TW518331B - Process for the production of 2H-1-benzopyrans - Google Patents

Abstract

A process for the production of 2H-1-benzopyrans with the general formula where R1 is hydrogen, a (C1-C4) alkyl group, R2 is hydrogen, a (C1-C6) alkyl group and R3 is hydrogen, a (C1-C4) alkyl group, a (C1-C4) haloalkyl group, a (C2-C4) alkenyl group, a (C1-C4) alkoxycarbonyl group, a (C1-C4) alkoxymethyl group, a (C1-C4) alkanoyl group, a (C1-C4) alkoxy group, a (C1-C4) alkylsulphonyl group, halogen, amino, alkylamino, dialkylamino, nitril, nitro or hydroxy, is characterised in that in a first stage an aliphatic aldehyde with the general formula where R1 and R2 have the above-mentioned meaning, is converted with an aliphatic alcohol with the formula R4OH or HOR4OH, where R4 is a (C1-C4) alkyl group or a (C2-C4) alkyldiyl group, in the presence of a dehydrating compound with the formula HC(OR5)3, where R5 is a (C1-C4) alkyl group, and an aluminium oxide/silicium oxide catalyst into a aliphatic acetal with the general formula where R1 and R2 have the above-mentioned meaning and R4 as stated above is a (C1-C4) alkyl group or the two R4 together are a cyclical (C2-C4) alkyldiyl group, and this is then condensed in a second stage with a phenol with the general formula where R3 has the above-mentioned meaning, in the presence of a base in an inert organic solvent, to the end product with the general formula I.

Description

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 518331 A7 ____B7 V. Description of the Invention (1) The present invention relates to a process for preparing tables and naming, which is the first step in the process of ordering aliphatic aldehydes and aliphatics. Alcohols are converted into aliphatic acetals in the presence of dehydrated compounds and gastric alumina / silica catalysts and they react in the second stage with T-beautiful organic solvents in the presence of Cang. 2h + benzoαArans are important intermediate or end products in the manufacture of pharmaceuticals (North et al., J.0.C., 60.3397, 1995; Bell et al.,

Synthesis, 707, 1995) is, for example, an important intermediate or end product in the manufacture of oitaminocyanoguanidines for the treatment of epilepsy and migraine (EP-A 0 629 619). The 2H ~ 1-benzopyrans which can be produced according to the present invention have the following general formula R2:; r:? Ll1: 卞 'generation 丨 where Ri is 氲, (Ci-C4) alkyl, and R2 is hydrogen , (C ^ g6) alkyl and R 3 is fluorene, (C 1 -C 4) fluorenyl, (C 1 -C 4) alkyl, (C 2 -C4) alkenyl, (Cl -C4) fluorene Oxycarbonyl group, (C! -C4) oxymethyl group, (Cl-C4) oxy group, (Cl-C4) oxy group, (C! -C4) oxy group, halogen, amine group, amidine Amine, dialkylamino, hydrazone, nitro or hydroxyl. The use of alumina / silica catalysts has been described in the literature based on ketones (Thuy et Maite, Bui 1. Soc. Chim. Fr 11 2558; 1975) and based on paraformaldehyde (Deshmukh et al., Synth commun 25, 3939; 1995) to make acetals. The disadvantages of the synthetic methods known in these documents are the high proportion of the catalyst used in the synthesis relative to the starting product. 0-3-This paper size is applicable to the Chinese National Standard (CNS) M specification (210 X 297 mm) (please Read the notes on the back before filling this page) Order 518331 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (3) or two R4 are cyclic (C2-C4) alkanediyl . R 1 means hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms. It may be methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl. R 1 is particularly a straight bond or branched chain radical of I and a measure or the like. It may be methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, pentyl and its isomers, and hexyl and its isomers. It is particularly preferred if R 2 is hydrogen and methyl. R4 means a straight or branched chain alkyl group having 1 to 4 carbon atoms, which may be methyl, ethyl, n-propyl, isopropyl, n-, iso, second-butyl. R4 is particularly preferably methyl and hexyl. The two R4s collectively refer to a cyclic fluorenediyl group having 2-4 carbon atoms. May be ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, Butane-1,2-diyl. It is particularly preferred if the two R 4 are common to the ethane-1,2-, and the C-1,3 ~ · diyl groups. R5 means a straight or branched chain alkyl group having 1 to 4 carbon atoms. It may be methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl. It is particularly preferred if R5 is methyl and ethyl. Aliphatic aldehydes can be prepared from 2-methyl-3-butydin-2-ol simply by isomerization as described in US-A 3 994 936 and EP-A 0 240 431. The conversion is carried out favorably with an aliphatic alcohol R4 0Η or HOR4 0Η, where R4 has the definition described. Preferably, methanol, ethanol, ethylene glycol or propylene glycol is used. It is preferred to use trimethyl orthoformate or triethyl orthoformate as the dehydrating compound HC (0R5) 3, wherein R5 has the above-mentioned definition. It has a specific surface area of 100 to 27〇m2 / g (BET-measurement) and a size greater than 0. The standard is China Standard (CNS) A4 (210X297 mm) (please read the precautions on the back before filling this page) , A * 5 τ 518331

