CA1110254A - Preparation of gamma-pyrones - Google Patents
Preparation of gamma-pyronesInfo
- Publication number
- CA1110254A CA1110254A CA363,273A CA363273A CA1110254A CA 1110254 A CA1110254 A CA 1110254A CA 363273 A CA363273 A CA 363273A CA 1110254 A CA1110254 A CA 1110254A
- Authority
- CA
- Canada
- Prior art keywords
- chlorine
- gamma
- solution
- carbon atoms
- bromine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
Abstract
A B S T R A C T
The preparation of gamma-pyrones, by a process which comprises reacting a furfuryl alcohol with at least two equivalents of a halogen-containing oxidant, selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or a mixture thereof, and heating the resulting 4-halo-dihydro-pyran intermediate until hydrolysis is substantially complete.
The preparation of gamma-pyrones, by a process which comprises reacting a furfuryl alcohol with at least two equivalents of a halogen-containing oxidant, selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or a mixture thereof, and heating the resulting 4-halo-dihydro-pyran intermediate until hydrolysis is substantially complete.
Description
z~i~
This is a divisional of Patent Application No.
279922 filed June 6th 1977.
Application No. 279922 describes and claims the preparation of gamma-pyrones and particularly the prepara-tion of gamma-pyrones by the hydrolysis of certain intermedi-ate compounds, some of which are novel, which intermediates are prepared from appropriate furfuryl alcohols by the use of halogen-containing oxidants. The present divisional is concerned with a one-pot process for preparing gamma-pyrones from furfuryl alcohols.
Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production was from the destructive distillation of wood.
The synthesis of maltol from 3-hydroxy-2-~1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J.
Am. Chem. Soc., 69 2908 (1947). Schenck and Spielman, J.
Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkaline hydrolysis of streptomycin salts. Chawla and McGonigal, J. Org. Chem., 39, 3281 (1974) and Lichtenthaler and Heildel, Angew. Chem., 81, 998 (1969), reported the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), describ-ed a five step synthesis of maltol starting with methyl furfuryl alcohol.
The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one as one of the characteristic sweet-aroma compon-ents in refinery final molasses was reported by Hiroshi Ito in Agr. Biol. Chem., 40 (5), 827-832 (1976) This compound was previously synthesized by the process described in ZS~
United States Patent Specification No. 3,468,915.
Syntheses of gamma-pyrones such as pyromeconic acid, maltol, e~hyl maltol and other 2-subs~ituted-3-hydroxy-gamma-pyrones are described in United States Patents No. 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,469;
3,376,317; 3,468,915; 3,440,183; and 3,446,629.
Maltol and ethyl maltol enhance the flavor and aroma of a variety of food products. In addition, these compounds are used as ingredients in perfumes and essences.
- 10 The 2-alkenylpyromeconic acids reported in United States Patent No 3,644,635 and the 2-arylmethylpyromeconic acids described in United States Patent No. 3,365,469 inhibit the growth of bacteri and fungi and are useful as flavor and aroma enhancers in foods and beverages and aroma enhancers in perfumes.
The present invention Provides a proaess for preparing a gamma-pyrone of the formula:
~ OH
/\o ~~ R
R''' wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R''' is hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a compound of the formula:
~ ~ OH o~(III) R''' R
wherein R and R''' are as defined above, in aqueous solution at a temperature of -50 to 50C. with at least two equival-ents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof and heating the resulting 4-halo-dihydropyran intermediate until hydrolysis is substantially complete.
Thus, the present invention provides a novel and 25~
facile synthesis of gamma-pyrones of formula (I) above, par-ticularly maltol t2-methyl-3-hydroxy-4H-pyran-4-one~ and related compounds, by a one-pot process from a furfuryl al-cohol of formula (III) above.
In accordance with this one-pot process, a furfuryl alcohol in aqueous medium is reacted with two equivalents of a halogen-containing oxidant and the reac-tion mixture is then heated to hydrolyze the resulting inte~
mediate. The one pot process may be represented by the following equation.
R ' ~ ~ ~R
R' "
(III) (I) wherein R i9 hydrogen, alkyl of I to 4 carbon atoms, phenyl or benzyl; R" ' iS hydrogen or alkyl of 1 to 4 carbon atoms;
and XY is C12, Br2, ClBr, HOCl, HOBr or mixture~ thereof.
The full reaction pathway is shown in the following scheme:
R ' ' ' ~o (III) R' ' ' (~=0 H
~H
~H op~n ~=O chain H- ~OH tautomér R " ~ R ' '~
~1 l~ (II') (I) open chain tautomer Lefebvre and co-workers in J. Med. Chem., 16, 1084 (1973) demonstrated that furfuryl alcohols could be direat-ly converted to 6-hydroxy-2H-pyran-3(6H)one6 when a peracid oxidant such as peracetic acid or m-chloroperben~oic acid is employed, The first step on the Lefebvre work uses a peracid in an orqanic solvent and probably leads to a 6-acetoxy or 6-m-chlorobenzoyloxy pyran derivative which is hydrolyzed to the 6-hydroxy compound during the aqueous work-up. Water is not used in the first step of the reac-tion, and would in fact be deleterious. In any case, theprocess of Lefebvre and co-workers cannot lead directly to the conversion of a furfuryl alcohol to a gamma-pyrone.
Critical to the process for the preparation of the intermediates of the present invention is the use of an 15 aqueous solution of a halgen-containing oxidant. A furfuryl alcohol may be cleanly oxidized to a 6-hydroxy-2H-pyran-3 (6H)-one using one equivalent of a halogen-containing oxidant in water or water/organic co-solvent. It is a surprising and unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can be converted to gamma-pyrones. A 6-hydroxy-2H-pyran-3(6H)-one may be regarded as a hemi-acetal of an aldehyde and as such might be expected to undergo numerous undesired si~e reactions such as over oxidation or an aldol-type condensations. By employing two equivalents of a 25 halogen-containing oxidant in water or water and organic co-solvent, the reaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone. This novel one pot process offers the advantages of employing low cost Cl2, Br2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant.
30 Isolation of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and may be removed in vacuo to afford crude gamma-pyrone directly in high yield by simple concentration.
