The present invention relates to a stereoselective synthesis of enantiomerically en- riched pantolactone.

Pantolactone has two optically active enantiomers. (R)-pantolactone which is the compound of formula (I)

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

(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. An usual way to produce vitamin B5 is the reaction of calcium b-alaninate with (R)-pantolactone in boiling ethanol or metha- nol.

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.

Due to the importance of vitamin B5 and therefore the relevance of (R)-pantolactone as a starting material to produce vitamin B5 and for the use of (S)-pantolactone, there is always a need for an improved process of production of enantiomerically enriched pantolactone.

Nowadays there are several processes known to produce (R)-pantolactone as well as for (S)-pantolactone. There are chemical as well as biochemical methods to pro- duce (R)-pantolactone as well as (S)-pantolactone. Also, combinations of chemical and biochemical methods are known.

A summary of the most important synthesis of (R)-pantolactone are to be found for example in Ullmans Industrial Chemistry (Vitamins 8 Pantothenic Acid 2012, p.299- 308). A common way is to synthesize racemic pantolactone and resolve the enantio- mers, however this results in a maximum yield of 50%.

The present invention relates to a two-step stereoselective synthesis of enantiomeri- cally enriched pantolactone, which allows the production of (R)-pantolactone and/or (S)-pantolactone in good yields and good optical purity.

Preferably, the present invention relates to a two-step and one-pot synthesis of (R)- pantolactone in good yields and good optical purity and avoids the need for a resolu- tion step.

The newly found process of production of (R)-pantolactone has the following reaction schemes

The newly found process of production of (S)-pantolactone has the following reaction schemes

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

Preferably the organo-catalyst is a compound of formula (VII)

wherein

Ri is H, CHs or OH,

R ₂ is H, CHs or OH,

R ₃ is H or CH ₃ ,

R ₄ is H or CH ₃ ,

R ₅ and R ₆ are independently from each other H or a moiety of formula (VIII)

wherein

R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC ₄ alkyl group)

R ₁₁ is H, CH ₃ or forms together with R ₁₀ a tetrazole ring, which can be substi- tuted (by a CrC ₄ alkyl group), and

R12 is H or CH3 when R10 and Rn form a tetrazole ring, or

R12 is an aromatic ring system or a C2-C ₄ alkyl group, which can be substituted, and the ^* marks the bond to the pyrrolidine ring,

R7 is H or CH3,

Rs is H or CH3, and

Rg is H or CH ₃ ,

with the proviso that R5 is never identical to R6. The substituent Rs or R6 contains a moiety, that can form a hydrogen bond.

More preferably the organo-catalyst is a compound of formula (VI G)

wherein

R1 is H, CHs or OH,

R ₂ is H, CHs or OH,

Rs and R ₆ are independently from each H or a moiety of formula (VIII)

wherein

R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC ₄ alkyl group)

R ₁₁ is H, CH ₃ or forms together with R ₁₀ a tetrazole ring, which can be substi- tuted (by a CrC ₄ alkyl group), and

R ₁₂ is H or CH ₃ when R ₁₀ and Rn form a tetrazole ring, or

R ₁₂ is an aromatic ring system or a C ₂ -C ₄ alkyl group, which can be substituted, and the ^* marks the bond to the pyrrolidine ring,

with the provisos that

R ₅ is never identical to R ₆ , and

when R ₁ is OH or CH ₃ , then R ₂ is H and

when R ₂ is OH or CH ₃ , then R ₁ is H.

An especially preferred org a no-catalyst is a compound of formula (VN”a)

wherein

R1 is H, CHs or OH,

R ₂ is H, CHs or OH,

R ₁₀ is O or NR ₁₃ , wherein R ₁₃ forms together with Rn a tetrazole ring, which can be substituted (by CH ₃ )

R ₁₁ is H, CH ₃ or forms together with R ₁₀ a tetrazole ring, which can be substituted (by CH ₃ ),

R ₁₂ is H or CH ₃ when R- and Rn form a tetrazole ring, or

R ₁₂ is an aromatic ring system or a C ₂ -C ₄ alkyl group, which can be substituted with the provisos that

when Ri is OH or CH ₃ , then R ₂ is H and

when R2 is OH or CH3, then R1 is H.

