KR101505097B1 - FURO[2,3-b]CHROMONE DERIVATIVES AND PREPARATION THEREOF - Google Patents

FURO[2,3-b]CHROMONE DERIVATIVES AND PREPARATION THEREOF Download PDF

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KR101505097B1
KR101505097B1 KR1020140133303A KR20140133303A KR101505097B1 KR 101505097 B1 KR101505097 B1 KR 101505097B1 KR 1020140133303 A KR1020140133303 A KR 1020140133303A KR 20140133303 A KR20140133303 A KR 20140133303A KR 101505097 B1 KR101505097 B1 KR 101505097B1
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furo
methyl
chromone
phenyl
chromones
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이구연
김재현
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강원대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
    • B01J23/74—Iron group metals
    • B01J23/745—Iron
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Abstract

The present invention relates to novel furo[2,3-b]chromone derivatives and a preparation method thereof and, more specifically, to furo[2,3-b]chromone derivatives which are simple and effective using an iron catalyst, have high selectivity, and can be manufactured in high yield, and to a preparation method thereof. The novel furo[2,3-b]chromone derivatives can be used for important raw materials or intermediates of drugs and natural substances.

Description

FURO [2,3-b] CHROMONE DERIVATIVES AND PREPARATION THEREOF FIELD OF THE INVENTION The present invention relates to furo [2,3-b] chromone derivatives,

The present invention relates to a furo [2.3- b ] chromone derivative which can be produced with a high selectivity and a high yield by using an iron catalyst, and a process for producing the same.

Furochromon is a heterocyclic compound containing oxygen, which is frequently found in natural products and shows a variety of physiological activities. Some of the physiological activities of the furocoumarin have been reported, such as anti-aromatase inhibitory effect, anti-HIV activity, and potential anticancer ability. Accordingly, in order to verify the medicinal efficacy of furocoumarin, which can exhibit anticancer effects, many new compounds have been developed for the synthesis and synthesis of furosomalin compounds.

Furo [2.3- b ] chromone has been extracted from Ferula ferulaeoides (STEUD.) KOROVIN in Mongolian potent mosquito-borne medicines in traditional Mongolian medicine. Such a furo [2.3- b ] chromone structure is a structure that is not commonly found in natural products, and the synthesis method is also unknown.

As a method for synthesizing a conventionally known furo [2.3- b ] chromone, a method using a 4-hydroxycoumarin derivative and a phenylacetylene derivative as starting materials and using an oxidizing agent such as Ceric Ammonium Nitrate, And sodium bicarbonate (NaHCO 3 ), and a method of reacting diazocoumarin with phenylacetylene under a diiodine tetraacetate (Rh 2 (OAc) 4 ) catalyst.

Recently, it has been known that the 3-position of 4-methoxycoumarin is replaced with an alkane as a starting material and an equivalent amount of iodine (I 2 ) is added to cyclize the starting material [ Phytochemistry. 1997 , 16, 1261; Chem. Pharm. Bull. 2002 , 50 , 675; Bioorg. Med. Chem. Lett. 2009 , 19. 2420; Bioorg. Med. Chem. Lett. 2004 , 14. 455; Anticacncer Agents Med. Chem. 2006 , 6 , 319; Tetrahedron , 1998, 51 , 12215; Bioorg. Med. Chem. Lett. 2009 , 19, 3389; J. Nat. Prod. 1986, 49, 48; Synlett. 2012, 23, 2227; Eur. J. Med. Chem. 2010 , 45, 4920; J. Heterocycles Chem. 1989 , 26 , 605; Bull. Korean Chem. Soc. 1990 , 19 , 1080; Synthesis. 2001 , 5 , 735; Org. Biomol. Chem. 2011 , 9 , 1474].

However, among the known methods, the method of reacting with phenylacetylene as a starting material is disadvantageous in that furo [3.2- c ] coumarin is produced together with furo [2.3- b ] chromone and exhibits low selectivity. Further, the method using 4-methoxy coumarin in which the 3-position is substituted with an alkyl group has a disadvantage in that it takes a lot of steps to synthesize the starting material.

Phytochemistry. 1997, 16, 1261; Chem. Pharm. Bull. 2002, 50, 675; Bioorg. Med. Chem. Lett. 2009, 19. 2420; Bioorg. Med. Chem. Lett. 2004, 14. 455; Anticacncer Agents Med. Chem. 2006, 6, 319; Tetrahedron, 1998, 51, 12215; Bioorg. Med. Chem. Lett. 2009, 19, 3389; J. Nat. Prod. 1986, 49, 48; Synlett. 2012, 23, 2227; Eur. J. Med. Chem. 2010, 45, 4920; J. Heterocycles Chem. 1989, 26, 605; Bull. Korean Chem. Soc. 1990, 19, 1080; Synthesis. 2001, 5, 735; Org. Biomol. Chem. 2011, 9, 1474

The present inventors have conducted various studies to solve the above problems. As a result, they have produced novel furo [2.3- b ] chromone derivatives through the profiling and cyclization of hydroxy coumarin compounds and propargyl alcohol compounds B ] chromone derivatives by using an iron catalyst, and that they can be produced at a high yield through a simple step. The present invention has been completed based on this finding.

Accordingly, it is an object of the present invention to provide a novel furo [2.3- b ] chromone derivative and a process for producing the same.

In order to achieve the above object, the present invention is characterized by a furo [2.3- b ] chromone derivative represented by the following formula 1:

[Chemical Formula 1]

Figure 112014094600918-pat00001

(Wherein R 1 and R 2 are as described in the specification)

Herein, the furo [2.3- b ] chromone derivative represented by the formula (1) is represented by the following reaction formula 1, and the hydroxy coumarin compound of formula (2) and the propargyl alcohol compound of formula (3) ≪ RTI ID = 0.0 >

[Reaction Scheme 1]

Figure 112014094600918-pat00002

(Wherein R 1 and R 2 are as described in the specification)

Wherein the reaction is carried out in the presence of an iron catalyst.

The amount of the iron catalyst used is in the range of 0.05 equivalent to 0.1 equivalent based on 1 equivalent of the propargyl alcohol compound of formula (3).

The novel furo [2.3- b ] chromone derivatives according to the present invention are applicable as raw materials or intermediates for pharmaceuticals and natural products.