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IV A7 V. Explanation of the invention (4 / g (measured by Hg porometer) microporous volume (75-80nm)) is a good choice for alumina / silica catalyst. It is K-catalyst , Such as κριό, Κ10, KIKKS (Sud-Chemie), are commercially available. Particularly good is a montmorillon right with 15〇⑼i8nrir / g 微 亦 礼 翁 · 5-gOirn), which is based on KP10 (Sud- Chemie) is commercially available. The amount of the catalyst to be advantageously added is from 0.05 to 30% by weight relative to the aliphatic aldehyde used, and preferably from ^ to the weight ratio relative to the aliphatic aldehyde used. The reaction is favorably carried out at a reaction temperature of -401 to 40 eC, preferably 51 to 201. After a normal conversion time of 3 to 6 hours, the compound of formula j | is obtained as a crude product. C can be processed as follows: the catalyst is separated by filtration, which can be reused after washing and drying, potassium carbonate is added and finally The product was distilled. Optionally, 'K2CO3 can be removed and washed with ethanol before distillation. In the second stage, the aliphatic acetal (formula IΠ) and the phenol of the following formula are used: hr «:

L 2 J · *** .; $ 553 · $ Τ 八 Wherein R3 has the aforementioned definition, in the presence of a base, the final product of Formula I is condensed in an inert organic solvent. R3 means hydrogen or a straight-chain or branched alkyl group having 1-4 carbon atoms, a straight-chain or branched alkyl group having 1 to 4 broken atoms, a straight-chain or branched group having 2 to 4 carbon atoms Branched alkenyl, linear or branched alkoxycarbonyl group with 1 to 4 carbon atoms, linear or branched alkoxy group with 1 to 4 carbon atoms This paper is applicable to China A4—ϋ I Order (read first read Note on the back, please fill in this page again) The economy is printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and printed by A7 by the Consumer ’s Cooperatives of the Central Standards Bureau. 5. Description of invention (ς) Environment-based environment oxymethyl, with 1 to 4 An atomic radical, a radical having 1 to 4 carbon atoms or a branched radical, an oxygen radical having 1 to 4 carbon atoms or a straight or branched radical, a southern element, An amine group, a frost group having a fluorene group with 1 to ^^ atoms, a dialkylamino group having two fluorene groups with i to 2 carbon atoms, a salted, nitro, or fluorenyl group. May be methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, halomethyl, haloethyl, propyl, 2-propyl, fluorenyl- Isopropyl, butyl, 2-butyl, 3-butyl, 1-syl-2-methyl-propyl, 2-syl-2-methyl-propyl, fluorenyl- Tertiary butyl, vinyl, fluorenyl, propenyl, iso-propenyl, butenyl, but-2-enyl, but-3-fluorenyl, iso-but-p-fluorenyl, iso-but- 2-alkenyl, methoxycarbonyl, ethoxyfluorenyl, n-, iso-propoxycarbonyl, n-, iso-, third-butoxycarbonyl, methoxymethyl, ethoxymethyl, n- ~, iso -Propoxymethyl, n-, iso-, tertiary butoxymethyl, formamidine, acetamidine, n-, iso-propylamidine, n-, iso-, third-butylammonium, methoxyethoxy Radical, n-, iso-, second-propoxy, n-, iso-, third-butoxy, formamidinesulfonium, acetamidinesulfonium, propane-3-sulfonium, propane-2-sulfonyl , Butane-4-sulfonium, butane-3-continium, butane-2-sulfonium, methylamino, ethylamino, diethylamino. Fluorine, gas and bromine can be interpreted as halogen or halo substituents. It is particularly preferred if R 3 is formamidine, acetamidine, methoxycarbonyl and ethoxycarbonyl. The conversion is facilitated by the presence of an inorganic or organic base in the amount of catalyst. Potassium carbonate (preferably anhydrous), or sodium hydroxide is convenient for use as an inorganic base, and pyridine or 3-methyl mtidine is used as an organic base. It is especially good if you use anhydrous carbonic acid clock. The amount of alkali to be added is relative to the 4-hydroxy-ethyl-7-used. This paper size is applicable to China National Standard (CNS) M specification (21〇 × 297 mm) (Please read the precautions on the back before filling (This page)-Order 518331 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (6) Donkey benzene is in a weight ratio of 0.001 to 5%, preferably relative to 41, although it is based on 1-B Benzene is in a weight ratio of 0.005 to 0.1%. Non-polar organic solvents such as xylene or toluene are favorable for selection as inert organic solvents. 1 Xylene is special. The second-stage reaction is convenient at 90 ° C to 180eC, which is convenient for reaction temperatures between 130¾ to 150¾. After a normal conversion time of a total of 24 hours, the compound of formula I was obtained as a crude product. The operation can be simply carried out as follows, for example: after cooling the organic phase, it can be washed with 5% NaOH and the solvent is completely evaporated. The final product can then be separated by high-altitude air distillation. Alternatively, the intermediate product (formula JU) can be converted into the final product (formula I) without isolation. Example 1 (Invention) 1 Preparation of diethoxy-3-methyl-2-butane in a nitrogen atmosphere, 1.25 g of undried catalyst κρ-10 (sud-Chemie) and 89.25 grams of triethyl orthoformate was placed in 225 ml of absolute alcohol in a flask. With 5¾ cooling, 0.5 g of 3-methyl-butenal was added dropwise over 30 minutes. After that, the cooling was stopped, the reaction mixture was slowly heated to 20 ° C, and after adding 3-methyl-butenal, it was stirred for a total of 3.5 hours. The reaction process was detected by gas chromatography. After that, the catalyst was filtered off through a suction filter and washed with 20 ml of ethanol. 2.6 g of potassium carbonate was added to the filtration solution and the ethanol was distilled off under a vacuum (23 mbar / 501 / 0.5 hour and mbar / 52ec / l hour). After filtering off the carbonic acid bell and washing it with 20 ml of ethanol, the product was steamed at 187 mbar / 114eC. The standard of Tongzhou Jiahuo National Standard (CNS) a4 (210X297 mm) (read the precautions on the back before reading) (Fill in this page)

1. Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs of 1T 518331 A7 __ ______B7_ V. Description of the invention (7) Distillation. The obtained 1,2-diethoxy-3-methyl-2-butene distillate (143.4 g '86 .4% yield) had a content of 97.1% (dead point at 187 mbar: 114eC) 〇, & u 11. Soc. Ch im. Fr. 11, 2558; 1975):

1. Preparation of didiethoxy-3 -methyl-2-butyrate was performed according to the procedure described in Example 1, but 4 g of undried catalyst KSF (Aldrich) was used instead of 1.25 g of undried catalyst KP -10 (sud-Chemie), 37.78 g of [sic] ethyl orthoformate was used instead of 189 25 g, 90 liters of ethanol was used instead of 225 ml, and 21.9 g of 3-methyl-butene substituted 110.5 g And use 4 grams of potassium carbonate instead of 2.6 grams. The product (29.82 g, 70.3% yield) has a content of 94.1%. Example 3 (based on the comparison of Thuy and Maite, Bull. Soc. Chim. Fr. 11, 2558; 1975): 1, 1 _Preparation of diethoxy-3 -methyl-2-butene

According to the procedure described in Example 1, but using 4 g of KSF (Aldrich) catalyst instead of 25 g of catalyst [P-ίο (Sud-Chemie)] 37.65 g of [sic] orthoformic acid Ethyl acetate was used instead of 25g, 90ml ethanol was used instead of 225ml, 22.25g 3-methyl-butenal was used instead of 10.5g and 4g potassium carbonate was used instead of 26g. The product (29 65 g, 69.5% yield) has a content of 95%. Example 4 (Invention) Preparation of 3-methyl-2-butyl 4,3_dioxane in a nitrogen atmosphere, 0.5 g of an un-dried catalyst was used as _1 () (Sud_ 9 ~ ---------! (Please read the notes on the back before filling this page)

