# Patent

## Title
Process for the manufacture of 3-oxo-tetrahydrofuran

## Abstract

This invention relates to a novel method for the preparation of 3-oxo-tetrahydrofuran comprising oxidizing 3-hydroxy-tetrahydrofuran in the presence of a catalytic amount of 2,2,6,6-tetramethyl-piperidine-N-oxyl (TEMPO) with trichloroisocyanuric acid.

## Background
FIELD OF THE INVENTION
This invention relates to a novel method for the preparation of 3-oxo-tetrahydrofuran.
BACKGROUND OF THE INVENTION
3-Oxo-tetrahydrofuran (3-Oxo-THF, compound I) is an important intermediate in the manufacture of pharmaceutically active ingredients.
The known chemical syntheses of this compound offer only limited access to 3-Oxo-THF and all face severe drawbacks that do not allow for a sustainable and environmentally friendly supply with this important intermediate. Therefore, there has been need to develop a novel approach to this compound. The present invention provides a simple, inexpensive, chemoselective and environmentally friendly process for the manufacture of 3-Oxo-THF (I) that can be run under mild conditions.
Up to date, the following methods for the preparation of 3-Oxo-THF (I) have been described: 3-Oxo-THF (I) can be prepared by using transition-metal, especially Cr (VI) as an reagent (scheme 1) to oxidize of 3-hydroxy tetrahydrofuran (3-OH-THF, compound II) [J. Org. Chem. 1989, 54, 1249-1256].




The disadvantage of this process is the toxicity and environmental hazards associated with chromium compounds. Additionally, this process delivers low yields only (up to 46%).
A modification of this synthesis is disclosed in WO 2006/067430. Therein, solvent was changed from acetone to dichloromethane (DCM) and crude yield was improved to 79%. However, all major disadvantages remain.




Another process for making 3-Oxo-THF is disclosed in CN 102321054A. This involves a two-step synthesis starting from but-2-yne-1,4-diol (compound III) followed by cyclization (Scheme 3). This process has the disadvantage of low conversion and high level of impurities which render it inappropriate for practical use.




In J. Org. Chem. 1987, 52, 2559, oxoammonium salts like 2,2′,6,6′-tetramethylpiperidine-N-oxyl or derivatives (TEMPO) were employed as oxidants in the conversion of primary and secondary alcohol function to the corresponding carbonyl function. In particular, the variant using the TEMPO-bleach combination including bromide as co-catalyst is nowadays often applied in organic syntheses [Scheme 4].




The major drawbacks of this method include (1) the use of NaClO as oxidant, (2) the need for the addition of KBr and buffering of pH at 8.6 with NaHCO3 and (3) the necessity to use mixtures of chlorinated organic solvent with water. These conditions prove to be difficult for large scale applications because of the uncontrollable highly exothermic nature of the reaction.
The resulting 3-oxo-THF is unstable in the presence of excess of bleach causing the decomposition of the product. In addition, yields vary with incomplete conversion of starting material and decrease of concentration of NaClO upon the prolonged storage. Therefore, this method is not feasible for an economically competitive and robust way to allow for industrial scale production of 3-oxo-THF.
A modification of the variant 3 process is the TEMPO-TCCA protocol described in J. Org. Chem. 2003, 68, 4999-5001. Using trichloroisocyanuric acid (TCCA) in the presence of catalytic amount of TEMPO makes it possible to run the reaction under mild conditions. However, it is still a lab procedure. Excess use of TCCA (2 eq.) is required to complete the reaction in time. Using mixtures of solvents (water and acetone) complicates solvent recovery. Adding the oxidant TCCA after charging the TEMPO catalyst may result in an accumulation of unreacted starting materials thereby leading to a run away reaction.