The one pot process is operated by dissolving 35 a furfuryl alcohol in water or water and a co-solvent. The co-solvent may be water-miscible or water-immiscible and may be selected from a wide range of solvents such as Cl to ;ZS~
C4 alkanols or diols, for example, methanol; C2 to C10 ethers, for example, tetrahydrofuran or isopropyl ether;
low molecular weight ketones, for example, acetone; low molecular weight nitriles; low molecular weight esters and low molecular weight amides. The preferred co-solvents are Cl to C4 alkanols and C2 to C10 ethers, with methanol the choice of solvents because of cost. The solution is kept at a temperature of -50 to 50C., preferably -10 to 10C To this solution is charged a desired furfuryl alcohol while simultanteously adding a halogen-containing oxidant (two equivalents) to the reaction mixture. The temperature of the reaction mixture is maintained at -50 to 50C., preferably -10 to 10C,, during halogen addition.
If a low-boiling co-solvent is employed, it is removed by distillation after all additions are complete. The reaction mixture is then heated to a temperatue at which the hydro-lysis proceeds at a reasonable rate, for example, 70 to 160C, The generally employed hydrolysis temperature is 100 to 110C. The heating is continued until the hydrolysis of the formed 4-halo-dihydropyran intermediate is substantially complete (usually 1 to 2 hours). The acid necessary to catalyze this final hydrolysis is generated ln situ by loss of acid from the intermediates formed during the course of the reaction. Additional acid may be added if desired.
The halogen-containing oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous or hypobromous acid or mixtures thereof. Bromine chloride is a commercially available gas, It may be prepared ln situ by the addition of chlorine to a solution of sodium or potassium bromine or by the addition of bromine to a solu-tion of sodium or potassium chloride. Hypochlorous and hypobromous acid conveniently may be generated in situ by the addition of aqueous acid (HCl, H2SO4 or HBr) to a - 35 solution of an alkali metal or alkaline earth metal hypo-halite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred halogen-containing oxidants, based ~n cost factors, are chlorine and bromine chloride prepared in situ.
ZS~
The following Examples illustrate the preparation of the gamma-pyrones according to the procegs of the inven-tion.
In the Examples where spectral data are given, 5 NMR chemical shift data are reported by conventional liter-ature symbolism and all shifts are expressed as ~ units fran tetramethyl silane:
s = singlet t = triplet q = quartet Example 1 In a 3-neck round bottom f lask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an additional funnel was added 20 ml of tetrahydrofuran 15 and 50 ml of water. The solution was cooled to a temper-ature of 0 to 10C. The addition funnel was charged with a solution of 1(2-furyl) -l-ethanol ~0,089 moles~ in 20 ml of tetrahydrofuran and this was added dropwise to the reac-tion flask while chlorine (0.30 mole) was added via the 20 gas inlet tube. The rate of addition was such that all the alcohol was added in the f irst 1.3 to 1.5 equivalents of chlorine (approximately 30 minutes) while maintaining the temperature below 10C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation.
25 When the reaction mixture reached a temperature of about 105C,, a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2.2 and the reaction mixture was cooled to 5C. Crystallization and filtration yielded 30 3.43 grams of crude 3-hydroxy-2-methyl-~-pyrone ~maltol) .
The aqueous filtrate was extracted with chloroform to o~tain a second crop of 2.58 g of maltol. Distillation of the combined solids and recrystallization f~om methanol gave 5.5 g (49%) of pure white maltol, m.p. 159.5 to 160.5C.
Example 2 The procedure of Example 1 was repeated under varying conditions as shown in Table I with furfuryl alco-hols of the formula ~ ~ ~ H
Table 1. One Pot Process using ~hlorine as the oxidant.
RCosolvent Temp. (C) Temp. ~C) Yield of oxidation of hydrolysis ~%~
CH3methanol lO 100 45 CH3methanol 5 110 56 CH3methanol -5 104 60 CH3methanol -lO 104 77 10 CH3methanol -20 106 62-67 CH3acetone -5 110 36 CH3Et OAc O llO 26 15 CH3none 10 110 17-30 CH3 benzene lO llO 26 CH3 methyl isobutyl ketone 5 llO 44 CH3 isopropyl alcohol O llO 49 20CH2CH3 methanol 5 llO 49 CH2CH3 methanol -lO 110 58 H methanol -10 110 57 CH3 methanol -30 110 50 THF - tetrahydrofuran EtOAc = ethyl acetate Example 3 The method of Example 2 was repeated with compar-able results employing each of the following co-solvents:
ethanol ethyl ether n-propanol isopropyl ether iso-butanol dimethoxy ethane n-butanol 2-methoxy ethanol t-butanol 2-ethoxy ethanol dioxane ethylene glycol 111~254 Example 4 In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml of water and sodium 5 bromide (0.20 mole) . The solution was cooled to a tempera-ture of 0 to 20C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuran and this was added dropwise to the rapid-ly stirred reaction flask while gaseous chlorine (0.40 mole) 10 was added via the gaseous inlet tube. The rate of the alcohol addition was such that a yellow orange color was maintained. The temperature was kept bèlow 20C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction flask, the temperature was raised 15 to reflux to distill off the tetrahydrofuran. The isolation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield) . ~
Substantially the same results were obtained sub-stituting potassium bromide for sodium bromide.
; 20 Example 5 The method of Example 4 was repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula .
/~ ~OH
25 Table 2. One Pot Process using BrCl as the oxidant, generat-ed by addition of chlorine in situ to NaBr, R CosolventTemp, (C) Temp, (C) Yield of oxidation of hydrolysis ~96) CH3Isopropyl ether 25 110 ~ 46 CH3 ethyl ether 20 110 43 CH3 acetone 15 105 47 R Co~olvent Temp. (C) Temp. (C) Yield of oxidation of hvdrolvsis (%) _ -THF = tetrahydrofuran - Example 6 In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-1-ethanol (0.09 mole) was added dropwise.
The temperature of the reaction mixture was not allowed to exceed 10C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isola-tion procedure of Example 1, a yield of 5.7 g of maltol was obtained.
Example 7 To a 4-neck round flask equipped with a thermo-meter, a condensor and two addition funnels was charged50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole~ and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the mixture was maintained at 15C. throughout the double addition. The reaction mixture was then heated to 75C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53~ yield).