In particular, the manufacturing method using the iron catalyst as a by-product is furo [3.2- c] furo without generation of coumarin [2.3- b] chromones derivatives only and is selectively generated, the furo under mild conditions [2.3- b] chromones derivative Can be synthesized at a high yield and the reaction step can be simplified.

The present invention provides novel furo [2.3- b ] chromone derivatives which can be used as important raw materials or intermediates in pharmaceuticals and natural products.

Preferably, the furo [2.3- b ] chromone derivative is represented by the following formula 1:

Figure 112014094600918-pat00003

(In the formula 1,

R 1 is hydrogen; Halogen; C 1 C 6 alkyl; C 1 To C 6 haloalkyl; C 1 Alkoxy of from 1 to 6 carbon atoms; C 1 Alkoxycarbonyl of from 1 to 6 carbon atoms; C 3 To cycloalkyl (cycloalkyl) of C 20; C 6 To an aryl (aryl) C of 20; Or C < 3 > in which the carbon atoms in the ring are replaced by N, S, or O To C 20 , saturated or unsaturated heteroaryl, wherein said aryl or heteroaryl is capable of fused ring formation,

R 2 is C 6 To an aryl (aryl) C of 20; Or C < 3 > in which the carbon atoms in the ring are replaced by N, S, or O To a saturated or unsaturated heteroaryl (heteroaryl) C of 20, wherein the aryl (aryl) or heteroaryl (heteroaryl) is at least one of the hydrogen-halogen (halogen), C 1 To C 6 alkyl, C 1 To C 6 haloalkyl, C 1 To C 6 alkoxy, C 1 To C 6 alkoxycarbonyl, C 3 To C 20 cycloalkyl, C 6 To C 20 aryl, or C 3 To be unsubstituted or substituted with heteroaryl, (heteroaryl) for C 20)

In this case, the halogen in Formula 1 is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

In the above formula (1), the aryl is phenyl, naphtyl, biphenyl, anthryl, indenyl, or fluorenyl.

In the above formula (1), heteroaryl may be pyrrolyl, furanyl, thiophenyl, thienyl, thiazolyl, pyridinyl, pyranyl, For example, piranyl, indolyl, piperidinyl, pyrazinyl, or piperazinyl.

Preferably, R < 1 > is hydrogen; halogen; C 1 To C 4 alkyl; C 1 To the C 4 haloalkyl; C 1 Alkoxy of from 1 to 4 carbon atoms; C 6 C12 aryl; Or C 3 Lt; RTI ID = 0.0 > C12 < / RTI > fused ring.

Also, R 2 is C 6 C12 aryl; Or C < 3 > in which the carbon atoms in the ring are replaced by N, S, or O To a saturated or unsaturated C 12 heteroaryl, wherein the aryl and heteroaryl radicals are at least one of hydrogen halogen, C 1 To C 4 alkyl, C 1 To C 4 haloalkyl, C 1 To alkoxy of C 4, C 6 To C 12 aryl, C 3 Lt; RTI ID = 0.0 > C12 < / RTI > heteroaryl.

More preferably, R 1 is selected from the group consisting of hydrogen, fluorine (F), chlorine (Cl), bromine (Br), methyl, ethyl, ethyl, propyl, methoxy, ethoxy ethoxy, n-propoxy or fused phenyl, and R 2 is fluorine (F), chlorine (Cl), bromine (Br), iodine (I) thiol, methyl, ethyl, propyl, methoxy, ethoxy, n-propoxy, fluoromethyl, difluoro, Substituted or unsubstituted phenyl, naphthyl, biphenyl, anthryl, pyrrolyl, furanyl (substituted or unsubstituted) with difluoromethyl or trifluoroethyl furanyl or thiophenyl.

Most preferably, the furo [2.3- b ] chromone derivative is selected from the following compounds:

1) 2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (2-methyl-3-phenyl -4 H -furo [2.3- b] chromone)

2) 3- (4-methoxyphenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (4-methoxyphenyl) -2 -methyl-4 H -furo [2.3- b] chromone )

3) 2-methyl-3- (4- (trifluoromethyl) phenyl) -4 H - furo [2.3- b] chromones (2-methyl-3- (4- (trifluoromethyl) phenyl) -4 H - furo [2.3- b ] chromone)

4) 3- (3- (chlorophenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (3-chlorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone )

5) 2-methyl-3 (ortho-tolyl) -4 H-furo [2.3- b] chromones (2-methyl-3- (o -tolyl) -4 H -furo [2.3- b] chromone)

6) 3- (3-methoxyphenyl) -2-phenyl -4 H - furo [2.3- b] chromones (3- (3-methoxyphenyl) -2 -methyl-4 H -furo [2.3- b] chromone )

7) 2-methyl-3- (thiophen-2-yl) -4 H - furo [2.3- b] chromones (2-methyl-3- (thiophen -2-yl) -4 H -furo [2.3- b ] chromone)

8) 2-methyl-3- (naphthalene-1-yl) -4 H - furo [2.3- b] chromones (2-methyl-3- (naphthalen -1-yl) -4 H -furo [2.3- b ] chromone)

9) 3- (2-Bromo-phenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (2-bromophenyl) -2 -methyl-4 H -furo [2.3- b] chromone )

10) 3- (4-Chloro-phenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (4-chlorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone)

11) 2-methyl-3- (meta-tolyl) -4 H-furo [2.3- b] chromones (2-methyl-3- (m -tolyl) -4 H -furo [2.3- b] chromone)

12) 6-methoxy-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (6-methoxy-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)

13) 6-chloro-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (6-chloro-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)

14) 7-methoxy-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (7-methoxy-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)

15) 2,8-dimethyl-3-phenyl -4 H - furo [2.3- b] chromones (2,8-dimethyl-3-phenyl -4 H -furo [2.3- b] chromone)

16) 3- (3-fluorophenyl) -2-methyl -4H H furo [2.3- b] chromones (3- (3-fluorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone)

17) 2,6-dimethyl-3-phenyl -4 H - furo [2.3- b] chromones (2,6-dimethyl-3-phenyl -4 H -furo [2.3- b] chromone)

18) 9-methyl-8-phenyl -7 H - benzo [h] furo [2.3- b] chromones (9-methyl-8-phenyl -7 H -benzo [h] furo [2.3- b] chromone)

The furo [2.3- b ] chromone derivative represented by the above formula (1) can be obtained by subjecting a hydroxy coumarin compound of the formula (2) and a propargyl alcohol compound of the formula (3) to a cyclization reaction in the presence of a solvent, Lt; / RTI >

[Reaction Scheme 1]

Figure 112014094600918-pat00004

(In the above Reaction Scheme 1, R 1 and R 2 are as described above)

The hydroxy coumarin compound of formula (2) used as the starting material is not particularly limited in the present invention as long as it satisfies the definition of the R 1 functional group.

