WO2017189477A1

WO2017189477A1 - Process for producing isohexides

Info

Publication number: WO2017189477A1
Application number: PCT/US2017/029243
Authority: WO
Inventors: Chi Cheng Ma
Original assignee: Archer Daniels Midland Company
Priority date: 2016-04-26
Filing date: 2017-04-25
Publication date: 2017-11-02

Abstract

A process is described for producing an isohexide by a base catalyzed conversion of a 1,2:5,6-diacetal of a hexitol to the isohexide.

Description

PROCESS FOR PRODUCING ISOHEXIDES

TECHNICAL FIELD

[0001] The present invention relates to processes for the manufacture of isohexides, such as isomannide, isosorbide and isoidide.

BACKGROUND ART

[0002] There are fundamentally three isohexides, or dianhydrohexitols:

isomannide, isoidide, and isosorbide. Isosorbide is a commercially-produced, bicyclic diol that is easily available from biological feedstock, by the hydrogenation of dextrose to provide sorbitol and then a typically acid-catalyzed dehydration of the sorbitol. Isosorbide is currently primarily used in medical applications, for example, as a diuretic in the treatment of hydrocephalus, in the treatment of glaucoma, and in the form of isosorbide dinitrate and isosorbide mononitrate as vasodilators for the treatment of angina pectoris. The double hydroxyl functionality of isosorbide has also made isosorbide of interest as a building block for polymerization, especially for making polycarbonates and polyesters. However, the making of polymers of suitable properties from isosorbide is hampered by the molecule's stereochemistry, since the two hydroxyl groups are directed to different sides of the molecule's plane, i.e., the up to now more easily obtainable isosorbide is unsymmetrical with one endo hydroxyl group and one exo hydroxyl group, resulting in asymmetrical reactivity and amorphous polymers (due to the lack of symmetry).

[0003] Isomannide is a renewable, inexpensive and commercially available bicyclic diol that is easily obtained in like manner to isosorbide, by again a typically acid-catalyzed dehydration from naturally occurring D-mannitol. Isomannide has two endo hydroxyl groups and has largely proven to be unfavorable for polymerization due to its low reactivity and low linearity, though derivatives of isomannide have been described as useful as tastants or flavoring agents, flavor or taste modifiers, and/or flavor/taste enhancers, see US 2012/0183660. Isomannide has also been viewed as an attractive biologically derived scaffold for synthetic applications, including as a starting material for pharmaceutically useful derivatives, and has found use as a phase transfer catalyst (PTC) in asymmetric synthesis, as a chiral ligand and auxiliary, and in the synthesis of chiral ionic liquids (CILs).

[0004] Isoidide for its part has two exo-hydroxyl groups, and has been viewed as far better suited for use as a building block for polymerization than either isosorbide or isomannide. The symmetrical structure of isoidide eliminates the regiochemical reactivity difference between the two hydroxyl functionalities. Isoidide, however, is not currently manufactured on a commercial scale, in part (but not exclusively) because of the high cost of the synthetic precursor iditol from which isoidide might be made by an analogous double dehydration pathway as employed for making isosorbide. An alternative pathway to isoidide through the epimerization of isosorbide has been investigated as a way of getting around this difficulty, though the literature related to this alternative pathway is quite limited.

[0005] In one recent publication, LeNotre et al. reported a highly efficient method for obtaining highly pure, resin-grade isoidide through catalytic epimerization of isosorbide using a ruthenium-on-carbon catalyst (LeNotre et al. "Synthesis of Isoidide through Epimerization of Isosorbide using Ruthenium on Carbon"

ChemSusChem 6, 693-700, 2013). This reference shows the synthesis of isoidide from highly purified (>99.5% pure) isosorbide (Polysorb, Roquette, Lestrem, France). We have recently developed other epimerization-based processes that seek to improve upon the LeNotre et al. method, at least one of which is able to use a less highly purified isosorbide feedstock, but a challenge common to all such methods is presented in the fact that the epimerization product inherently exists as a mixture of the three isohexides and further in that the capacity to make one isomer in preference to the others (as dictated by market demand, for example) is limited by equilibrium considerations.

