances and cosmetic. Meanwhile, as a method of obtaining spilanthol there is known a method, for example, in which spilanthol is derived from naturally-occurring products such as by extraction from Spilanthes oleracea. In addition, Non Patent Literatures 1, 2 and 3, and so forth disclose methods of synthesizing spilanthol. However, such methods are not considered as industrially-applicable production methods. Incidentally, Patent Literature 1 discloses several industrially-applicable production methods. 1 Citation List Patent Literature Patent Literature 1: WO2009/091040 Al Non Patent Literatures Non Patent Literature 1: J. Am. Chem. Soc, 2461-2463, (1955) Non Patent Literature 2: Naturally Occurring Insecticides, 149-156 (1971) Non Patent Literature 3: Tetrahedron, 731-741 (1987) Summary of Invention Technical Problem An object of the present invention is to provide a method for manufacturing aromatically favorable spilanthol in high yield, and a novel intermediate used in the method. Solution to Problem The present inventors have earnestly studied to achieve the above-described object. As a result, the inventors have found out that by using a novel amide ester as an intermediate, high-purity, aromatically favorable spilanthol is obtained in high yield. In other words, the present invention includes the following contents. [1] An amide ester represented by the following general formula (1): O U Ri^^O O jp-^^^^N-^' (1) where R'"' represents an alkyl group having 1 to 6 carbon atoms; 2 and a phenyl group may have a substituent selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms and a halogen atom, R^ represents a hydrocarbon group having 1 to 8 carbon atoms, and each wavy line represents a cis configuration, a trans configuration, or a mixture of the two configurations. [2] The amide ester according to [1] , in which R-^ is an alkyl group having 1 to 4 carbon atoms. [3] The amide ester according to [2] , in which R''' is a methyl group. [4] The amide ester according to any one of [1] to [3], in which R^ is an isobutyl group or a s-butyl group. [5] A method for producing 2, 6, 8-decatrienamide, including reacting the amide ester according to any one of [1] to [4] with a basic compound. [6] A food, beverage, fragrance, cosmetic, or pharmaceutical, including 2,6,8-decatrienamide synthesized by the method according to [5] and having a chemical purity of 80% or more and a content of a 2E,6Z,8E-isomer of 65% or more. Advantageous Effects of Invention The present invention provides a novel intermediate useful in manufacturing N-isobutyl-2,6,8-decatrienamide (spilanthol) useful as flavors and fragrances. The use of the intermediate enables manufacturing of high-purity, aromatically favorable spilanthol in high yield. Description of Embodiments Hereinafter, the present invention will be described in more details. A compound of the present invention represented by a 3 general formula (1) is an amide ester which can be obtained by the following method. acyjating o (h) " „) " Examples of an alkyl group having 1 to 6 carbon atoms represented by R'"' include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl group, and the like. Moreover, R^ represents a phenyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom. Examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group, and a t-butyl group. Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, and a t-butoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. R''' is preferably an alkyl group having 1 to 4 carbon atoms. Above all, a methyl group is more preferable. Examples of a hydrocarbon group having 1 to 8 carbon atoms represented by R^ include: linear or branched alkyl groups such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a pentyl group, a 2-methylbutyl group, and a hexyl group; a phenyl group and alkyl-substituted phenyl groups 4 such as a tolyl group and a xylyl group; and aralkyl groups such as a benzyl group and a phenethyl group. R^ is preferably an isobutyl group or a s-butyl group. Examples of an acylating agent used herein include acid anhydrides (R^COOCORM, acid chlorides (R-^COCl), and the like. Examples of R'"' include those described above. Specific examples of the acid anhydride include acetic anhydride, propanoic anhydride, butyric anhydride, and the like. Examples of the acid chloride include acetyl