Figure 112014094600918-pat00005

For example, in an embodiment of the present invention, 4-hydroxycoumarin, 4-hydroxy-6-methoxycoumarin, 4-hydroxy-6-chlorocoumarin, 4-hydroxy- 8-methylcoumarin, 4-hydroxy-6-methylcoumarin and 7,8-benzo-4-hydroxycoumarin were used. These materials can be used either directly or by purchasing commercial products.

In the above Reaction Scheme 1, the propargyl alcohol compound of Formula 3 is not particularly limited in the present invention as long as it satisfies the definition of the R 2 functional group.

Figure 112014094600918-pat00006

For example, in an embodiment of the present invention, 1-phenyl-2-propyn-1-ol, 1- (4-methoxyphenyl) 1-ol, 1- (ortho-tolyl) -2-propyn-1-ol, Propan-1-ol, 1- (3-methoxyphenyl) -2-propyn- 1- (2-bromophenyl) -2-propyn-1-ol, 1- 1-ol and 1- (3-fluorophenyl) -2-propyn-1-ol, etc. These materials were used either directly or by purchasing a commercial product This is possible.

As shown in Reaction Scheme 1, in addition to the furo [2.3- b ] coumarin derivative of the formula (1) according to the present invention in the process of propanation and cyclization of the hydroxy coumarin compound of formula (2) and the propargyl alcohol of formula [3.2- b ] coumarin derivatives can be obtained. The production of the above-mentioned furo [3.2- b ] coumarin derivative requires a further separation and purification process, which may lower the yield of furo [2.3- b ] coumarin required in the present invention.

Thus, in the present invention, the reaction is selectively carried out under an iron catalyst to obtain only a high yield of the furo [2.3- b ] coumarin derivative.

The iron catalyst that can be used is not particularly limited in the present invention, and all the iron catalysts known in this field are possible. Typical examples of the iron catalyst include FeSO 4 x H 2 O, Fe 2 (SO 4 ) 3 , FeS, iron (Ⅲ) p-toluenesulfonate hexahydrate (p-toluenesulfonate hexahydrate), trifluoromethanesulfonate iron salt (iron (ⅱ) trifluoromethanesulfonate, Fe (OTf) 3), FeBr 2, FeBr 3, FeCl 2, FeCl 3, Fe (OTf) 3, Fe (acac) 3, Fe (CO) 5, FeCl 3 6H 2 O , FeCl 3 4H 2 O, Fe 2 O 3 , Fe (NO) 3 9H 2 O, acetylferrocene, Benzoylferrocene, Bromoferrocene, Vinylferrocene, And the like. Preferably, FeSO 4 x H 2 O, Fe 2 (SO 4 ) 3 , FeS, p-toluenesulfonate hexahydrate iron salt, or trifluoromethanesulfonate iron salt is most preferable and the reaction selectivity and yield Trifloromethanesulfonate < / RTI >

The amount of the iron catalyst used is in the range of 0.05 equivalent to 0.1 equivalent based on 1 equivalent of the propargyl alcohol compound represented by the general formula (3). If the amount of the iron catalyst is less than 0.05 equivalent, the amount of the iron catalyst is insufficient, so that it is difficult to smoothly work as a catalyst and the reaction yield may be lowered. If the amount is more than 0.1 equivalent, There is a problem in that it causes an increase in the number of users.

The solvent is not particularly limited as long as it is an organic solvent and a solvent that dissolves the reaction material and does not hinder the reaction. Preferably, a mixture of dioxins, nitromethane, chlorobenzene, dichloroethane, toluene, acetonitrile, tetrahydrofuran, N, N' -dimethylformamide, N, N' -dimethylacetamide and mixtures thereof Solvent, and more preferably, dichloromethane is used in consideration of reaction time, solubility of reactants, and ease of removal.

These solvents may further be used in combination with other solvents such as butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cyclopentane, cyclohexane, cycloheptane, 2 , 2,4-trimethylpentane, butyl acetate, t-butyl methyl ether, dioxane, ethyl ether, isopropyl ether, butyl ether, 2-methoxyethyl ether, benzene, xylene, ethylbenzene, But are not limited to, nitrile, anisole, pyridine, bromobenzene, dichlorobenzene, trichlorobenzene, dibromobenzene, methylene chloride, chloroform, chlorobutane, carbon tetrachloride, dichloromethane, trichloroethane, trichlorethylene, Tetrachlorethylene, chlorodifluoroacetic acid, or a mixed solvent thereof.

At this time, the reaction temperature can be used at a temperature used in conventional organic synthesis, but it may vary depending on the reaction time and the amount of the starting material, and is preferably performed in the range of 50 to 160 ° C. There is a problem that the reaction yield may be lowered when the reaction temperature is outside the above temperature range.

The reaction time is suitably adjusted according to the starting material, the kind of the solvent, the amount of the solvent, the reaction temperature, and the like. For example, the reaction is carried out through Thin-layer chromatography or the like, and the propargyl alcohol compound of formula (3) as a starting material is consumed, and the reaction is completed after confirming that the intermediate is completely consumed before the cyclization .

When the reaction is completed, the catalyst dissolved in the organic layer is dissolved and removed in the water layer, and the organic solvent is removed under reduced pressure, and then the target product can be separated and purified through a conventional method such as column chromatography.

The novel furo [2.3- b ] chromone derivative according to the present invention can be used as a target substance or an intermediate of medicines and natural products.

In this case, the production method using the iron catalyst shows almost no generation of furo [2.3- c ] chromone derivative as a by-product and shows high selectivity to furo [2.3- b ] chromone derivative, and yield can be also increased. In addition, only water is generated as a byproduct of the reaction, so that the process after the process is simple and the step or cost of the additional separation and purification process can be reduced.