[0006] The separation of these isomers has generally been by fractional distillation. While distillation is effective to a certain extent, the isohexides have relatively close boiling points at elevated temperatures and reduced pressures. This results in added cost and complexity.

[0007] A related further challenge to the production of isosorbide, whether as a feed to an epimerization process for producing isoidide or per se as a monomer for polymer applications, has been presented by the side reactions and byproducts that inevitably result from the conventional acid catalyzed dehydration methods by which isosorbide has been produced.

[0008] As summarized in United States Patents No. US 7,122,661 to Fleche et al. and US 8,008,477 to Fuertes et al, a number of approaches had been suggested previously (that is, previous to these two patents) for obtaining the internal dehydration products of hexitols (and particularly for obtaining the dianhydrohexitols such as isosorbide especially) in greater purity, for a variety of reasons. Some of these approaches sought improvements in purity through changes to the dehydration process by which the dianhydrohexitols were made, while other approaches involved a form of purification after the dianhydrohexitol compositions were formed. Other approaches have been suggested subsequent to the measures summarized and described in these two patents, including certain approaches we ourselves have suggested, but as a practical matter it must be acknowledged that the side reactions and byproducts that accompany the known acid catalyzed dehydration methods in the very best concept or scenario still unavoidably and undesirably increase the cost and complexity of making any of the individual isohexides.

SUMMARY OF THE INVENTION

[0009] The present invention in one aspect relates to a novel base-catalyzed process for producing an isohexide, comprising combining a 1,2:5,6 diacetal of a hexitol with a base catalyst at an elevated temperature to produce the corresponding isohexide of the hexitol.

[0010] In certain embodiments, the reaction is conducted under an inert gas blanket.

[0011] In certain embodiments, the reaction is conducted at a temperature of at least 170 degrees Celsius.

[0012] In certain embodiments, the reaction is conducted at a temperature of less than 200 degrees Celsius.

[0013] In certain embodiments, the base catalyst is in the form of an aqueous solution of from 0.5 percent by weight of sodium hydroxide in water up to 5 percent by weight of sodium hydroxide in water.

[0014] In certain embodiments, the reaction is carried out over a period of from 0.5 hours to 10 hours. [0015] In certain embodiments wherein the 1,2:5,6 diacetal used is

organosubstituted, the isohexide is recovered by allowing the product mixture to phase separate into organic and aqueous phases, and the aqueous phase is recovered, neutralized and the water evaporated therefrom to recover an isohexide solid.

DETAILED DESCRIPTION OF EMBODIMENTS

[0016] As used in this application, the singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. The term "comprising" and its derivatives, as used herein, are similarly intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. This understanding also applies to words having similar meanings, such as the terms "including", "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers, and/or steps. The term "consisting essentially of, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps, as well as those that do not materially affect the basic and novel characteristic(s) of stated features, elements, components, groups, integers, and/or steps. Terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term (beyond that degree of deviation understood by the precision (significant figures) with which a quantity is expressed) such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least plus or minus five (5) percent from the stated value, provided this deviation would not negate the meaning of the term modified.

[0017] Unless otherwise indicated, any definitions or embodiments described in this or in other sections are intended to be applicable to all embodiments and aspects of the subjects herein described for which they would be suitable according to the understanding of a person of ordinary skill in the art.

[0018] As indicated above, the present invention in one aspect relates to a novel base-catalyzed process for producing an isohexide, comprising combining a 1,2: 5,6 diacetal of a hexitol with a base catalyst at an elevated temperature to produce the corresponding isohexide of the hexitol.