Example 8 The method of Example 7 was repeated under varying conditions shown in Table 3 with furfuryl alcohols of the formula ~OH
O
Table 3 R CosolventTemp. (C) Temp. ~C) Yield of oxidation of hydrolysis (~) CH3 none 15 100 30 CH3 THF 50 lO0 20 Example 9 A 2.8 M sodium hypochlorite solution was prepared by passing chlorine gas (42.6 g) into a solution of 48 g of sodium hydroxide in 150 ml of water at 0C. A solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydro-furan and 15 ml of water was prepared in a 3-neak flask and cooled to 5C. While maintaining a pH from 1.0 to 0.8 with 6 N HCl, 21.7 ml of the hypochlorite solution was added dropwise to the reaction flask over a period of about 33 minutes while maintaining the temperature below 5C.
A 15 ml portion of concentrated hydrochloric acid was then - added to the reaction mixture which was then heated to remove the tetrahydrofuran by distillation. Heating was continued for an additional hour, Maltol was isolated as described in Example 1, Substantially the same results are obtained when sadium hypobromite is used in place of sodium hypochlorite.
Example 10 To a solution of 1(2-furyl)-1-ethanol (O.D5 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5C. was 30 added 21.7 ml of 2.8 M sodium hypochlorite solution, Chlorine (0.05 mole) was added to the reaction flask via a gas inlet tube while maintaining the temperature below 5C.
The reaction mixture was then heated to reflux and the tetrahydrofuran removed by distillation. Heating was con-tinued for an additional hour. The reaction mixture was cooled and maltol was isolated by the procedure described in Example 1.
Example ll To a 3-neck round bottom flask was charged a solu-tion of 50 ml of water and 20 ml of tetrahydrofuran and the solution was cooled to 0C. An addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran and this solution was added dropwise to the reaction flaskwhile BrCl ~0.30 mole~ was added via a gas inlet tube. The rate of addition was such that all the furfuryl alcohol was added in the first 1.3 to 1.5 equivalents of BrCl while maintaining the temperature below 30C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reached 105C., a condensor was attached and the reaction mixture heated under reflux for about 2 hours.
The reaction mixture was cooled and maltol isolated by the procedure of Example 1.
Example 12 In a 3-neck round bottom flask equipped with a ; magnetic bar, a thermometer and two addition funnels was charged 25 ml of tetrahydrofuran and 50 ml of water. To this solution was added 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran while bromine (0.16 mole) was added dropwise while maintaining the temperature below 15C. After the additions were complete, chlorine ~0.10 mole) was added via a gas inlet tube and the reaction was heated to reflux. Maltol was isolated from the cooled solution by the procedure of Example 1.
Example 13 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one In a three necked round bottom flask were added 28 ml of methanol and 38 ml of water. The solution was cooled to -15C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the temperature was maintained between -16 and -8C. When addition was completed, the solution was warmed to 80C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2 1 and the mixture extracted with chloroform (3 x 100 ml.). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solidO Sublimation yielded pure product, m.p. 157 to 159C
Analysis Calc'd for C8H103 C, 62-33; H~ 6.54 Found: C, 62.05; H, 6.44 NMR (CDC13, ~); 6-CH3, 2 33 (3H, s); 2-CH3, 1.30 (3H, t);
This is a divisional of Patent Application No.
279922 filed June 6th 1977.
Application No. 279922 describes and claims the preparation of gamma-pyrones and particularly the prepara-tion of gamma-pyrones by the hydrolysis of certain intermedi-ate compounds, some of which are novel, which intermediates are prepared from appropriate furfuryl alcohols by the use of halogen-containing oxidants. The present divisional is concerned with a one-pot process for preparing gamma-pyrones from furfuryl alcohols.
Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production was from the destructive distillation of wood.
The synthesis of maltol from 3-hydroxy-2-~1-piperidylmethyl)-1,4-pyrone was reported by Spielman and Freifelder in J.
Am. Chem. Soc., 69 2908 (1947). Schenck and Spielman, J.
Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkaline hydrolysis of streptomycin salts. Chawla and McGonigal, J. Org. Chem., 39, 3281 (1974) and Lichtenthaler and Heildel, Angew. Chem., 81, 998 (1969), reported the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), describ-ed a five step synthesis of maltol starting with methyl furfuryl alcohol.
The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one as one of the characteristic sweet-aroma compon-ents in refinery final molasses was reported by Hiroshi Ito in Agr. Biol. Chem., 40 (5), 827-832 (1976) This compound was previously synthesized by the process described in ZS~
United States Patent Specification No. 3,468,915.
Syntheses of gamma-pyrones such as pyromeconic acid, maltol, e~hyl maltol and other 2-subs~ituted-3-hydroxy-gamma-pyrones are described in United States Patents No. 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,469;
3,376,317; 3,468,915; 3,440,183; and 3,446,629.
Maltol and ethyl maltol enhance the flavor and aroma of a variety of food products. In addition, these compounds are used as ingredients in perfumes and essences.
- 10 The 2-alkenylpyromeconic acids reported in United States Patent No 3,644,635 and the 2-arylmethylpyromeconic acids described in United States Patent No. 3,365,469 inhibit the growth of bacteri and fungi and are useful as flavor and aroma enhancers in foods and beverages and aroma enhancers in perfumes.
The present invention Provides a proaess for preparing a gamma-pyrone of the formula:
~ OH
/\o ~~ R
R''' wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R''' is hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a compound of the formula:
~ ~ OH o~(III) R''' R
wherein R and R''' are as defined above, in aqueous solution at a temperature of -50 to 50C. with at least two equival-ents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof and heating the resulting 4-halo-dihydropyran intermediate until hydrolysis is substantially complete.
Thus, the present invention provides a novel and 25~
facile synthesis of gamma-pyrones of formula (I) above, par-ticularly maltol t2-methyl-3-hydroxy-4H-pyran-4-one~ and related compounds, by a one-pot process from a furfuryl al-cohol of formula (III) above.
In accordance with this one-pot process, a furfuryl alcohol in aqueous medium is reacted with two equivalents of a halogen-containing oxidant and the reac-tion mixture is then heated to hydrolyze the resulting inte~
mediate. The one pot process may be represented by the following equation.
R ' ~ ~ ~R
R' "
(III) (I) wherein R i9 hydrogen, alkyl of I to 4 carbon atoms, phenyl or benzyl; R" ' iS hydrogen or alkyl of 1 to 4 carbon atoms;
and XY is C12, Br2, ClBr, HOCl, HOBr or mixture~ thereof.