Hereinafter, the structure of the present invention will be described in more detail with reference to examples. However, the following examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

[ Example  1] 2- methyl -3- Phenyl -4 H - furo [2.3- b ] Cromon (2- methyl -3- phenyl -4 H -furo [2,3- b ] chromone )

Figure 112014094600918-pat00007

Hydroxy-coumarin (58.37 mg, 0.36 mmol) and 1-phenyl-2 (4-methylpiperazin-1-ylamine) in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) -Prop-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours, the reaction was terminated, the catalyst was removed with water and extracted with dichloromethane. Subsequently, the solvent was removed and the residue was purified by column chromatography to obtain 2-methyl-3-phenyl- 4H -furo [2.3- b ] chromone (63 mg, 76%) as a starting material. At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.30 (dd, 1H, J 1 = 1.3Hz, J 2 = 7.9Hz), 7.69-7.64 (m, 1H), 7.59-7.53 (m, 3H) , 7.47-7.42 (m, 3H), 7.38-7. 34 (m, 1H), 2.46 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.4, 161.8, 152.7, 142.9, 133.1, 130.6, 129.9, 128.1, 127.6, 126.7, 125.2, 124.0, 119.2, 117.5, 102.4, 12.6

[ Example  2] 3- (4- Methoxyphenyl )-2- methyl -4 H - Furo [2.3- b ] Cromon  (3- (4- 메틸oxyphenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00008

Hydroxyquimarine (58.37 mg, 0.36 mmol) and l- (4-methylpiperazin-1-yl) quinazoline hydrochloride were added to a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) Methoxyphenyl) -2-propyn-1-ol (48.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the resultant was purified by column chromatography to obtain the title compound, 3- (4-methoxyphenyl) -2-methyl-4H-furo [2,3- b ] chromone- 55%). At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.32 (dd, 1H, J 1 = 1.6Hz, J 2 = 7.9Hz), 7.69-7.64 (m, 1H), 7.53-7.50 (m, 3H) , 7.45-7.41 (m, 1H), 7.00-6.98 (m, 2H), 3.85 (s, 1H), 2.40 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.5, 161.7, 159.1, 152.7, 142.3, 133.0, 131.1, 126.7, 125.2, 124.0, 122.8, 118.8, 117.5, 113.6, 102.7, 55.3, 12.1

[ Example  3] 2- methyl -3- (4- ( Trifluoromethyl ) Phenyl )-4 H - furo [2.3- b ] Cromon (2- methyl -3- (4- (trifluoromethyl) phenyl) -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00009

Hydroxyquimarine (58.37 mg, 0.36 mmol) and l- (4-methylpiperazin-1-yl) quinazoline hydrochloride were added to a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) (Trifluoromethyl) phenyl) -2-propyn-1-ol (60.48 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 48 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, after separation by column chromatography to remove the solvent (4- (trifluoromethyl) phenyl) The title compound, 2-methyl-3 of the formula 6 -4H- furo [2.3- b] chromones (17 mg, 16%). At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.31 (dd, 1H, J 1 = 1.7Hz, J 2 = 7.9Hz), 7.73-7.69 (m, 5H), 7.58-7.56 (m, 1H) , 7.49-7. 45 (m, 1H), 2.48 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.5, 161.9, 152.7, 143.6, 134.4, 133.3, 130.2, 126.7, 125.5, 125.1, 125.0, 123.9, 118.3, 117.6, 102.1, 12.1

[ Example  4] 3- (3- ( Chlorophenyl )-2- methyl -4 H - Furo [2.3- b ] Cromon  (3- (3- klorophenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00010

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (3-fluoropyrimidin-4-yl) quinazoline were reacted in a test tube with chlorobenzene (1.5 mL) as a solvent in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, (49.98 mg, 0.3 mmol), and the mixture was stirred at 100 ° C. After 12 hours, the reaction was terminated, the catalyst was removed by using water and extracted with dichloromethane was Subsequently, 3- (3- (chlorophenyl) of formula (VII) is separated by column chromatography after removal of solvent the title compound 2-methyl -4H- furo [2.3- b] chromones (44.2 mg, 47% ). At this time, the by-product, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.30 (dd, 1H, J 1 = 1.4Hz, J 2 = 7.8Hz), 7.69-7.67 (m, 1H), 7.56-7.34 (m, 6H) , 2.45 (s, 3 H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.4, 161.7, 152.7, 143.3, 133.9, 133.2, 132.4, 129.7, 129.4, 128.3, 127.7, 126.7, 125.4, 123.9, 118.1, 117.6, 102.1, 12.1

[ Example  5] 2- methyl -3- ( Oso - Toril )-4 H - Furo [2.3- b ] Cromon  (2- methyl -3- (o- tolyl )-4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00011

Hydroxy coumarin (58.37 mg, 0.36 mmol) and 1- (ortho-thiomorpholinecarboxylate) in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) Propyl) -2-propyn-1-ol (43.85 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 12 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, after separation by column chromatography to remove the solvent to give the title compound, 2-methyl-3 of formula (8) (ortho-tolyl) -4 H-furo [2.3- b] chromones (41.2 mg, 47%) to give the . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.26 (dd, 1H, J 1 = 1.9Hz, J 2 = 7.9Hz), 7.69-7.65 (m, 1H), 7.56-7.54 (m, 1H) , 7.45-7.41 (m, 1H), 7.31-7.23 (m, 4H), 2.27 (s, 3H), 2.26 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.3, 161.6, 152.8, 143.0, 137.8, 133.0, 130.4, 130.3, 130.0, 128.2, 126.6, 125.5, 125.1, 124.0, 117.9, 117.6, 103.8, 19.9, 12.2

[ Example  6] 3- (3- Methoxyphenyl )-2- Phenyl -4 H - Furo [2.3- b ] Cromon  (3- (3- 메틸oxyphenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00012