Another especially preferred organo-catalyst is a compound of formula (VN”b)

wherein

R ₁ is H, CHs or OH,

R ₂ is H, CHs or OH,

R ₁₀ is O or NR ₁₃ , wherein R ₁₃ forms together with Rn a tetrazole ring, which can be substituted (by CH3)

R ₁₁ is H, CH ₃ or forms together with R ₁₀ a tetrazole ring, which can be substituted (by CH ₃ ),

R _I2 is H or CH ₃ when R- and Rn form a tetrazole ring, or

R _I2 is an aromatic ring system or a C ₂ -C ₄ alkyl group, which can be substituted with the provisos that

when R1 is OH or CH3, then R ₂ is H and

when R ₂ is OH or CH ₃ , then R ₁ is H.

Especially preferred organo-catalyst of formula (VII) are the following ones of formula (Vila) - (VI Ig) and (ent-Vlla) - (ent-Vllg): and

The organo-catalyst as described above 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 organo-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) or 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) or 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. One method to prepare a range of organocatalysts is described be- low.

General procedure for preparation of various organocatalysts

An oven-dried flask was charged with Cbz-D-proline or Cbz-L-proline (1.00 eq.) or a proline derivative and dry dichloromethane (0.20 mol/L). The solution was cooled to 0 °C and triethylamine (1 .00 eq.) and isobutyl chloroformate (1.00 eq.) were added. The mixture was stirred for 0.5 h, and the relevant amine (1 .00 eq.) was added. The mixture was warmed to room temperature and stirred until complete conversion (mon- itored by TLC). The mixture was washed with aq. sat. NH ₄ CI, aq. sat. NaHC0 ₃ and brine. Each aqueous layer was re-extracted with dichloromethane. The combined or- ganic layers were dried over Na2S0 ₄ , filtered and concentrated in vacuo. The crude intermediate could be purified or used in the following step without further purification. The intermediate (1.00 eq.) was dissolved in MeOH (0.40 mol/L), the flask was flushed with argon three times and Pd/C (10.0 wt.%, 5.00 mol%) was added in one portion. The mixture was evacuated and flushed with hydrogen five times. The black suspension was stirred at room temperature under a hydrogen atmosphere until com- plete conversion (monitored by TLC). The reaction mixture was filtered over a plug of celite and rinsed with methanol.

Example 1 - (R)-N-(2-hvdroxyethyl)pyrrolidine-2-carboxamide (ent-Vllb)

According to the procedure above: Cbz-D-proline (2.49 g, 10.0 mmol, 1.00 eq.), tri ethylamine (1.41 mL, 10.0 mmol, 1 .00 eq.), isobutyl chloroformate (1.30 mL, 10.0 mmol, 1.00 eq.) and ethanolamine (1.21 mL, 10.0 mmol, 1.00 eq.) were reacted to form the intermediate (2.08 g).

The intermediate (2.03 g, 6.94 mmol, 1 .00 eq.) and Pd/C (10.0 wt.%, 368 mg, 347 pmol, 5.00 mol%) yielded organocatalyst (ent-Vllb) as a colorless liquid (1.10 g, quant.). Example 2: General procedure for step (i) testing various orqanocatalvsts producing

(R)-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 mI_, 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 and enantiose- lectivity was determined by chiral HPLC.

The results of the experiment are shown in the table below. Where a negative enan- tioselectivity is reported, this means that the major isomer produced is (S)-isomer. It is clearly understood that if opposite enantiomer of the organocatalyst is used, the identical yield and enantioselectivity for (R)-ethyl-2-hydroxy-3,3-dimethyl-4-oxobuta- noate (VI) will be obtained

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

H ₂ N NH ₂

A B

Example 3

To a solution of (R)-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (ent-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 ace- tate, 4:1 ) yielding ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) (1.47 g, 84%, 72% ee) as a colorless 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 (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) from example 2. 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 con- centrated in vacuo. Example 4

Ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) (74% ee) 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 (R)-pantolactone (I) (72% ee)

Example 5 - One pot, sequential synthesis of (R) oantolactone (I)

To a solution of (R)-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (ent-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 ((R)- pantolactone, 2.41 g, 62%, 70% ee) as a white solid. The analytical data was in agree- ment with an authentic sample.