When applying this procedure to oxidize 3-OH-THF (II), complete conversion of starting material was reached after 1 h and 3-oxo-THF (I) was obtained in a yield of 69% (GC area %; comparative example 1). Lots of unidentified impurities were found by GC-MS during the reaction rendering purification difficult.
The present invention provides a method for the preparation of 3-oxo-THF that overcomes the disadvantages of these methods known in the prior art.
The process according to the present invention does not require the use of NaHCO3 buffering, NaBr or other additives and delivers 3-oxo-THF with good yields and in high quality without toxic by-products and transition metal wastes.


DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for preparing 3-oxo-tetrahydrofuran comprising reacting 3-hydroxy tetrahydrofuran (II)




with 0.5-2 mol equivalent of trichloroisocyanuric acid





in the presence of 0.001-1 mol equivalent 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in a solvent selected from the group consisting of dichloromethane, ethyl acetate, isopropyl acetate, acetone, acetonitrile and toluene;

at a temperature from −20° C. to 40° C.

In a second embodiment, the process according to the first embodiment above further comprises neutralization of the reaction mixture with an inorganic base such as NaHCO3, Na2CO3, or NaOH; preferably NaHCO3.
In another embodiment, the process according to any one of the embodiments above further comprises quenching the reaction mixture with a reducing agent, preferably sodium sulfite.
In another embodiment, the process according to any one of the embodiments above is conducted at a temperature of −10° C. to 25° C.
In another embodiment, the process according to any one of the embodiments above is conducted in the absence of HCO3− buffering and a bromide or other additives.
In another embodiment, in the process according to any one of the embodiments above the amount of trichloroisocyanuric acid is 1.0 to 2.0 mole equivalent, preferably 1.0 to 1.05 mol equivalent.
In another embodiment, in the process according to any one of the embodiments above the amount of TEMPO is 0.01 to 0.02 mol equivalent.
In another embodiment, in the process according to any one of the embodiments above, a solution of TEMPO in dichloromethane or ethylacetate is slowly added to the solution of 3-OH-THF and TCCA to allow for safer process and better quality control.
Another aspect of the present invention is a two-step process for preparing 3-Oxo-THF comprising the following steps

    
    
        (a) conversion of butane-1,2,4 triol (III) in the presence of an acid to 3-hydroxy tetrahydrofuran (II), and
        (b) conversion of 3-hydroxy terahydrofuran according to any of the embodiments of the oxidation process above.
    
    


The cyclization in step a) is conducted in the presence of a strong acid, such as p-toluenesulfonic acid (PTSA) at a temperature of 150° C. to 200° C., preferably 160° C. to 180° C.