chloride, propionyl chloride, pivaloyl chloride, benzoyl chloride, and the like. Meanwhile, when the compound (h) is subjected to an acylation reaction, it is preferable that a basic compound coexist. Examples of the basic compound used include triethylamine, tributylamine, pyridine, sodium carbonate, sodium hydroxide, potassium hydroxide, and the like. Among these, triethylamine is preferable. The acylation reaction for the compound (h) can be performed at a temperature of approximately -5°C to 100°C, preferably 10°C to 30°C. The reaction period of around approximately 1 hour to 6 hours is sufficient. Examples of a solvent which can be used in the reaction include toluene, hexane, heptane, diethyl ether, and tetrahydrofuran. Among these, toluene is preferable. The amount of the acylating agent used is 1 time to 2 times, preferably 1.05 times to 1.2 times, as large as the compound (h) in terms of mole. After the reaction is completed, the product can be purified by extraction, distillation, various chromatographies, or the like. Note that the compound (h) which is the raw material of 5 the amide ester of the compound of the present invention can be produced, for example, by the following method. " ^ T " aPh3P-^^°'* i^^^ (a) (b) '^ base ^^^ 8 >L/CI 0 0 IL OH . i t ^ o ^ ^ ^^=WO'^N^>r^ (g) " *9^ (h) Methyl 3-hydroxy-6,8-decadienoate (g) (86.1 g, 0.43 mol) and isobutylamine (95. 3 g, 1.3 mol) were put into a 500-ml flask, followed by stirring at 90°C for 24 hours. After isobutylamine was recovered under a reduced pressure, heptane (700 ml) was added thereto, followed by cooling to 0°C. A white solid thus precipitated was filtered and dried under a reduced pressure. Thus, N-isobutyl-3-hydroxy-6,8-decadienamide (h) was obtained (85.2 g, 0.35 mol, yield 82%). (Example 1) Production of N-isobutyl-3-acetoxy-6,8-decatrienamide 13 o •9 OH 0 AC2O ^ (h) " ' In a stream of nitrogen, H-'iSofeiu^l" 3-hydr'oxy-6,8-ciecadien/simi OH O NEt3 MeO^S^Q ^ (h) " ,i, f< NaOMe .^^ O In a stream of nitrogen, N-isobutyl-3-hydroxy-6, 8-decadienamide (h) (85.2 g, 0.35mol), ethyl acetate (680 ml), and triethylamine (72.1 g, 0.70 mol) were put into a 1-L flask equipped with a stirrer, a thermometer, and a dropping funnel, followed by cooling to 5°C. Then, methanesulfonyl chloride (44.7 g, 0.392 mol) was added dropwise thereto for 1 hour. After completion of the dropwise addition, water (170 ml) was added thereto, followed by separation of liquid. Further washing with water (170 mL) was carried out three times, and the solvent was removed under a reduced pressure. Thus, N-isobutyl-3-sulfonyloxy-6,8-decadienamide (i) was obtained (108.9 g, yield 98%). N-isobutyl-3-sulfonyloxy-6,8-decadienamide (i) GC/MS (m/e); 317 (M+, 3%), 301 (18), 288 (2), 260 (3), 243 (1), 222 (48), 206 (12), 192 (7), 178 (5), 155 (4), 141 (18), 128 (40), 115 (50), 107 (53), 93 (63), 79 (80), 57 (100), 41 (68) 16 For 1 hour, a 28% sodium methoxide-methanol solution (75.5 g, 0.39 mol) was added dropwise to a solution prepared by dissolving N-isobutyl-3-sulfonyloxy-6,8-decadienamide (i) (108.9 g) in THF (425 ml) and cooling to 0°C. After completion of the dropwise addition, stirring was further carried out for 2 hours. Water (170 g) was added thereto, followed by separation of liquid. Washing with water (170 mL) was carried out twice, and the solvent was removed under a reduced pressure to obtain a crude product. This crude product was distilled under a reduced pressure (140°C/0.3 torr), and N-isobutyl-2,6,8-decatrienamide (spilanthol) (58.8 g) was obtained with a 76% yield (from N-isobutyl-3-hydroxy-6,8-decadienamide (h)). In this connection, the purity of N-isobutyl-2,6,8-decatrienamide was 97.2%, and the isomer ratios of the alkene moiety were: 78.2% for (2E,6Z,8E), 18.0% for (2E,6E,8E), and 3.8% for (2E,6Z,8Z). (Stability evaluation) The crude product of N-isobutyl-2,6,8-decatrienamide obtained in Example 2 before the distillation and the crude product obtained in Comparative Example 1 were compared as follows in terms of thermal stability at 180°C assuming distillation at high temperature. In a stream of nitrogen, 1 g of each of the crude products was put into a flask together with 0.1 g of hexadecane as an internal standard substance, followed by stirring at 180°C for 6 hours. By gas chromatography, the area ratio of N-isobutyl-2,6,8-decatrienamide was compared with the area ratio of the internal standard substance to measure the remaining percentage of N-isobutyl-2,6,8-decatrienamide. 