The full reaction pathway is shown in the following scheme:
R ' ' ' ~o (III) R' ' ' (~=0 H
~H
~H op~n ~=O chain H- ~OH tautomér R " ~ R ' '~
~1 l~ (II') (I) open chain tautomer Lefebvre and co-workers in J. Med. Chem., 16, 1084 (1973) demonstrated that furfuryl alcohols could be direat-ly converted to 6-hydroxy-2H-pyran-3(6H)one6 when a peracid oxidant such as peracetic acid or m-chloroperben~oic acid is employed, The first step on the Lefebvre work uses a peracid in an orqanic solvent and probably leads to a 6-acetoxy or 6-m-chlorobenzoyloxy pyran derivative which is hydrolyzed to the 6-hydroxy compound during the aqueous work-up. Water is not used in the first step of the reac-tion, and would in fact be deleterious. In any case, theprocess of Lefebvre and co-workers cannot lead directly to the conversion of a furfuryl alcohol to a gamma-pyrone.
Critical to the process for the preparation of the intermediates of the present invention is the use of an 15 aqueous solution of a halgen-containing oxidant. A furfuryl alcohol may be cleanly oxidized to a 6-hydroxy-2H-pyran-3 (6H)-one using one equivalent of a halogen-containing oxidant in water or water/organic co-solvent. It is a surprising and unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can be converted to gamma-pyrones. A 6-hydroxy-2H-pyran-3(6H)-one may be regarded as a hemi-acetal of an aldehyde and as such might be expected to undergo numerous undesired si~e reactions such as over oxidation or an aldol-type condensations. By employing two equivalents of a 25 halogen-containing oxidant in water or water and organic co-solvent, the reaction proceeds smoothly from a furfuryl alcohol to a gamma-pyrone. This novel one pot process offers the advantages of employing low cost Cl2, Br2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant.
30 Isolation of the desired gamma-pyrone is greatly simplified since solvent, oxidant and by-product mineral acid are all volatile and may be removed in vacuo to afford crude gamma-pyrone directly in high yield by simple concentration.
The one pot process is operated by dissolving 35 a furfuryl alcohol in water or water and a co-solvent. The co-solvent may be water-miscible or water-immiscible and may be selected from a wide range of solvents such as Cl to ;ZS~
C4 alkanols or diols, for example, methanol; C2 to C10 ethers, for example, tetrahydrofuran or isopropyl ether;
low molecular weight ketones, for example, acetone; low molecular weight nitriles; low molecular weight esters and low molecular weight amides. The preferred co-solvents are Cl to C4 alkanols and C2 to C10 ethers, with methanol the choice of solvents because of cost. The solution is kept at a temperature of -50 to 50C., preferably -10 to 10C To this solution is charged a desired furfuryl alcohol while simultanteously adding a halogen-containing oxidant (two equivalents) to the reaction mixture. The temperature of the reaction mixture is maintained at -50 to 50C., preferably -10 to 10C,, during halogen addition.
If a low-boiling co-solvent is employed, it is removed by distillation after all additions are complete. The reaction mixture is then heated to a temperatue at which the hydro-lysis proceeds at a reasonable rate, for example, 70 to 160C, The generally employed hydrolysis temperature is 100 to 110C. The heating is continued until the hydrolysis of the formed 4-halo-dihydropyran intermediate is substantially complete (usually 1 to 2 hours). The acid necessary to catalyze this final hydrolysis is generated ln situ by loss of acid from the intermediates formed during the course of the reaction. Additional acid may be added if desired.
The halogen-containing oxidant is selected from chlorine, bromine, bromine chloride, hypochlorous or hypobromous acid or mixtures thereof. Bromine chloride is a commercially available gas, It may be prepared ln situ by the addition of chlorine to a solution of sodium or potassium bromine or by the addition of bromine to a solu-tion of sodium or potassium chloride. Hypochlorous and hypobromous acid conveniently may be generated in situ by the addition of aqueous acid (HCl, H2SO4 or HBr) to a - 35 solution of an alkali metal or alkaline earth metal hypo-halite, e.g., NaOCl, KOCl or Ca(OCl)2. The preferred halogen-containing oxidants, based ~n cost factors, are chlorine and bromine chloride prepared in situ.
ZS~
The following Examples illustrate the preparation of the gamma-pyrones according to the procegs of the inven-tion.
In the Examples where spectral data are given, 5 NMR chemical shift data are reported by conventional liter-ature symbolism and all shifts are expressed as ~ units fran tetramethyl silane:
s = singlet t = triplet q = quartet Example 1 In a 3-neck round bottom f lask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an additional funnel was added 20 ml of tetrahydrofuran 15 and 50 ml of water. The solution was cooled to a temper-ature of 0 to 10C. The addition funnel was charged with a solution of 1(2-furyl) -l-ethanol ~0,089 moles~ in 20 ml of tetrahydrofuran and this was added dropwise to the reac-tion flask while chlorine (0.30 mole) was added via the 20 gas inlet tube. The rate of addition was such that all the alcohol was added in the f irst 1.3 to 1.5 equivalents of chlorine (approximately 30 minutes) while maintaining the temperature below 10C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation.
25 When the reaction mixture reached a temperature of about 105C,, a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2.2 and the reaction mixture was cooled to 5C. Crystallization and filtration yielded 30 3.43 grams of crude 3-hydroxy-2-methyl-~-pyrone ~maltol) .
The aqueous filtrate was extracted with chloroform to o~tain a second crop of 2.58 g of maltol. Distillation of the combined solids and recrystallization f~om methanol gave 5.5 g (49%) of pure white maltol, m.p. 159.5 to 160.5C.
Example 2 The procedure of Example 1 was repeated under varying conditions as shown in Table I with furfuryl alco-hols of the formula ~ ~ ~ H
Table 1. One Pot Process using ~hlorine as the oxidant.