Experimental Section
Example 1
Preparation of 3-OH-tetrahydrofuran (II)
To a 500 mL flask, 1,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 eq.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 eq.) were added. The solution was heated to 160-180° C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3% yield).
Example 2
Preparation of 3-Oxo-tetrahydrofuran (3-OH-THF) in DCM
To a 1 L jacket reactor (reactor A), 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 eq.) was charged, followed by DCM (500 mL). The solution was cooled to −5° C. To which TCCA (159.6 g, 0.68 mol, 1 eq.) was added in one portion. The resulting slurry was stirred for 10 min. TEMPO (1.08 g, 0.0069 mol, 0.01 eq.) DCM solution (120 mL) was added dropwise while controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS until the 3-OH-THF was less than 1%.
The mixture was filtered and washed with DCM (60 mL*3), followed by washing with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM (60 mL*2). The combined organic phase was concentrated in normal pressure and then distilled under vacuum to give product as pale yellow oil (55.4 g, 93.6%) with 95% HPLC purity.
Example 3
Preparation of 3-Oxo-tetrahydrofuran (3-OH-THF) in acetone
To a 250 mL flask, 3-tetrahydrofuran (3-OH-THF, 6.06 g, 0.068 mol, 1 eq.) was charged, followed by acetone (50 mL). The solution was cooled to −5° C. To which TCCA (16.0 g, 0.068 mol, 1 eq.) was added in one portion. The resulting mixture was stirred for 10 min. TEMPO (0.11 g, 0.00069 mol, 0.01 eq.) acetone solution (12 mL) was added dropwise while controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS, the reaction was finished in 1 h to give 52% yield (GC area %).
Example 4
Preparation of 3-Oxo-Tetrahydrofuran (3-OH-THF) in Ethyl Acetate
To a 500 mL flask, 3-tetrahydrofuran (3-OH-THF, 30.3 g, 0.34 mol, 1 eq.) was charged, followed by ethyl acetate (250 mL). The solution was cooled to −5° C. To which TCCA (80.0 g, 0.34 mol, 1 eq.) was added in one portion. The resulting mixture was stirred for 10 min. TEMPO (0.54 g, 0.0035 mol, 0.01 eq.) ethyl acetate solution (60 mL) was added dropwise while controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS. Reaction was finished in 1 h to give 90% yield (GC area %).
Example 5
Preparation of 3-Oxo-Tetrahydrofuran (3-OH-THF) in Isopropyl Acetate
To a 50 mL flask, 3-tetrahydrofuran (3-OH-THF, 0.44 g, 0.005 mol, 1 eq.) was charged, followed by isopropyl acetate (4.5 mL). The solution was cooled to −5° C. To which TCCA (1.16 g, 0.005 mol, 1 eq.) was added in one portion. The resulting mixture was stirred for 10 min. TEMPO (0.008 g, 0.00005 mol, 0.01 eq.) was added in drops while controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS, Reaction was finished in 1 h to give 90% yield (GC area %).
Example 6
Preparation of 3-Oxo-Tetrahydrofuran (3-OH-THF) in Toluene
To a 50 mL flask, 3-tetrahydrofuran (3-OH-THF, 0.44 g, 0.005 mol, 1 eq.) was charged, followed by toluene (4.5 mL). The solution was cooled to −5° C. To which TCCA (1.16 g, 0.005 mol, 1 eq.) was added in one portion. The resulting mixture was stirred for 10 min. TEMPO (0.008 g, 0.00005 mol, 0.01 eq.) was added in drops while controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS, Reaction was finished in 1 h to give 89% yield (GC area %).
Example 7
Changing the Adding Sequence (First TEMPO, then TCCA)
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 eq.) was charged, followed by DCM (620 mL) and TEMPO (1.08 g, 0.0069 mol, 0.01 eq.) The solution was cooled to −5° C. To which TCCA (159.6 g, 0.68 mol, 1 eq.) was added in portions controlling the temperature around −5° C. to 0° C. The resulting mixture was allowed to warm to room temperature and monitored by GC-MS, Reaction was finished in 1 h to give 95% yield (GC area %).

## Claims

1. A process for preparing 3-oxo-tetrahydrofuran comprising reacting 3-hydroxy tetrahydrofuran (II)



with 0.5-2 mol equivalents of trichloroisocyanuric acid




in the presence of 0.001-1 mol equivalent 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in a solvent selected from the group consisting of dichloromethane, ethyl acetate, isopropyl acetate and toluene; and
at a temperature of −20° C. to 40° C., wherein the process is conducted in the absence of HCO3−, a bromide or other additives.

2. The process according to claim 1 wherein the reaction is conducted at a temperature of −10° C. to 25° C.

3. The process according to claim 1 wherein the amount of trichloroisocyanuric acid is 1.0 to 2.0 mol equivalent.

4. The process according to claim 1 wherein the amount of TEMPO is 0.01 to 0.02 mol equivalent.

5. The process according to claim 1 wherein in the oxidation step a solution of TEMPO in dichloromethane or ethylacetate is added to the solution of 3-hydroxy tetrahydrofuran and trichloroisocyanuric acid.

6. The process according to claim 1 wherein the trichloroisocyanuric acid is added in portions to the solution of 3-hydroxy tetrahydrofuran and TEMPO in dichloromethane or ethylacetate.