[0019] The 1,2:5,6 diacetals of D-mannitol ((2R,3R,4R,5R)-hexane-l,2,3,4,5,6- hexol, CAS Number 69-65-8) and D-sorbitol ((2S,3R,4R,5R)-hexane-l,2,3,4,5,6-hexol, CAS Number 50-70-4) are well-known, commercially-available intermediates that are widely used to synthesize various optically active biomolecules and pharmaceutical molecules. The 1,2:5,6 diacetal synthetic intermediates are prepared by reacting these sugar alcohols with aldehydes and/or ketones of various types to protect certain hydroxyl groups in the transformation of other hydroxyl groups of the D-mannitol or D-sorbitol. It is noted that the 1,2:5,6 diacetals of L- or D-iditol ((2R,3S,4S,5R)-hexane-l,2,3,4,5,6- hexol, CAS No. 488-45-9 (L) or CAS No. 9001-32-5 (D)) could be prepared by the same methods but are not presently commercially available, as idose is not a naturally-occurring monosaccharide and commercial methods for producing iditol in either of the L- or D- stereoisomer do not currently exist.

[0020] Various synthesis methods are reported in the literature for preparing these

1,2:5,6 diacetals, and for purposes of the present invention, any of the known methods are considered suitable for preparing the 1,2:5,6 diacetal starting materials. For example, in Wu et al., "Synthesis of Diisopropylidene-D-mannitol Catalyzed by Zinc Chloride", Fine and Specialty Chemicals, Vol. 14., No. 1 (2006), catalysis by p-toluenesulfonic acid, stannous chloride and zinc chloride is reported as known, with the cited article employing zinc chloride to catalyze the combination of D-mannitol and acetone at various ratios of D-mannitol: acetone, various dosages of zinc chloride catalyst, various reaction times and temperatures. The best combination of conditions tested, providing a 62.8% yield, corresponded to a molar ratio of (D-mannitol): (acetone): (zinc chloride) of 1 :21.4: 1.85, a reaction temperature from 30 to 35 degrees Celsius and a reaction time of 12 hours. Other references describing the synthesis of the 1,2:5,6 diacetals include Ye et al., "Acetonation of Hexabasic Alcohol and its Application", Guangxi Chemical Industry, Vol. 29, No. 3 (September 2000) and Debost et al., "Selective Preparation of Mono- and Diacetals of D- Mannitol", Journal of Organic Chemistry, 48, 1381-1382 (1983). The Ye et al. and Debost et al. articles in fact indicate that still other catalyst systems and methods had been previously known and described in the literature beyond the three catalysts later reported by Wu et al., and contain citations to those prior catalyst systems and methods. Still earlier references may be found describing the reaction of carbohydrates inclusive of the hexitols with aldehydes and ketones under various conditions, see, e.g., Barker et al, "Acetals and Ketals of the Tetritols, Pentitols and Hexitols", Advan. Carbohydr. Chem, vol. 7, pp. 137-207 (1952); de Belder, "Cyclic Acetals of the Aldoses and Aldosides", Adv. Carbohydr. Chem., vol. 20, pp. 219-302 (1965); de Belder, " Cyclic Acetals of the Aldoses and Aldosides", Adv. Carbohydr. Chem., vol. 34, pp. 179-241 (1977); Brady, "Cyclic Acetals of Ketoses", Adv. Carbohydr. Chem. Biochem, vol. 26, pp. 197-278 (1971); Stoddart, Stereochemistry of Carbohydrates, pp. 186-220 (1971); Hough et al, Rodd's Chemistry of Carbon Compounds. Vol. 1, Part F, pp. 32-38 and 351-362 (1967); Lemieux, Molecular Rearrangements. Part II, pp. 723-733 (1963); Clode, "Carbohydrate Cyclic Acetal Formation and Migration", Chem. Rev., vol. 79, pp. 491-513 (1979).

[0021] However produced, a 1,2:5,6 diacetal of a hexitol is, according to a first aspect of the present invention, combined with a base catalyst at an elevated temperature to produce the corresponding isohexide of the hexitol. The acetal groups may be unsubstituted (with hydrogen only, using formaldehyde as the aldehyde) or substituted, for example, with methyl, ethyl or phenyl groups, based on what is selected for use in the acetonation reaction with the hexitol.

[0022] Preferably, the 1,2:5,6 diacetal is combined with from 0.5 percent by weight up to 5 percent by weight of sodium hydroxide in water in the presence of as little oxygen as can be managed (as oxygen might lead to the formation of ethers), for example, under an inert gas blanket, and the combination is maintained at a temperature of from 170 degrees Celsius up to 200 degrees Celsius for a period of from 1 to 5 hours.

