The present invention relates to an improved synthesis of a racemic mixture of pan- tolactone.

Pantolactone, which is the compound of formula (I)

has two optically active enantiomers.

(R)-Pantolactone which is the compound of formula (G)

and (S)-pantolactone, which is the compound of formula (I”)

(R)-pantolactone is a starting material for the synthesis of calcium (R)-pantothenate (compound of formula (II))

which is the commercial form of pantothenic acid (compound of formula (III))

Pantothenic acid, which also known as vitamin B5, is a water-soluble vitamin. Pan- tothenic acid is an essential nutrient. There are many health benefits of vitamin B5, some of which include a healthy heart, lower stress levels, and applications in skin and hair care.

Instead of pantothenic acid, calcium pantothenate is often used in dietary supple- ments because, as a salt, it is more stable than pantothenic acid. Natural sources of vitamin B5 are for example mushrooms, broccoli, cabbage, leg umes, salmon, eggs, fish, brewer’s yeast, nuts, milk, and dairy products like cheese, wheat, peanuts, soybeans, molasses, and collard greens.

An alternative way to obtain vitamin B5 is by chemical synthesis. An important starting material is as said above (R)-pantolactone. A usual way to produce vitamin B5 is the reaction of calcium b-alaninate with (R)-pantolactone in boiling ethanol or methanol.

The other enantiomer of pantolactone, which is (S)-pantolactone, can be used as such or it can be used as intermediate in various synthesis. Alternatively, (S)-panto- lactone can also be transformed into (R)-pantolactone.

The racemic mixture of pantolactone is a 1 :1 mixture of (R)-pantolactone and (S)- pantolactone. This mixture can be used as such (or in any formulation) or it can be used as intermediate for further chemical (or biochemical) reactions.

Due to the importance of the racemic mixture of pantolactone, there is always a need for an improved process of production of a racemic mixture of pantolactone. Nowadays there are several processes known to produce a racemic mixture of pan- tolactone. There are chemical as well as biochemical methods. Also, combinations of chemical and biochemical methods are known. The present invention relates to a two-step synthesis of a racemic mixture of panto- lactone. Preferably the present invention relates to a two-step and one-pot synthesis of in good yields.

The newly found process of the racemic mixture of pantolactone has the following reaction schemes

wherein R is a C1-C10 alkyl moiety which is a substituted or an un-substituted alkyl.

The first step (step (i)) is carried out in the presence of at least one specific organo- catalyst.

The reaction steps are discussed in more detail below.

Step (i)

The first step (step (i)) is carried out in the presence of a least one organo-catalyst.

The organo-catalyst has a pyrrolidine ring, which is substituted.

The organo-catalysts used in step (i) are known. They are available commercially or they can be produced according to known methods.

The reaction of step (i) is usually carried out in a solvent (or a mixture of solvents). Suitable solvents are alcohols, hydrocarbons, halogenated hydrocarbons (for exam- pie chloroform and dichloromethane), ethers, esters and amides (for example DMF). Especially preferred are secondary and tertiary alcohols (such as isopropanol (pro- pan-2-ol) and tert- butyl alcohol (2-methylpropan-2-ol)).

The reaction mixture of step (i) should not comprise any water. This means that the water content is kept to a minimum and that no water is added to the reaction mixture of step (i) intentionally. Therefore, another preferred embodiment of the present invention is a process as described wherein step (i) the reaction mixture does not comprise any water

The reaction is usually carried at temperatures of 0°C - 80°C, preferably 10°C - 40°C, more preferably 20°C - 30°C.

The amount of the organo-catalyst is usually from 0.1 - 10 mol-% (in regard to the starting material). Preferably from 1 - 5 mol-%. The starting material (the compounds of formula (IV) and (V)) are usually added in equimolar amounts. A slight excess of one of the compounds is acceptable as well.

Step (ii)

The reaction of step (ii) is a transfer hydrogenation. The reaction of step (ii) is carried out in the presence of a hydrogen donor (such as a formate or an alcohol).

The transfer hydrogenation is catalyzed by at least one transition metal catalyst.

The transition metal catalyst can be added as such to the reaction mixture.

Alternatively, the transition metal catalyst can be formed by the addition of ligand and by the addition of the transition metal in the form of a salt.

Furthermore, it is also possible that the org a no-catalyst of step (i) serves as ligand to form the transition metal catalyst used in step (ii). In this case the transition metal is added to the reaction mixture in the form of a salt.

