CN102241649A

CN102241649A - Method for preparing tetrahydro-3-furanmethanol

Info

Publication number: CN102241649A
Application number: CN2011101908180A
Authority: CN
Inventors: 陈飞; 李鑫源
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-07-08
Filing date: 2011-07-08
Publication date: 2011-11-16

Abstract

The invention belongs to the technical field of medicines and relates to a method for preparing tetrahydro-3-furanmethanol which is an important medicine intermediate. The method comprises: firstly, reducing 3-furfural or 3-furancarboxylic acid to obtain corresponding 3-furanmethanol; and secondly, deeply reducing 3-furanmethanol by a catalytic hydrogenation process to obtain tetrahydro-3-furanmethanol. The method is simple and high in yield, produces less waste water, waste gas and waste residue and is and ideal method for synthesizing tetrahydro-3-furanmethanol.

Description

The preparation method of 3-tetrahydrofurfuryl carbinol

Technical field

The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of preparation method of important pharmaceutical intermediate 3-tetrahydrofurfuryl carbinol.

Background technology

The 3-tetrahydrofurfuryl carbinol is the important intermediate of preparation agricultural chemicals MTI-446 and medical Penciclovir. uses Wakita etc. 2003 accordingly in 1022 pages of article The discovery of dinotefuran:a novel neonicotinoid that deliver of " Pest Management Science " the 59th volume P1016 – (invention of MTI-446 compounds; The nicotinic insecticide of one class novelty) and the 2004 article Synthesis and Structure-Activity Relationships of DinotefuranDerivatives:Modification in the Nitroguanidine Part that deliver 355 pages of " Journal of Pesticide Science " the 29th volume 4 phase P348 – (synthetic and structure-activity research MTI-446 derivative is modified corresponding dinitro guanidine part) and Chen Meiling equal clearly it to be used in corresponding pharmic function molecule in Study on Synthetic Technique of Penciclovir that " drug research " the 15th volume 7 phase 33-35 page or leaf is delivered etc. in 2005. Still have and mention its synthetic (WO2007091391 and US20070254951) accordingly.

Its important intermediate tetrahydrofuran (THF) three methyl alcohol are raw material with diethyl malonate and ethyl chloroacetate mainly, through the synthetic 3-tetrahydrofurfuryl carbinol of three-step reactions such as replacement, reduction and condensation.This route has that step is long, inorganic salt are numerous, is difficult to purifying, intermediate is difficult for shortcomings such as detections, and how to obtain more excellent synthetic route is emphasis and the difficult point that this compound synthesizes always.

Summary of the invention

The 3-tetrahydrofurfuryl carbinol receives much concern as the important intermediate of agricultural chemicals and medicine all the time, and its synthetic method is as seen less, and existing method is pure at various factors, for mass production certain restraining factors is arranged all.The present invention adopts industrial technology commonly used to carry out corresponding study on the synthesis in order to solve the difficult problem on its synthetic method, has obtained satisfied result.The problem that the present invention need solve provides a kind of optimum synthetic method of synthetic 3-tetrahydrofurfuryl carbinol, and its purpose compound structure is as follows:

Its raw material general formula is as follows:

In the raw material general formula R can for-COOH ,-CHO and CH ₂OH.

Its main synthetic method is as follows:

Formula 1: with the 3-furancarboxylic acid is the synthetic 3-furfuralcohol of raw material

The synthetic method of 3-furfuralcohol can use the 3-furancarboxylic acid to be raw material under mild conditions, uses zirconium tetrachloride, zinc chloride, iodine or phosphorus hexafluorophosphate are made catalyzer, tetrahydrofuran (THF), and ethanol or methyl alcohol are made solvent, make reductive agent with sodium borohydride, can realize its conversion.

Formula 2: with the 3-furfural is the synthetic 3-furfuralcohol of raw material

The synthetic method of 3-furfuralcohol also can be used tetrahydrofuran (THF) by the conversion of 3-furtural, and ethanol or methyl alcohol are made solvent, make reductive agent with sodium borohydride, can realize its conversion.

Formula 3: synthetic 3-tetrahydrofurfuryl carbinol

The synthetic of 3-tetrahydrofurfuryl carbinol is raw material with the 3-furfuralcohol, and with interval type autoclave hydrogenating reduction furan nucleus, Pd/C catalysis can obtain target product.

In formula 1 and formula 2, the reaction system solvent can be selected tetrahydrofuran (THF), ethanol or methyl alcohol isopolarity and intensive polar solvent for use, and the usage quantity scope is 3-furfural or 3-furancarboxylic acid weight 4-8 a times; The usage quantity of sodium borohydride is 3-6 a times of material quantity; The reaction optimal temperature be zero degree to room temperature, and top temperature must not surpass the boiling temperature of coordinative solvent.Catalyzer can be zirconium tetrachloride, zinc chloride, iodine or phosphorus hexafluorophosphate (BOP reagent); Reaction time range 8-15 h is advisable.