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (3-fluoropyrimidin-4-yl) quinazoline were reacted in a test tube with chlorobenzene (1.5 mL) as a solvent in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, Methoxyphenyl) -2-propyn-1-ol (48.66 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the residue was purified by column chromatography to obtain the title compound, 3- (3-methoxyphenyl) -2-phenyl-4H-furo [2.3- b ] chromone (24.2 mg, 26% . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.38 (dd, 1H, J 1 = 1.3Hz, J 2 = 7.8Hz), 7.70-7.66 (m, 1H), 7.55-7.53 (m, 1H) , 7.46-7.42 (m, IH), 7.83-7.34 (m, IH), 7.18-7.14 (m, 2H), 6.93-6.90 ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.3, 161.7, 159.3, 152.6, 142.9, 133.0, 131.8, 129.0, 126.7, 125.2, 124.0, 122.3, 119.1, 117.5, 115.7, 113.2, 102.4,

[ Example  7] 2- methyl -3 ( Thiophene Yl) -4 H - Furo [2.3- b ] Cromon  (2- methyl -3- ( thiophen -2- yl )-4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00013

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (3-fluoropyrimidin-4-yl) quinazoline were reacted in a test tube with chlorobenzene (1.5 mL) as a solvent in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, Thiophen-2-yl) -2-propyn-1-ol (41.46 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 24 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, after separation by column chromatography to remove the solvent to give the title compound, 2-methyl-3 of formula 10 (thiophen-2-yl) -4 H - furo [2.3- b] chromones (21.7 mg, 26%) ≪ / RTI > At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400 MHz, CDCl 3 , 293 K, TMS) ? 8.34 (dd, 1H, J 1 = 1.5 Hz, J 2 = 7.9 Hz), 7.82 (dd, 1H, J 1 = 1.1 Hz, J 2 = ), 7.71-7.67 (m, IH), 7.54-7.52 (m, IH), 7.48-7.44 (m, IH), 7.37-7.36 , 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.4, 161.6, 152.5, 142.8, 133.2, 131.5, 129.4, 127.3, 126.8, 125.4, 125.3, 123.9, 117.5, 113.4, 102,

[ Example  8] 2- methyl -3- (naphthalen-1-yl) -4 H - Furo [2.3- b ] Cromon  (2- methyl -3- ( naphthalen -One- yl )-4 H -furo [2,3- b ] chromone)]

Figure 112014094600918-pat00014

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (naphthalene-2-carboxylate) were dissolved in a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) Yl) -2-propyn-1-ol (54.67 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 22 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, after separation by column chromatography to remove the solvent the title compound, 2-methyl-3- (naphthalene-1-yl) of formula 11 -4 H - furo [2.3-b] chromones (38.7 mg, 40%) ≪ / RTI > At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.22 (dd, 1H, J 1 = 1.6Hz, J 2 = 7.9Hz), 7.90 (d, 1H, J = 8.2Hz), 7.76 (d, 1H , J = 8.3 Hz), 7.67-7.65 (m, 1H), 7.58-7.41 (m, 6H), 2.27 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.2, 161.8, 152.9, 144.1, 133.7, 133.1, 132.4, 128.7, 128.5, 128.4, 128.3, 126.8, 125.9, 125.7, 125.2, 124.1, 117.6, 116.8, 104.1,

[ Example  9] 3- (2- Bromophenyl )-2- methyl -4 H - Furo [2.3- b ] Cromon  (3- (2- bromophenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00015

Hydroxyquimarine (58.37 mg, 0.36 mmol) and l- (2-methylpiperazin-1-yl) quinazoline hydrochloride were added to a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) Bromophenyl) -2-propyn-1-ol (63.31 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 24 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, of the separated by column chromatography and then removing the solvent the title compound formula (12) 3- (2-Bromo-phenyl) -2-methyl -4 H - furo [2.3- b] chromones (34.5 mg, 32%) ≪ / RTI > At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.32 (dd, 1H, J 1 = 1.3Hz, J 2 = 7.8Hz), 7.69-7.66 (m, 2H), 7.56 (dd, 1H, J 1 = 0.7 Hz, J 2 = 7.8 Hz), 7.46-7.38 (m, 3H), 7.28-7.25 (m, 1H), 2.31 (s, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ 173.2, 161.4, 152.9, 143.9, 133.1, 132.8, 132.2, 131.9, 129.7, 127.1, 126.7, 125.3, 124.7, 124.0, 117.9, 117.6, 103.4, 12.1

[ Example  10] 3- (4- Chlorophenyl )-2- methyl -4 H - Furo [2,3- b ] Cromon  (3- (4- klorophenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00016

Hydroxyquimarine (58.37 mg, 0.36 mmol) and l- (4-methylpiperazin-1-yl) quinazoline hydrochloride were added to a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) Chlorophenyl) -2-propyn-1-ol (49.98 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the residue was purified by column chromatography to obtain the title compound, 3- (4-chlorophenyl) -2-methyl- 4H -furo [2.3- b ] chromone (64 mg, 68% . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400 MHz, CDCl 3, 293 K, TMS) ? 8.28 (dd, 1H, J 1 = 1.5 Hz, J 2 2 = 7.9 Hz), 7.70-7.65 , 7.46-7.40 (m, 3H), 2.43 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.4, 161.8, 152.6, 150.0, 133.6, 133.2, 131.2, 129.0, 128.5, 128.3, 126.6, 125.3, 123.9, 118.2, 117.6, 102.2, 12.1

[ Example  11] 2- methyl -3 ( Meta - Toril )-4 H - Furo [2.3- b ] Cromon  (2- methyl -3- (m- tolyl )-4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00017

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (meta- and diisopropylethylamine) were added to a test tube in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) 2-propyn-1-ol (43.86 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 7 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, after separation by column chromatography to remove the solvent the title compound, 2-methyl-3 of the formula 14 (meta-tolyl) -4 H-furo [2.3- b] to give the chromones (54.3 mg, 63%). At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.31 (dd, 1H, J 1 = 1.5Hz, J 2 = 8.0Hz), 7.68-7.64 (m, 1H), 7.53-7.51 (m, 1H) , 7.45-7.32 (m, 4H), 7.18-7.16 (m, 1H), 2.44 (s, 3H), 2.43 (s, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ 173.4, 161.7, 152.7, 142.8, 137.6, 133.0, 130.5, 128.4, 128.0, 127.0, 126.7, 125.2, 124.0, 119.3, 117.5, 102.4, 21.6, 12.1

[ Example  12] 6- Methoxy -2- methyl -3- Phenyl -4 H - Furo [2.3- b ] Cromon  (6- 메틸oxy -2- methyl -3- phenyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00018