RCosolvent Temp. (C) Temp. ~C) Yield of oxidation of hydrolysis ~%~
CH3methanol lO 100 45 CH3methanol 5 110 56 CH3methanol -5 104 60 CH3methanol -lO 104 77 10 CH3methanol -20 106 62-67 CH3acetone -5 110 36 CH3Et OAc O llO 26 15 CH3none 10 110 17-30 CH3 benzene lO llO 26 CH3 methyl isobutyl ketone 5 llO 44 CH3 isopropyl alcohol O llO 49 20CH2CH3 methanol 5 llO 49 CH2CH3 methanol -lO 110 58 H methanol -10 110 57 CH3 methanol -30 110 50 THF - tetrahydrofuran EtOAc = ethyl acetate Example 3 The method of Example 2 was repeated with compar-able results employing each of the following co-solvents:
ethanol ethyl ether n-propanol isopropyl ether iso-butanol dimethoxy ethane n-butanol 2-methoxy ethanol t-butanol 2-ethoxy ethanol dioxane ethylene glycol 111~254 Example 4 In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml of water and sodium 5 bromide (0.20 mole) . The solution was cooled to a tempera-ture of 0 to 20C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuran and this was added dropwise to the rapid-ly stirred reaction flask while gaseous chlorine (0.40 mole) 10 was added via the gaseous inlet tube. The rate of the alcohol addition was such that a yellow orange color was maintained. The temperature was kept bèlow 20C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction flask, the temperature was raised 15 to reflux to distill off the tetrahydrofuran. The isolation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield) . ~
Substantially the same results were obtained sub-stituting potassium bromide for sodium bromide.
; 20 Example 5 The method of Example 4 was repeated under varying conditions shown in Table 2 with furfuryl alcohols of the formula .
/~ ~OH
25 Table 2. One Pot Process using BrCl as the oxidant, generat-ed by addition of chlorine in situ to NaBr, R CosolventTemp, (C) Temp, (C) Yield of oxidation of hydrolysis ~96) CH3Isopropyl ether 25 110 ~ 46 CH3 ethyl ether 20 110 43 CH3 acetone 15 105 47 R Co~olvent Temp. (C) Temp. (C) Yield of oxidation of hvdrolvsis (%) _ -THF = tetrahydrofuran - Example 6 In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-1-ethanol (0.09 mole) was added dropwise.
The temperature of the reaction mixture was not allowed to exceed 10C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isola-tion procedure of Example 1, a yield of 5.7 g of maltol was obtained.
Example 7 To a 4-neck round flask equipped with a thermo-meter, a condensor and two addition funnels was charged50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole~ and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the mixture was maintained at 15C. throughout the double addition. The reaction mixture was then heated to 75C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53~ yield).
Example 8 The method of Example 7 was repeated under varying conditions shown in Table 3 with furfuryl alcohols of the formula ~OH
O
Table 3 R CosolventTemp. (C) Temp. ~C) Yield of oxidation of hydrolysis (~) CH3 none 15 100 30 CH3 THF 50 lO0 20 Example 9 A 2.8 M sodium hypochlorite solution was prepared by passing chlorine gas (42.6 g) into a solution of 48 g of sodium hydroxide in 150 ml of water at 0C. A solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydro-furan and 15 ml of water was prepared in a 3-neak flask and cooled to 5C. While maintaining a pH from 1.0 to 0.8 with 6 N HCl, 21.7 ml of the hypochlorite solution was added dropwise to the reaction flask over a period of about 33 minutes while maintaining the temperature below 5C.
A 15 ml portion of concentrated hydrochloric acid was then - added to the reaction mixture which was then heated to remove the tetrahydrofuran by distillation. Heating was continued for an additional hour, Maltol was isolated as described in Example 1, Substantially the same results are obtained when sadium hypobromite is used in place of sodium hypochlorite.
Example 10 To a solution of 1(2-furyl)-1-ethanol (O.D5 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5C. was 30 added 21.7 ml of 2.8 M sodium hypochlorite solution, Chlorine (0.05 mole) was added to the reaction flask via a gas inlet tube while maintaining the temperature below 5C.
The reaction mixture was then heated to reflux and the tetrahydrofuran removed by distillation. Heating was con-tinued for an additional hour. The reaction mixture was cooled and maltol was isolated by the procedure described in Example 1.
Example ll To a 3-neck round bottom flask was charged a solu-tion of 50 ml of water and 20 ml of tetrahydrofuran and the solution was cooled to 0C. An addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran and this solution was added dropwise to the reaction flaskwhile BrCl ~0.30 mole~ was added via a gas inlet tube. The rate of addition was such that all the furfuryl alcohol was added in the first 1.3 to 1.5 equivalents of BrCl while maintaining the temperature below 30C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reached 105C., a condensor was attached and the reaction mixture heated under reflux for about 2 hours.
The reaction mixture was cooled and maltol isolated by the procedure of Example 1.
Example 12 In a 3-neck round bottom flask equipped with a ; magnetic bar, a thermometer and two addition funnels was charged 25 ml of tetrahydrofuran and 50 ml of water. To this solution was added 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran while bromine (0.16 mole) was added dropwise while maintaining the temperature below 15C. After the additions were complete, chlorine ~0.10 mole) was added via a gas inlet tube and the reaction was heated to reflux. Maltol was isolated from the cooled solution by the procedure of Example 1.
Example 13 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one In a three necked round bottom flask were added 28 ml of methanol and 38 ml of water. The solution was cooled to -15C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the temperature was maintained between -16 and -8C. When addition was completed, the solution was warmed to 80C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2 1 and the mixture extracted with chloroform (3 x 100 ml.). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solidO Sublimation yielded pure product, m.p. 157 to 159C
Analysis Calc'd for C8H103 C, 62-33; H~ 6.54 Found: C, 62.05; H, 6.44 NMR (CDC13, ~); 6-CH3, 2 33 (3H, s); 2-CH3, 1.30 (3H, t);
2-CH2-, 2.75 (2H, quartet), 5H, 6.23 (lH, s).
Example 14 2,6-dimethyl-3-hydroxy-4H-pyran-4-one In a three necked round bottom flask were added 28 ml of water and 32 ml of methanol and the mixture was cooled to -15C. The solution was treated with 0.167 mole of 5-methyl-2-(~-hydroxy-ethyl)furan (J. Org. Chem., 26, 1673,1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10C. during addition.