In the formula 3, the reaction system solvent can select for use alcohols such as methyl alcohol, ethanol or propyl alcohol to do reaction solvent, and the usage quantity scope is 4-8 a times of raw materials quality; Reacting kettle inner pressure is 2-4Mpa; Reaction times is 2-6 h; Temperature of reaction is 100-140 ℃; The Pd/C catalyst levels is 2% to 5% of a raw materials quality, can select promotor such as triethylamine or pyridines alkaline medium for use simultaneously.

The present invention compared with prior art its beneficial effect is:

Catalytic hydrogenation not only can reduce the generation of three industrial wastes largely, forms free of contamination industrial chain, also can recycle the hydrogen as energy source that other links form to a great extent, reduces industrial discharge.Present method is also very high than other method synthesizing tetrahydrofuran three methyl alcohol efficient, can obtain large-tonnage product at short notice, is more suitable in suitability for industrialized production.

Description of drawings

Fig. 1, furans-3-formic acid ¹H NMR spectrogram.

Fig. 2, furans-3-formaldehyde ¹H NMR spectrogram.

Fig. 3, furans-3-methyl alcohol ¹H NMR spectrogram.

Fig. 4,3-tetrahydrofurfuryl carbinol ¹H NMR spectrogram.

Embodiment

Example 1

The 3-furancarboxylic acid of 112 g is dissolved in the tetrahydrofuran (THF) of 560 g, adds the zinc chloride of 5.6 g again, stirring at room is even, adds 136.8 g sodium borohydrides in batches, finishes room temperature reaction 12 h.Regulate pH to neutral with 2 L/mol hydrochloric acid, cross filter solid, wash solid at twice, merge organic layer, concentrate the furans-3-methyl alcohol that obtains 95.8 grams with 200 mL tetrahydrofuran (THF)s.Purity 98.7%, yield 96.5%, boiling point 79.4-80.2 ℃ (17 mm Hg), ¹H NMR (500MHz, DMSO-d6) δ: 7.80 (t, J=1.5,1H), 7.53 (d, J=0.5,1H), 6.44 (s, 1H), 4.94 (t, J=5.5,1H), 4.35 (s, 1H), 4.34 (s, 1H).

Embodiment 2

The 3-furfural of 96g is dissolved in the tetrahydrofuran (THF) of 480g, adds the zinc chloride of 4.8g again, stirring at room is even, adds the sodium borohydride of 136.8g in batches, finishes room temperature reaction 12h.Regulate pH to neutral with 2/mol hydrochloric acid, cross filter solid, wash solid at twice, merge organic layer, concentrate, obtain the 3-furfuralcohol of 96.2 grams with the 200ml tetrahydrofuran (THF).Purity 99.1%, yield 97.3%, boiling point 78.6-79.4 ℃ (17 mm Hg), nuclear-magnetism test result such as example 1.1.

Embodiment 3

The triethylamine of furans-3-methyl alcohol, 490 g dehydrated alcohols, 3.92 g Pd/C catalyzer and 4.9 g of 98g is added in the intermittent type autoclave airtight stirring; Take out most air, feed hydrogen, the system internal pressure is maintained 3 Mpa with behind the air in the nitrogen replacement still three times, and in 140 ℃ of reaction 4h down; System is reduced to room temperature, and the discharging remaining hydrogen eliminates hydrogen in the still with nitrogen, drives still; Filter, regulate pH to neutral with 2L/mol hydrochloric acid, filter, concentrate ethanol, the colourless viscous liquid tetrahydrofuran (THF)-3-methyl alcohol that obtains 87.6g is collected in surplus solution rectifying, purity 98.7%, and yield 94.8%, boiling point 75.8-77.2 ° C (4 mm Hg), ¹H NMR (500MHz, CDCl3) δ: 4.032-3.649 (m, 5H), 3.600-3.444 (m, 3H), 2.458-2.366 (m, 1H), 2.019-1.911 (m, 1H), 1.632-1.522 (m, 1H) .m/s:(101, M ⁺-1).

Claims

1. the synthetic method of a 3-tetrahydrofurfuryl carbinol, it is characterized in that: be raw material at first with 3-furancarboxylic acid or 3-furfural, under the condition of gentleness, make catalyzer with zirconium tetrachloride or zinc chloride or iodine or phosphorus hexafluorophosphate, tetrahydrofuran (THF) or ethanol or methyl alcohol are made solvent, make reductive agent with sodium borohydride, 3-6 h can change into methylol fully with carboxyl or aldehyde radical, use interval type autoclave hydrogenating reduction furan nucleus again, Pd/C catalysis can obtain the 3-tetrahydrofurfuryl carbinol.