Hydroxy-6-methoxyquimarine (69.18 mg, 0.36 mmol) in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) and chlorobenzene (1.5 mL) 1-phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the resultant was purified by column chromatography to obtain the title compound, 6-methoxy-2-methyl-3-phenyl- 4H -furo [2.3- b ] chromone (33 mg, 36% . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 7.70 (d, 1H, J = 3.1Hz), 7.59-7.57 (m, 2H), 7.47-7.43 (m, 3H), 7.38-7.34 (m, 1H), 7.25-7.22 (m, 1H), 3.87 (s, 3H), 2.45 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.3, 161.9, 156.9, 147.1, 142.8, 130.6, 129.9, 128.1, 127.6, 124.6, 122.4, 119.1, 118.7, 106.5, 101.9, 55.9, 12.1

[ Example  13] 6- Chloro -2- methyl -3- Phenyl -4 H - furo [2.3- b ] Cromon (6- chloro -2- methyl -3- phenyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00019

Hydroxy-6-chlorocoumarin (70.77 mg, 0.36 mmol) in the presence of trifluoromethanesulfonic acid (III) salt (15.09 mg, 0.03 mmol) and chlorobenzene (1.5 mL) Phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 11 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the residue was purified by column chromatography to obtain the title compound, 6-chloro-2-methyl-3-phenyl- 4H -furo [2.3- b ] chromone (54 mg, 59% . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.26 (d, 1H, J = 2.4Hz), 7.62 (dd, 1H, J 1 = 2.6Hz, J 2 = 8.9Hz), 7.57-7.55 (m , 2H), 7.50-7.44 (m, 3H), 7.39-7.37 (m, 1H), 2.51 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 172.1, 161.7, 151.0, 143.3, 133.2, 131.2, 130.3, 130.2, 130.0, 129.8, 128.3, 127.7, 126.2, 125.1, 119.2, 119.1, 102.5, 12.1

[ Example  14] 7- Methoxy -2- methyl -3- Phenyl -4 H - Furo [2.3- b ] Cromon  (7- 메틸oxy -2- methyl -3- phenyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00020

Hydroxy-7-methoxycoumarin (69.18 mg, 0.36 mmol) in the presence of trifluoromethanesulfonic acid (III) salt (15.09 mg, 0.03 mmol) and chlorobenzene (1.5 mL) 1-phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 19 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the resultant was purified by column chromatography to obtain the title compound, 8-methoxy-2-methyl-3-phenyl- 4H -furo [2.3- b ] chromone (20.5 mg, 22% . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.19 (d, 1H, J = 2.4Hz), 7.59-7.57 (m, 2H), 7.46-7.43 (m, 2H), 7.37-7.33 (m, 1H), 7.01 (dd, 1H , J 1 = 2.4Hz, J 2 = 8.9Hz), 6.94 (d, 1H, J = 2.4Hz), 3.88 (s, 3H), 2.50 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 161.7, 158.0, 157.0, 154.1, 150.7, 130.2, 129.9, 128.2, 127.7, 121.6, 120.1, 112.7, 107.2, 106.3, 101.1, 55.7, 12.5

[ Example  15] 2,8- Dimethyl -3- Phenyl -4 H - Furo [2.3- b ] Cromon  (2,8- dimethyl -3- phenyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00021

Hydroxy-8-methylcoumarin (63.42 mg, 0.36 mmol) in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) and chlorobenzene (1.5 mL) Phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 7 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the resultant was purified by column chromatography to obtain the title compound, 2,8-dimethyl-3-phenyl- 4H -furo [2.3- b ] chromone (58 mg, 67%). At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.14 (dd, 1H, J 1 = 1.3Hz, J 2 = 7.8Hz), 7.59-7.57 (m, 2H), 7.49-7.42 (m, 3H) , 7.37-7.28 (m, 2H), 2.53 (s, 3H), 2.44 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.7, 161.8, 151.2, 142.7, 134.3, 130.6, 129.9, 128.1, 127.6, 126.9, 124.7, 124.3, 123.9, 119.2, 102.1, 15.6, 12.1

[ Example  16] 3- (3- Fluorophenyl )-2- methyl -4 H - Furo [2.3- b ] Cromon  (3- (3- fluorophenyl )-2- methyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00022

Hydroxyquimarine (58.37 mg, 0.36 mmol) and 1- (3-fluoropyrimidin-4-yl) quinazoline were reacted in a test tube with chlorobenzene (1.5 mL) as a solvent in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, Fluorophenyl) -2-propyn-1-ol (44.43 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 12 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the residue was purified by column chromatography to obtain 3- (3-fluorophenyl) -2-methyl- 4H -furo [2.3- b ] chromone (30.6 mg, 35% ≪ / RTI > At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.34 (dd, 1H, J 1 = 1.4Hz, J 2 = 7.8Hz), 7.72-7.68 (m, 1H), 7.56-7.53 (m, 1H) , 7.48-7.36 (m, 3H), 7.32-7.26 (m, 1H), 7.09-7.04 (m, 1H), 2.46 (s, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ 173.4, 163.7, 161.8, 161.3, 152.7, 143.3, 133.2, 132.8, 132.7, 129.6, 129.5, 126.7, 125.7, 125.7, 125.4, 123.9, 118.4, 118.3, 117.6, 116.9 , 116.7, 114.6, 114.4, 102.2, 12.1

[ Example  17] 2,6- Dimethyl -3- Phenyl -4 H - Furo [2.3- b ] Cromon  (2,6- dimethyl -3- phenyl -4 H -furo [2,3- b ] chromone)

Figure 112014094600918-pat00023

Hydroxy-6-methylcoumarin (63.42 mg, 0.36 mmol) in the presence of trifluoromethanesulfonic acid (III) salt (7.55 mg, 0.015 mmol) and chlorobenzene (1.5 mL) Phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 6.5 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Subsequently, the solvent was removed and the resultant product was purified by column chromatography to obtain 2,6-dimethyl-3-phenyl- 4H -furo [2.3- b ] chromone (45.8 mg, 56%) of the title compound. At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.07 (s, 1H), 7.59-7.57 (m, 2H), 7.50-7.41 (m, 4H), 7.37-7.33 (m, 1H), 2.46 ( s, 3H), 2.45 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 173.6, 161.9, 150.9, 142.7, 135.1, 134.2, 130.6, 129.9, 128.1, 127.6, 126.2, 123.6, 119.2, 117.2, 102,