The mixture was allowed to warm to room temperature over 30 minutes and heated to reflux for 3 hours, The cooled solution was adjusted to pH 2.1 and extracted with chloro-form (3 X 100 ml.). The chloroform extracts were combined,washed with water and brine, dried over magnesium sulfate, filtered and evaporated The residue, a dark oil, was chromatographed on silica gel developed with methylene chloride/ethyl acetate (95:5). The product, isolated by evaporation, was recrystallized from methanol as a tan solid (yield, 25%). Sublimation yielded white crystals, m.p. 161 to 163C.
Analysis Calc'd- for C7H82 C, 59.99; H~ 5.75 Found: C, 59.83; H, 5.82 NMR (CDC13, ~); 6-CH3, 2.33 (3H, s); 2-CH3, 2.26 (3H, s);
5-H, 6.10 (lH, s).
Example 14 2,6-dimethyl-3-hydroxy-4H-pyran-4-one In a three necked round bottom flask were added 28 ml of water and 32 ml of methanol and the mixture was cooled to -15C. The solution was treated with 0.167 mole of 5-methyl-2-(~-hydroxy-ethyl)furan (J. Org. Chem., 26, 1673,1960) and 0.416 mole of chlorine simultaneously. The temperature was maintained at -15 to -10C. during addition.
The mixture was allowed to warm to room temperature over 30 minutes and heated to reflux for 3 hours, The cooled solution was adjusted to pH 2.1 and extracted with chloro-form (3 X 100 ml.). The chloroform extracts were combined,washed with water and brine, dried over magnesium sulfate, filtered and evaporated The residue, a dark oil, was chromatographed on silica gel developed with methylene chloride/ethyl acetate (95:5). The product, isolated by evaporation, was recrystallized from methanol as a tan solid (yield, 25%). Sublimation yielded white crystals, m.p. 161 to 163C.
Analysis Calc'd- for C7H82 C, 59.99; H~ 5.75 Found: C, 59.83; H, 5.82 NMR (CDC13, ~); 6-CH3, 2.33 (3H, s); 2-CH3, 2.26 (3H, s);
5-H, 6.10 (lH, s).
Claims (5)
1. A process for preparing a gamma-pyrone of the formula:
. . . (I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R''' is hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a compound of the formula:
. . . (III) wherein R and R''' are as defined above, in aqueous solution at a temperature of -50° to 50°C. with at least two equiva-lents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof and heating the resulting 4-halo-dihydropyran intermediate until hydrolysis is substantially complete.
. . . (I) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R''' is hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a compound of the formula:
. . . (III) wherein R and R''' are as defined above, in aqueous solution at a temperature of -50° to 50°C. with at least two equiva-lents of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or mixtures thereof and heating the resulting 4-halo-dihydropyran intermediate until hydrolysis is substantially complete.
2 A process according to claim 1, in which the temperature at which the hydrolysis is conducted is within the range of 70° to 160°C.
3. A process according to claim 1, in which the reaction is conducted in the presence of a co-solvent which is an alkanol or diol of 1 to 4 carbon atoms, an ether of 2 to 10 carbon atoms, a low molecular weight ketone, nitrile, ester or amide.
4. A process according to claim 3, in which the co-solvent is methanol, tetrahydrofuran, isopropyl ether, or acetone.
5. A process according to claim 1, in which the halogen-containing oxidant is chlorine or bromine chloride.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US71090176A | 1976-08-02 | 1976-08-02 | |
US710,901 | 1976-08-02 | ||
US05/721,885 US4082717A (en) | 1976-08-02 | 1976-09-09 | Preparation of gamma-pyrones |
US721,885 | 1985-04-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1110254A true CA1110254A (en) | 1981-10-06 |
Family
ID=27108548
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA279,922A Expired CA1095921A (en) | 1976-08-02 | 1977-06-06 | Preparation of gamma-pyrones |
CA363,273A Expired CA1110254A (en) | 1976-08-02 | 1980-10-24 | Preparation of gamma-pyrones |
CA000363274A Expired CA1117541A (en) | 1976-08-02 | 1980-10-24 | 4-halo-dihydropyrans and the preparation thereof |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA279,922A Expired CA1095921A (en) | 1976-08-02 | 1977-06-06 | Preparation of gamma-pyrones |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000363274A Expired CA1117541A (en) | 1976-08-02 | 1980-10-24 | 4-halo-dihydropyrans and the preparation thereof |
Country Status (36)
Country | Link |
---|---|
JP (7) | JPS5318578A (en) |
AR (1) | AR216080A1 (en) |
AT (3) | AT362790B (en) |
BE (1) | BE855965A (en) |
BG (4) | BG28849A3 (en) |
BR (1) | BR7703970A (en) |
CA (3) | CA1095921A (en) |
CH (4) | CH625798A5 (en) |
CS (3) | CS203921B2 (en) |
DD (1) | DD132494A5 (en) |
DE (3) | DE2760220C2 (en) |
DK (4) | DK153483C (en) |
EG (1) | EG13080A (en) |
ES (5) | ES459994A1 (en) |
FI (6) | FI72722C (en) |
FR (1) | FR2372821A1 (en) |
GB (5) | GB1538373A (en) |
GR (1) | GR68938B (en) |
HK (5) | HK30581A (en) |
HU (4) | HU185687B (en) |
IE (5) | IE45641B1 (en) |
IT (1) | IT1106258B (en) |
LU (1) | LU77600A1 (en) |
MX (1) | MX4597E (en) |
MY (3) | MY8100287A (en) |
NL (5) | NL170955C (en) |
NO (7) | NO150561C (en) |
NZ (1) | NZ184342A (en) |
PH (5) | PH13557A (en) |
PL (4) | PL115496B1 (en) |