17 The remaining percentage after 3 hours was 98% in Example 2, and 89% in Comparative Example 1. This confirmed that N-isobutyl-2,6,8-decatrienamide produced by the production method of the present invention apparently had improved thermal stability. (Sensory evaluation) The sensory evaluation was performed using aqueous solutions respectively containing 10 ppm of N-isobutyl-2,6,8-decatrienamide obtained in Example 2 and Comparative Example 1. Table 1 shows the result. [Table 1] Odor Sensory evaluation (numbing and astringent actions) Example 2 little odor clear and strong Comparative unpleasant fishy strong, but Example 1 odor and/or slightly foreign amine-lilce odor were taste smelled It was confirmed that, in comparison with N-isobutyl-2,6,8-decatrienamide obtained in Comparative Example 1, N-isobutyl-2,6,8-decatrienamide obtained in Example 2 hardly had an unusual odor and exhibited excellent numbing and astringent actions. Industrial Applicability The present invention provides a novel intermediate useful in manufacturing N-isobutyl-2,6,8-decatrienamide (spilanthol) useful as flavors and fragrances. The use of the intermediate enables manufacturing of high-purity spilanthol 18 in high yield, the spilanthol being also favorable in terms of thermal stability, odor, and effectiveness. Claims Claim 1 An amide ester represented by the following general formula (1): O y R1"^0 O wherein R'^ represents an alkyl group having 1 to 6 carbon atoms; and a phenyl group which may have a substituent selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms and a halogen atom, R^ represents a hydrocarbon group having 1 to 8 carbon atoms, and each wavy line represents a cis configuration, a trans configuration, or a mixture of the two configurations. Claim 2 The amide ester according to claim 1, wherein R""" is an alkyl group having 1 to 4 carbon atoms. Claim 3 The amide ester according to claim 2, wherein R'^ is a methyl group. Claim 4 The amide ester according to any one of claims 1 to 3, wherein R^ is an isobutyl group or a s-butyl group. Claim 5 20 A method for producing 2,6,8-decatrienaraide, comprising reacting the amide ester according to any one of claims 1 to 4 with a basic compound. Claim 6 A food, beverage, fragrance, cosmetic, or pharmaceutical comprising 2,6,8-decatrienamide synthesized by the method according to claim 5 and having a chemical purity of 80% or more and a content of a 2E,6Z,8E-isomer of 65% or more.

Documents

Application Documents

# Name Date
1 361-delnp-2012-Form-3-(13-07-2012).pdf 2012-07-13
2 361-delnp-2012-Correspondence Others-(13-07-2012).pdf 2012-07-13
3 361-delnp-2012-Form-3-(27-07-2012).pdf 2012-07-27
4 361-delnp-2012-Correspondence-Others-(27-07-2012).pdf 2012-07-27
5 361-delnp-2012-Form-3 (01-08-2012).pdf 2012-08-01
6 361-delnp-2012-Correspondence Others-(01-08-2012).pdf 2012-08-01
7 Abstract.jpg 2012-08-21
8 361-delnp-2012-GPA.pdf 2012-08-21
9 361-delnp-2012-Form-5.pdf 2012-08-21
10 361-delnp-2012-Form-3.pdf 2012-08-21
11 361-delnp-2012-Form-2.pdf 2012-08-21
12 361-delnp-2012-Form-1.pdf 2012-08-21
13 361-delnp-2012-Description (Complete).pdf 2012-08-21
14 361-delnp-2012-Correspondence Others.pdf 2012-08-21
15 361-delnp-2012-Claims.pdf 2012-08-21
16 361-delnp-2012-Abstract.pdf 2012-08-21
17 361-delnp-2012-Form-18-(12-04-2013).pdf 2013-04-12
18 361-delnp-2012-1-Form-3-(12-04-2013).pdf 2013-04-12
19 361-delnp-2012-1-Correspondence Others-(12-04-2013).pdf 2013-04-12
20 361-delnp-2012-Form-3-(20-02-2014).pdf 2014-02-20
21 361-delnp-2012-Correspondence-Others-(20-02-2014).pdf 2014-02-20
22 361-delnp-2012-Petition-137-(25-03-2014).pdf 2014-03-25
23 361-delnp-2012-Correspondence-Others-(25-03-2014).pdf 2014-03-25
24 361-delnp-2012-Form-3-(29-09-2014).pdf 2014-09-29
25 361-delnp-2012-Correspondence-Others-(29-09-2014).pdf 2014-09-29
26 361-delnp-2012-Form-3-(05-02-2015).pdf 2015-02-05
27 361-delnp-2012-Correspondance Others-(05-02-2015).pdf 2015-02-05
28 361-delnp-2012-Form-3-(28-08-2015).pdf 2015-08-28
29 361-delnp-2012-Correspondence Others-(28-08-2015).pdf 2015-08-28
30 361-DELNP-2012-FER.pdf 2017-08-03
31 361-DELNP-2012-AbandonedLetter.pdf 2018-02-08

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1 361delnp2012_01-08-2017.pdf