[ Example  18] 9- methyl -8- Phenyl -7 H - Benzo [ h ] Furo [2.3- b ] Cromon  (9- methyl -8- phenyl -7 H -benzo [ h ] furo [2,3- b ] chromone)

Figure 112014094600918-pat00024

Benzo-4-hydroxy coumarin (76.39 mg, 0.36 mmol) in the presence of trifluoromethane sulfonic acid (III) salt (7.55 mg, 0.015 mmol) with chlorobenzene (1.5 mL) And 1-phenyl-2-propyn-1-ol (39.65 mg, 0.3 mmol) were mixed and stirred at 100 ° C. After 8 hours the reaction was terminated, the catalyst was removed using water and extracted with dichloromethane. Then, H -7 separated by column chromatography and then removing the solvent to give the title compound 9-methyl-8-phenyl of the formula 21-benzo [h] furo [2.3- b] chromones (43.4 mg, 45%) to give the . At this time, the byproduct, furo [3.2- c ] coumarin compound was not produced.

1 H NMR (400MHz, CDCl 3 , 293K, TMS) δ 8.53-8.49 (m, 1H), 8.2 (d, 1H, J = 8.2Hz), 7.92-7.88 (m, 1H), 7.77 (d, 1H, J = 8.7 Hz), 7.68-7.61 (m, 4H), 7.49-7.45 (m, 2H), 7.39-7.35 (m, 1H) 2.49 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl 3): δ 173.5, 161.4, 149.5, 143.1, 135.8, 130.6, 129.9, 128.9, 128.1, 128.0, 127.6, 127.2, 125.1, 123.6, 121.9, 121.6, 120.0, 119.3, 103.2, 12.2

Experimental Example : Yield Analysis by Catalyst Type

Table 1 shows the results of analysis of the yield change according to the type of catalyst of the compound of formula (Ia) prepared in Example 1. To investigate the yield of the compound of formula (1a) according to the catalyst, 4-hydroxy coumarin of the following formula (2a) and 1-phenyl-2-propyn-1-ol of the following formula (3a) were reacted with dichloroethane . The yield of the reaction product was analyzed by 1 H NMR.

Figure 112014094600918-pat00025
R1 = H, R 2 =
Figure 112014094600918-pat00026
 division Catalyst used
(mol%) menstruum Temperature
(° C) Reaction time
(hr) Yield: 1a / 1b
(%) Example 1 Fe (OTf) 3 (5.0) Chlorobenzene 100 16 82% / 0% Comparative Example 1 TfOH (30.0) Dichloroethane 80 4 5% / 84% Comparative Example 2 Bi (OTf) 3 (5.0) Dichloroethane reflux 3.5 39% / 42% Comparative Example 3 Sc (OTf) 3 (5.0) Diglyme 100 3 0% / 0% Comparative Example 4 Ag (OTf) 3 (5.0) Diglyme 100 22 0% / 80%

Referring to Table 1, the yield of the ferrous [3.2- c ] coumarin derivative of Formula 1b was not produced as a by-product in Example 1 using the iron catalyst according to the present invention .

In comparison, in the case of Comparative Examples 1 and 2, two materials were produced together, and in the case of the cesium and silver catalysts of Comparative Examples 3 and 4, it was found that furo [2.3- b ] chromone was not produced.

From these results, it can be seen that not only the selectivity of the furo [2.3- b ] chromone is increased but also the yield is increased by using the iron catalyst.

The furo [2.3- b ] chromone derivatives according to the present invention can be used as important raw materials or intermediates for medicines and natural products.

Claims (11)

A furo [2.3- b ] chromone derivative represented by the following formula (1):
[Chemical Formula 1]
Figure 112014119608947-pat00027