, 1T

518331 A7 ____B7 V. Description of the invention (8)

Chemie), 79.6 grams of triethyl orthoformate, and 48.2 grams of 3-methyl-butyric acid tower were placed in 34.3 grams of ethylene glycol in the flask and stirred at 4¾ for 15 hours. The catalyst was then filtered off with a suction filter and washed with 20 ml of ethanol. The product is 3-methyl-2-butene-1,3-di-eocene with a residual fraction of (39 2 g) and 86.9 g. % (3 g) content (47¾ yield). Example 5 (Invention) Preparation of 6-Ethyl-2,2-dimethyl-2oxo-1-benzopyran in argon atmosphere 83.8 g of 4-Acetomethylbenzene and 0576 g of anhydrous potassium carbonate were placed in 600 ml of xylene and heated to 140 ¾. 162.3 g of 1,1-diethoxymethylbutane (in ethanol Medium, 77⑽) was added dropwise to this boiling solution over 5 hours and the ethanol formed was continuously distilled. After stirring the solution at 140eC for 18 hours, it was cooled to 20 ° C and washed with 200 ml of NaOH (5%) The organic phase was concentrated in the air. The crude product (orange oil) was distilled under high air (2 · 8 nbar / 1431〇). The resulting 6-acetamidine-2,2-dimethyl-2H-1- Benzo mt-distillate (90.2 g, 71.3% product) has a content of 94.9%. Example 6 (Invention) 6-Ethyl-2,2-dimethyl-211-1-benzopyran The Consumer Cooperative of the Central Standards Bureau of the Ministry of Preparation and Economics printed it in argon atmosphere, and 60 mg was not dried. The catalyst KP-10 (Sub-Chemie) and 35.8 g of triethyl orthoformate were placed in 45 ml of absolute alcohol in the flask. With 5¾ cooling, 19.56 g of 3-methyl-butenal was removed for 30 minutes. Add dropwise. After that, the reaction mixture was stirred for an additional hour at 51 ° C. 195 mg of potassium carbonate, 100 ml of xylene and 20.95 g of 4-anthyl-acetamidine were added. (CNS) A4 specification (210X297 mm) 518331 A7 B7 V. Description of the invention (9) After benzene, the reaction mixture is heated to 140eC for one hour and the ethanol formed is distilled off continuously. The solution is stirred at 140¾ and then stirred for 4 hours. Hours. After cooling, the organic phase was washed with NaOH (5%) and concentrated. The crude product was steamed under high vacuum (0.5 mbarYmj). The resulting fraction of the compound had 76.4% (0.91 g) and 94.3 % (15 · 8g) content (51.8¾ yield). (Please read the notes on the back before filling out this page.) Printed on the paper standard printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the Chinese National Standard (CNS) A4 specifications (210X297 mm)

Claims (1)

518331 1;: ί year; ί-: Α8 Β8 C8 D8 ϋ—Patent Scope Patent Application No. 86112051 ROCPatentAppln. No. 86112051 Amended Application Scope Chinese Text-Attachment (1) jn Enel · ⑴ (Si 9 · 1 Army 1 Factory Month— · 2 ·· 9 ... (SuFrniite3Tδη November 19, 2002) A method for preparing compounds of the formula 2H-1-benzopyrans Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where R1 is hydrogen, (CrC4) alkyl, R2 is hydrogen, (CrC6) alkyl, and R3 is (CrC4) alkanoyl, which is characterized by the following formula in the first order Aliphatic aldehyde II wherein R1 and R2 have the aforementioned definitions, and aliphatic alcohols of the formula R40H or HOR4 OH, wherein R4 (Cl_C4) alkyl or (C2_C4) alkyldiyl, in $ HC (〇R5) 3 Dehydrating compound, in which r5 is (Ci_C4) alkyl, and an aliphatic acetal R r4o C III of the following formula in the presence of alumina / silica catalyst, where R1 and R2 have the aforementioned definitions and R4 is (Ci_C4) Alkyl-12 86406-claim This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) JN A8 B8 C8 D8 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs oh Agents 2. 4. 5. Paragraph Application scope = Dico-one group 'and its IV. R in the second has the aforementioned definition. In the presence of a base, an inert organic solvent is used to condense the final compound of formula I. = Applicable wealth_No.1 slave material, whose dragon is used in the first stage of oxidation! Lu / Stone Oxide Catalyst is one with a specific surface area and a pore volume greater than 0.15mg / g (7.5-80nm). Montmorillonite. 3. The method according to item i or 2 of the patent application scope, characterized in that the oxide catalyst / stone oxide catalyst used in the first 4 is added from 0.05 to 30% relative to the aliphatic chain used. Amount by weight. For example, the method of item 1 of Shenqing Patent, characterized in that R4 of the aliphatic alcohol R4 0H used in the first stage and R5 of the dehydrated compound HC (〇R5) 3 used in the first stage are ethyl. For example, the method of applying for the first item of the patent scope is characterized in that R4 of the aliphatic alcohol HOR4 OH used in the first stage is ethyl; R5 of the dehydration compound HC (OR5) 3 used in the first stage is ethyl . For example, the method of claim 1 in the scope of patent application is characterized in that the reaction temperature for performing the first stage is -40 ° C to 40 ° C. For example, the method of applying for item 1 of the patent scope is characterized in that the paper size in the second stage applies the Chinese National Standard (CNS) A4 specification (210 X 297 public reply) 518331 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives Αδ Β8 C8 _D8_ 6. The alkali used in the scope of patent application is inorganic base. 8. If the method of applying for the scope of patent No. 7 is characterized in that the inorganic test used in the second stage is a carbon clock. 9. If the method of applying for the scope of patent No. 1 is characterized in that the reaction temperature at the second stage is 90 to 180 ° C. 10. The method of claim 1 in the scope of patent application, characterized in that the intermediate product of formula III is not isolated and converted. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)