These alternative ways how to obtain the transition metal catalyst could also be com- bined (which means that a catalyst can be added as well as a ligand and a transition metal salt).

Preferred transition metals are Ru, Ir, Rh, Fe, Co and Mn, more preferred are Ru, Ir and Rh.

As stated above, the transition metals can be added in form of a salt (such as di- chloro(p-cymene)ruthenium(ll) dimer).

The reaction of step (ii) is usually carried out at elevated temperatures. Preferably, the reaction temperature of step (ii) is between 20°C and 100 °C, more preferably be- tween 30°C and 70 °C.

In the reaction of step (ii), the amount of hydrogen donor is between 1 and 2 mol-eq in regard of the compound of formula (VI). In the reaction of step (ii), the amount of the transition metal salt used to form the catalyst is between 0.01 and 10 mol-%, preferably 0.1 - 10 mol, more preferably 1 - 5 mol-%, in regard of the compound of formula (VI).

The following examples serve to illustrate the invention. If not otherwise stated the temperature is given in °C.

Examples

The organocatalysts used are either commercially available or can be prepared using known methods

Example 1 : General procedure for step (i) testing various organocatalysts producing ethyl-2-hvdroxy-3.3-dimethyl-4-oxobutanoate (VI)

To a vial containing the organocatalyst (0.01 mmol, 10.0 mol%) 0.20 ml. of a stock solution of isobutanal (91.0 pL, 1.00 mmol) and ethyl glyoxalate (50.0 wt.% in toluene, 198 mI_, 1.00 mmol) in t-BuOH (2.00 ml.) was added. The mixture was stirred at room temperature for 4 - 72 h. Conversion was measured by NMR or GC.

The results of the experiment are shown in the table below.

Comparative examples (Comp-A and Comp-B) were performed with organocatalysts A and B under the same conditions.

Example 2 To a solution of N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (rac-Vllb, 79.1 mg, 500 pmol, 5.00 mol%) in t-BuOH (10.0 ml_), isobutanal (910 mI_,10.0 mmol, 1.00 eq.) and ethyl glyoxalate (50.0% in toluene, 1.98 ml_,10.0 mmol, 1.00 eq.) were added. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue purified by column chromatography (cyclohexane/ethyl acetate, 4:1 ) yielding ethyl 2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) (1.47 g, 84%) as a color- less oil. 1 H NMR (400 MHz, CDCI3) d = 9.57 (1 H, s), 4.32 (1 H, s), 4.30- 4.18 (2H, m), 3.06 (1 H, br), 1 .27 (3H, t), 1.14 (3H,s), 1.05 (3H, s). The analytical data was in agreement with an authentic sample. General procedure for transfer hydrogenation (step (ii))

The transition metal catalyst or the transition metal salt and the ligand were added to a solution of ethyl 2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) from example 1. The mixture was degassed, sodium formate was added and the mixture was stirred at the desired temperature until the reduction was complete. The reaction mixture extracted with MTBE and the combined organic phases were dried, filtered and concentrated in vacuo. Example 3

Ethyl 2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) was reacted with 5 equivalents of sodium formate and 0.5 mol% of RuCI(p-cymene)[(S,S)-Ts-DPEN] in water at 40 °C. Full conversion was obtained after 17 hours yielding pantolactone (I)

Example 4 - One pot, sequential synthesis of pantolactone (I)

To a solution of N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (rac-Vllb, 237 mg, 1 .50 mmol, 5.00 mol%) in t-BuOH (30.0 ml_), isobutanal (2.74 ml_, 30 mmol, 1.00 eq.) and ethyl glyoxalate (50.0 wt.% in toluene, 5.95 ml_, 30.0 mmol, 1.00 eq.) were added. The mixture was stirred at room temperature for 24 h. Water (150 ml.) was added and the solution was degassed with argon for 1 h, before (RuCl2(cymene))2 (91.9 mg, 150 mmol, 0.50 mol%) and sodium formate (10.2 g, 150 mmol, 5.00 eq.) were added. The mixture was stirred overnight. A solution of aq. HCI (1 M, 200 ml.) was added and the reaction mixture extracted with MTBE (3x 600 ml_). The combined organic phases were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane/ ethyl acetate, 2:1 ) yielding the product (rac- pantolactone, 2.4 g, 62%) as a white solid. The analytical data was in agreement with an authentic sample.