(In the formula 1,
R 1 is hydrogen; Halogen; C 1 to C 6 alkyl; C 1 to C 6 haloalkyl; C 1 to C 6 alkoxy; C 1 to C 6 alkoxycarbonyl; C 3 to C 20 cycloalkyl; Or C 6 to C 20 aryl, wherein said aryl is capable of forming a fused ring,
R 2 is C 6 to C 20 aryl; Or a C 3 to C 20 saturated or unsaturated heteroaryl wherein at least one carbon atom in the ring is replaced by N, S, or O, wherein the aryl or heteroaryl is at least one hydrogen Is selected from the group consisting of halogen, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkoxycarbonyl ( alkoxycarbonyl, C 3 to C 20 cycloalkyl, or C 6 to C 20 aryl) The method according to claim 1,
R < 1 > is hydrogen; halogen; C 1 to C 4 alkyl; C 1 to C 4 haloalkyl; C 1 to C 4 alkoxy; C 6 to C 12 aryl; Or aryl forming a C 6 to C 12 fused ring,
R 2 is C 6 to C 12 aryl; Or C 5 to C 12 unsaturated heteroaryl in which at least one carbon atom in the ring is substituted with S, wherein said heteroaryl is substituted with at least one of hydrogen, halogen, C 1 to C 4 alkyl, C 1 to C 4 halo alkyl, C 1 to C 4 alkoxy, or C 6 to furo characterized in that the substituted or unsubstituted aryl of C 12 [2.3- b] chromones derivative. The method according to claim 1,
R 1 is hydrogen, fluorine (F), chlorine (Cl), bromine (Br), methyl, ethyl, propyl, methoxy, ethoxy, n- N-propoxy, or fused phenyl,
The R 2 may be fluorine, chlorine, bromine, iodine, thiol, methyl, ethyl, propyl, methoxy, Phenyl, which is unsubstituted or substituted with ethoxy, n-propoxy, fluoromethyl, difluoromethyl or trifluoroethyl, naphthyl (naphtyl), biphenyl (biphenyl), or thiophenyl (thiophenyl), characterized in that furo [2.3- b] chromones derivative. The method according to claim 1, wherein the furo [2.3- b] furo chromones derivatives, characterized in that a compound selected from [2.3- b] chromones derivatives:
1) 2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (2-methyl-3-phenyl -4 H -furo [2.3- b] chromone)
2) 3- (4-methoxyphenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (4-methoxyphenyl) -2 -methyl-4 H -furo [2.3- b] chromone )
3) 2-methyl-3- (4- (trifluoromethyl) phenyl) -4 H - furo [2.3- b] chromones (2-methyl-3- (4- (trifluoromethyl) phenyl) -4 H - furo [2.3- b ] chromone)
4) 3- (3- (chlorophenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (3-chlorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone )
5) 2-methyl-3 (ortho-tolyl) -4 H-furo [2.3- b] chromones (2-methyl-3- (o -tolyl) -4 H -furo [2.3- b] chromone)
6) 3- (3-methoxyphenyl) -2-phenyl -4 H - furo [2.3- b] chromones (3- (3-methoxyphenyl) -2 -methyl-4 H -furo [2.3- b] chromone )
7) 2-methyl-3- (thiophen-2-yl) -4 H - furo [2.3- b] chromones (2-methyl-3- (thiophen -2-yl) -4 H -furo [2.3- b ] chromone)
8) 2-methyl-3- (naphthalene-1-yl) -4 H - furo [2.3- b] chromones (2-methyl-3- (naphthalen -1-yl) -4 H -furo [2.3- b ] chromone)
9) 3- (2-Bromo-phenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (2-bromophenyl) -2 -methyl-4 H -furo [2.3- b] chromone )
10) 3- (4-Chloro-phenyl) -2-methyl -4 H - furo [2.3- b] chromones (3- (4-chlorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone)
11) 2-methyl-3- (meta-tolyl) -4 H-furo [2.3- b] chromones (2-methyl-3- (m -tolyl) -4 H -furo [2.3- b] chromone)
12) 6-methoxy-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (6-methoxy-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)
13) 6-chloro-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (6-chloro-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)
14) 7-methoxy-2-methyl-3-phenyl -4 H - furo [2.3- b] chromones (7-methoxy-2-methyl -3-phenyl-4 H -furo [2.3- b] chromone)
15) 2,8-dimethyl-3-phenyl -4 H - furo [2.3- b] chromones (2,8-dimethyl-3-phenyl -4 H -furo [2.3- b] chromone)
16) 3- (3-fluorophenyl) -2-methyl -4H H furo [2.3- b] chromones (3- (3-fluorophenyl) -2 -methyl-4 H -furo [2.3- b] chromone)
17) 2,6-dimethyl-3-phenyl -4 H - furo [2.3- b] chromones (2,6-dimethyl-3-phenyl -4 H -furo [2.3- b] chromone)
18) 9-methyl-8-phenyl -7 H - benzo [h] furo [2.3- b] chromones (9-methyl-8-phenyl -7 H -benzo [h] furo [2.3- b] chromone) Represented by the following Reaction Scheme 1,
A method of producing a furo [2.3- b ] chromone derivative of the formula (1) by the reaction of a hydroxy coumarin compound of the formula (2) and a propargyl alcohol compound of the formula (3)
[Reaction Scheme 1]
Figure 112014119608947-pat00028

(In the above Reaction Scheme 1,
R 1 is hydrogen; Halogen; C 1 to C 6 alkyl; C 1 to C 6 haloalkyl; C 1 to C 6 alkoxy; C 1 to C 6 alkoxycarbonyl; C 3 to C 20 cycloalkyl; Or C 6 to C 20 aryl, wherein said aryl is capable of forming a fused ring,
R 2 is C 6 to C 20 aryl; Or a C 3 to C 20 saturated or unsaturated heteroaryl wherein at least one carbon atom in the ring is replaced by N, S, or O, wherein the aryl or heteroaryl is at least one hydrogen Is selected from the group consisting of halogen, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkoxycarbonyl ( alkoxycarbonyl, C 3 to C 20 cycloalkyl, or C 6 to C 20 aryl) The method of claim 5,
R < 1 > is hydrogen; halogen; C 1 to C 4 alkyl; C 1 to C 4 haloalkyl; C 1 to C 4 alkoxy; C 6 to C 12 aryl; Or aryl forming a C 6 to C 12 fused ring,
R 2 is C 6 to C 12 aryl; Or C 5 to C 12 unsaturated heteroaryl in which at least one carbon atom in the ring is substituted with S, wherein said heteroaryl is substituted with at least one of hydrogen, halogen, C 1 to C 4 alkyl, C 1 to C 4 halo Alkyl, C 1 to C 4 alkoxy, or C 6 to C 12 aryl. 11. A process for the preparation of a furo [2.3- b ] chromone derivative according to claim 1, The process for producing a furo [2.3- b ] chromone derivative according to claim 5, wherein the propanation and cyclization are carried out in the presence of an iron catalyst. The method of claim 7, wherein the iron catalyst is selected from the group consisting of FeSO 4 x H 2 O, Fe 2 (SO 4 ) 3 , FeS, p-toluenesulfonate hexahydrate hexahydrate (Iron (Ⅲ) p-toluenesulfonate hexahydrate) Eight iron salt (iron (ⅱ) trifluoromethanesulfonate, Fe (OTf) 3), FeBr 2, FeBr 3, FeCl 2, FeCl 3, Fe (OTf) 3, Fe (acac) 3, Fe (CO) 5, FeCl 3 6H 2 O, FeCl 3 4H 2 O, Fe 2 O 3 , Fe (NO) 3 9H 2 O, acetylferrocene, Benzoylferrocene, Bromoferrocene, Vinylferrocene, Wherein the furo [2,3- b ] chromone derivative is selected from the group consisting of the following compounds. The method for producing a furo [2.3- b ] chromone derivative according to claim 7, wherein the iron catalyst is used in an amount of 0.05 equivalent to 0.1 equivalent based on 1 equivalent of the propargyl alcohol compound represented by the general formula (3). The method of claim 5, wherein the solvent is selected from the group consisting of dioxin, nitroethane, chlorobenzene, dichloroethane, toluene, acetonitrile, tetrahydrofuran, N, N' -dimethylformamide, N, N' -dimethylacetamide And a mixed solvent thereof. 2. A process for producing a furo [2.3- b ] chromone derivative according to claim 1, The process for preparing a furo [2.3- b ] chromone derivative according to claim 5, wherein the reaction is carried out at a temperature ranging from 50 to 160 ° C.
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