PT (1) | PT66694B (en) |
RO (4) | RO78953A (en) |
SE (6) | SE433079B (en) |
SU (2) | SU955859A3 (en) |
TR (1) | TR19652A (en) |
YU (4) | YU40166B (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1095921A (en) * | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
FR2402654A1 (en) * | 1977-09-12 | 1979-04-06 | Shinetsu Chemical Co | Tetra:hydro-pyranone derivs. - useful as intermediates for cpds. used as food flavours |
JPS5444675A (en) * | 1977-09-12 | 1979-04-09 | Shin Etsu Chem Co Ltd | Production of 3-hydroxy-4-pyrone analog |
JPS5741226U (en) * | 1980-08-20 | 1982-03-05 | ||
JPS59135008U (en) * | 1983-02-28 | 1984-09-10 | 松下電工株式会社 | Distribution board device |
JPS6050245A (en) * | 1983-08-29 | 1985-03-19 | Nissan Motor Co Ltd | Fuel injection device in internal-combustion engine |
JPH0226945Y2 (en) * | 1985-09-11 | 1990-07-20 | ||
JP2586607B2 (en) * | 1987-10-30 | 1997-03-05 | 日産化学工業株式会社 | Production method of optically active alcohol |
CA2627529A1 (en) | 2007-03-28 | 2008-09-28 | Apotex Technologies Inc. | Fluorinated derivatives of deferiprone |
CA2722393A1 (en) | 2008-04-25 | 2009-10-29 | Apotex Technologies Inc. | Liquid formulation for deferiprone with palatable taste |
PL2448922T3 (en) | 2009-07-03 | 2015-02-27 | Apotex Tech Inc | Fluorinated derivatives of 3-hydroxypyridin-4-ones |
WO2017168309A1 (en) * | 2016-03-29 | 2017-10-05 | Dr. Reddy’S Laboratories Limited | Process for preparation of eribulin and intermediates thereof |
CN108609456B (en) * | 2016-12-13 | 2021-03-12 | 奥的斯电梯公司 | Openable expansion panel and elevator suspended ceiling, elevator car and elevator system with same |
CN111606879A (en) * | 2020-05-25 | 2020-09-01 | 安徽金禾实业股份有限公司 | Method for preparing 2-hydroxymethyl-3-alkoxy-4H-pyran-4-ketone by one-pot method |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3491122A (en) * | 1966-09-14 | 1970-01-20 | Monsanto Co | Synthesis of 4-pyrones |
US3547912A (en) * | 1968-07-29 | 1970-12-15 | American Home Prod | Derivatives of 2h-pyran-3(6h)-ones and preparation thereof |
JPS5145565B1 (en) * | 1968-10-12 | 1976-12-04 | ||
US3621063A (en) * | 1968-12-24 | 1971-11-16 | Monsanto Co | Unsaturated acyclic ketones |
US3832357A (en) * | 1971-05-26 | 1974-08-27 | Daicel Ltd | Process for preparation of 3-hydroxy-2-alkyl-4-pyrone |
JPS5212166A (en) * | 1975-07-17 | 1977-01-29 | Tatsuya Shono | Process for preparation of 4-pyron derivatives |
IE42789B1 (en) * | 1975-08-28 | 1980-10-22 | Pfizer | Preparation of gamma-pyrones |
CA1095921A (en) | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
-
1977
- 1977-06-06 CA CA279,922A patent/CA1095921A/en not_active Expired
- 1977-06-08 NZ NZ184342A patent/NZ184342A/en unknown
- 1977-06-09 GR GR53666A patent/GR68938B/el unknown
- 1977-06-13 YU YU1469/77A patent/YU40166B/en unknown
- 1977-06-15 MX MX775807U patent/MX4597E/en unknown
- 1977-06-16 JP JP7157277A patent/JPS5318578A/en active Granted
- 1977-06-16 SE SE7707035A patent/SE433079B/en not_active IP Right Cessation
- 1977-06-17 PH PH19887A patent/PH13557A/en unknown
- 1977-06-20 BR BR7703970A patent/BR7703970A/en unknown
- 1977-06-21 BE BE1008209A patent/BE855965A/en not_active IP Right Cessation
- 1977-06-21 FI FI771934A patent/FI72722C/en not_active IP Right Cessation
- 1977-06-21 NL NLAANVRAGE7706811,A patent/NL170955C/en not_active IP Right Cessation
- 1977-06-22 LU LU77600A patent/LU77600A1/xx unknown
- 1977-06-22 EG EG371/77A patent/EG13080A/en active
- 1977-06-22 CH CH765877A patent/CH625798A5/en not_active IP Right Cessation
- 1977-06-22 DE DE2760220A patent/DE2760220C2/de not_active Expired
- 1977-06-22 DE DE2728499A patent/DE2728499C2/en not_active Expired
- 1977-06-22 ES ES459994A patent/ES459994A1/en not_active Expired
- 1977-06-22 NO NO772193A patent/NO150561C/en unknown
- 1977-06-22 DE DE2760221A patent/DE2760221C2/de not_active Expired
- 1977-06-22 AT AT0440477A patent/AT362790B/en not_active IP Right Cessation
- 1977-06-22 PT PT66694A patent/PT66694B/en unknown
- 1977-06-22 TR TR19652A patent/TR19652A/en unknown
- 1977-06-22 DK DK276177A patent/DK153483C/en active
- 1977-06-23 AR AR268164A patent/AR216080A1/en active
- 1977-06-23 FR FR7719250A patent/FR2372821A1/en active Granted
- 1977-06-23 IT IT49950/77A patent/IT1106258B/en active
- 1977-06-23 DD DD7700199657A patent/DD132494A5/en not_active IP Right Cessation
- 1977-07-14 BG BG7736892A patent/BG28849A3/en unknown
- 1977-07-14 BG BG7942607A patent/BG28989A4/en unknown
- 1977-07-14 CS CS774705A patent/CS203921B2/en unknown
- 1977-07-14 BG BG7742606A patent/BG28988A4/en unknown
- 1977-07-14 BG BG7942608A patent/BG29136A3/en unknown
- 1977-07-20 RO RO7799830A patent/RO78953A/en unknown
- 1977-07-20 RO RO7799826A patent/RO78952A/en unknown
- 1977-07-20 RO RO7799825A patent/RO78951A2/en unknown
- 1977-07-20 RO RO7791106A patent/RO74367A/en unknown
- 1977-07-21 PL PL1977215007A patent/PL115496B1/en unknown
- 1977-07-21 PL PL1977199798A patent/PL115586B1/en unknown
- 1977-07-21 GB GB4241/78A patent/GB1538373A/en not_active Expired
- 1977-07-21 HU HU82157A patent/HU185687B/en unknown
- 1977-07-21 HU HU82155A patent/HU185686B/en unknown
- 1977-07-21 GB GB4240/78A patent/GB1538372A/en not_active Expired
- 1977-07-21 HU HU82156A patent/HU186026B/en unknown
- 1977-07-21 HU HU77PI584A patent/HU180040B/en unknown