[0023] Where the 1,2:5,6 diacetal of the hexitol is organosubstituted, the corresponding isohexide can be recovered in certain embodiments by allowing the organic leaving groups to phase separate from the remaining aqueous phase, then decanting the organic phase, neutralizing the aqueous phase and evaporating the water to yield an isohexide product in solid form. Those of skill in the art will appreciate that this isohexide may then be refined or purified in a conventional manner, for example, by melt recrystallization or the like. Unlike in other isohexide synthesis methods, for example, acid-catalyzed dehydration of the hexitols, isohexides prepared in the base-catalyzed method described herein appear not to undergo epimerization to the other isohexides, at least to any appreciable degree. [0024] The present invention is more particularly illustrated by the following, non-limiting examples:

[0036] Example 1

[0037] 2.65 grams of l,2: 5,6-diisopropylidene-D-mannitol and 2 grams of NaOH in 100 milliliters of water were loaded into a 300 cubic centimeter Parr reactor, and hydrogen was thereafter supplied to the reactor at 1 1.7 MPa (1700 pounds per square inch). The mixture of l,2: 5,6-diisopropylidene-D-mannitol and NaOH was stirred under the hydrogen atmosphere for 3 hours at 180 degrees Celsius. The product mixture was then neutralized and evaporated to provide essentially only isomannide as a product, as confirmed through a combination of ¾ and ¹³ C nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry, with 86% of the 1 ,2:5, 6-diisopropylidene- D-mannitol having been converted.

[0038] Example 2

[0039] 2 grams of 1,2:5, 6-diisopropylidene-D-mannitol and 2 grams of NaOH in 100 mL of water were loaded into a 300 cubic centimeter Parr reactor, and hydrogen was thereafter supplied to the reactor at 1 1.7 MPa (1700 pounds per square inch). After stirring at 190 degrees Celsius for 3 hours, the product mixture was neutralized and evaporated to again provide isomannide as the sole product.

[0040] Example 3

[0041] 2 grams of 1,2:5, 6-bis-ortho-(l -methylethylidene)-D-glucitol and 2 grams of NaOH in 150 mL of water were loaded into a 300 cubic centimeter Parr reactor, and hydrogen was thereafter supplied to the reactor at 3.4 MPa (500 pounds per square inch). The mixture was stirred at 185 degrees Celsius for 3 hours. The resultant product mixture was neutralized and evaporated to provide isosorbide as the only product, with 56% of the starting material having been converted.

Claims

CLAIMS What is claimed is:

1. A process for producing an isohexide, comprising combining 1 ,2:5,6 diacetal of a hexitol with a base catalyst at an elevated temperature to provide a product mixture including the corresponding isohexide of the hexitol.

2. The process of claim 1, conducted under an inert gas blanket.

3. The process of any of claims 1- 2, conducted at a temperature of at least 170 degrees Celsius.

4. The process of any of claims 1- 3, conducted at a temperature of less than 200 degrees Celsius.

5. The process of any of claims 1-4, wherein the base catalyst is in the form of an aqueous solution of from 0.5 percent to 5 percent by weight of sodium hydroxide in water.

The process of any of claims 1-5, carried out over a period of from 0.5 hours to 10 hours.

The process of claim 6, carried out over a period of from 1 to 5 hours.

8. The process of any one of claims 5-7, wherein the 1 ,2: 5,6 diacetal is organosubstituted and the isohexide is recovered by allowing the product mixture to phase separate into organic and aqueous phases, isolating the aqueous phase from the organic phase, neutralizing the isolated aqueous phase and evaporating water from the neutralized aqueous phase to provide an isohexide solid.

9. The process of claim 8, wherein 1 ,2:5, 6-diisopropylidene-D-mannitol is converted to isomannide. The process of claim 8, wherein 1 ,2:5, 6-bis-ortho-(l -methylethylidene)- D-glucitol is converted to isosorbide.