- 1977-07-21 SU SU772508256A patent/SU955859A3/en active
- 1977-07-21 PL PL1977215006A patent/PL115497B1/en unknown
- 1977-07-21 GB GB30759/77A patent/GB1538371A/en not_active Expired
- 1977-07-21 GB GB4242/78A patent/GB1538374A/en not_active Expired
- 1977-07-21 PL PL21500877A patent/PL215008A1/en unknown
- 1977-07-21 GB GB4243/78A patent/GB1538375A/en not_active Expired
- 1977-07-29 IE IE1587/77A patent/IE45641B1/en not_active IP Right Cessation
- 1977-07-29 IE IE587/79A patent/IE45645B1/en not_active IP Right Cessation
- 1977-07-29 IE IE586/79A patent/IE45644B1/en not_active IP Right Cessation
- 1977-07-29 IE IE585/79A patent/IE45643B1/en not_active IP Right Cessation
- 1977-07-29 IE IE584/79A patent/IE45642B1/en not_active IP Right Cessation
-
1978
- 1978-02-03 PH PH20746A patent/PH13926A/en unknown
- 1978-02-03 PH PH20745A patent/PH15185A/en unknown
- 1978-05-25 JP JP6281778A patent/JPS5436266A/en active Pending
- 1978-05-25 JP JP6282278A patent/JPS5436271A/en active Granted
- 1978-05-25 JP JP53062820A patent/JPS5814433B2/en not_active Expired
- 1978-05-25 JP JP6281978A patent/JPS5436268A/en active Pending
- 1978-05-25 JP JP6282178A patent/JPS5436270A/en active Granted
- 1978-05-25 JP JP6281878A patent/JPS5436267A/en active Granted
- 1978-06-07 CS CS783706A patent/CS203923B2/en unknown
- 1978-06-07 CS CS783705A patent/CS203922B2/en unknown
- 1978-06-13 ES ES470744A patent/ES470744A1/en not_active Expired
- 1978-06-13 ES ES470743A patent/ES470743A1/en not_active Expired
- 1978-06-13 ES ES470746A patent/ES470746A1/en not_active Expired
- 1978-06-13 ES ES470745A patent/ES470745A1/en not_active Expired
- 1978-07-05 SU SU782631651A patent/SU1015826A3/en active
-
1979
- 1979-02-01 PH PH22149A patent/PH14625A/en unknown
- 1979-02-01 PH PH22150A patent/PH13874A/en unknown
-
1980
- 1980-03-06 AT AT0124380A patent/AT364356B/en not_active IP Right Cessation
- 1980-03-06 AT AT0124480A patent/AT363470B/en not_active IP Right Cessation
- 1980-10-24 CA CA363,273A patent/CA1110254A/en not_active Expired
- 1980-10-24 CA CA000363274A patent/CA1117541A/en not_active Expired
- 1980-10-30 CH CH808580A patent/CH625235A5/en not_active IP Right Cessation
-
1981
- 1981-02-20 CH CH116081A patent/CH626357A5/en not_active IP Right Cessation
- 1981-02-20 CH CH116181A patent/CH626358A5/en not_active IP Right Cessation
- 1981-07-02 HK HK305/81A patent/HK30581A/en unknown
- 1981-07-02 HK HK303/81A patent/HK30381A/en unknown
- 1981-07-02 HK HK306/81A patent/HK30681A/en unknown
- 1981-07-02 HK HK304/81A patent/HK30481A/en unknown
- 1981-07-02 HK HK307/81A patent/HK30781A/en unknown
- 1981-12-09 NL NLAANVRAGE8105538,A patent/NL182477C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105537,A patent/NL182476C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105539,A patent/NL182478C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105540,A patent/NL182805C/en not_active IP Right Cessation
- 1981-12-30 MY MY287/81A patent/MY8100287A/en unknown
- 1981-12-30 MY MY267/81A patent/MY8100267A/en unknown
- 1981-12-30 MY MY262/81A patent/MY8100262A/en unknown
-
1982
- 1982-01-29 SE SE8200518A patent/SE445041B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200522A patent/SE444565B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200520A patent/SE444564B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200519A patent/SE445042B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200521A patent/SE452616B/en not_active IP Right Cessation
- 1982-06-03 NO NO821847A patent/NO150042C/en unknown
- 1982-06-03 NO NO821850A patent/NO821850L/en unknown
- 1982-06-03 NO NO821851A patent/NO150560C/en unknown
- 1982-06-03 NO NO821848A patent/NO150043C/en unknown
- 1982-06-03 NO NO821849A patent/NO150559C/en unknown
- 1982-12-07 YU YU02703/82A patent/YU270382A/en unknown
- 1982-12-13 YU YU2747/82A patent/YU42613B/en unknown
-
1983
- 1983-05-16 FI FI831701A patent/FI72723C/en not_active IP Right Cessation
- 1983-05-16 FI FI831702A patent/FI72720C/en not_active IP Right Cessation
- 1983-05-16 FI FI831703A patent/FI73424C/en not_active IP Right Cessation
- 1983-05-16 FI FI831704A patent/FI72721C/en not_active IP Right Cessation
- 1983-05-16 FI FI831700A patent/FI72119C/en not_active IP Right Cessation
- 1983-08-08 YU YU1663/83A patent/YU43190B/en unknown
- 1983-11-18 NO NO834236A patent/NO151365C/en unknown
-
1986
- 1986-07-09 DK DK325986A patent/DK153484C/en active
- 1986-07-09 DK DK326086A patent/DK153401C/en not_active IP Right Cessation
- 1986-07-09 DK DK326186A patent/DK154079C/en active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1110254A (en) | Preparation of gamma-pyrones | |
US4082717A (en) | Preparation of gamma-pyrones | |
US4435584A (en) | Preparation of gamma-pyrones | |
US4387235A (en) | Intermediates for the preparation of gamma-pyrones | |
US4289704A (en) | Preparation of gamma-pyrones | |
US4126624A (en) | Preparation of gamma-pyrones from 3-substituted furans | |
US4147705A (en) | Preparation of gamma-pyrones | |
US4368331A (en) | 3,4-Dihalo-tetrahydrophyran-5-one useful as intermediates for the preparation of gamma-pyrones | |
US4323506A (en) | Preparation of gamma-pyrones | |
KR810000289B1 (en) | Process for preparing gamma-pyrone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |