US2967869A - Process for obtaining d(-)-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone - Google Patents

Description

United States Patent PROCESS FOR OBTAINING D()-a-HYDROXY-B,B- DIMETHYL-y-BUTYROLACTONE Charles 0. Beckmann, Bayville, and Howard C. Klein, Brooklyn, N.Y., and Richard Griflith, Middletown, N.J., assignors to Nopco Chemical Company, Harrison, N.J., a corporation of New Jersey No Drawing. Filed June 19, 1958, Ser. No. 742,996

23 Claims. (Cl. 260-343.6)

The present invention relates to a process for directly obtaining D -a-hydroxy- 8,fl-dimethyl-'y-butyrolactone from a racemic mixture of a,'y-dihydroxy-fl,p-dimethyl butyramide or from a racemic mixture of a-hydroxy-;8,fi dimethyl-y-butyrolactone.

The material a,' -dihydroxy-fi,fl-dimethylbutyramide, also referred to as pantamide, is of great utility in the preparation of pantothenic acid as well as derivatives thereof, e.g., calcium pantothenate. One of the procedures which utilizes pantamide has involved the preparation of a-hydroxy-,B,p-dimethylw-butyrolactone also known as pantolactone and thereafter converting it to pantamide by treatment with ammonia. Subsequently, the pantamide is reconverted to the lactone. Such procedure is carried out in order to purify the lactone. Since the pantothenic acid or a derivative thereof which would be obtained from the L(+)-pantolactone has no physiological activity, it is necessary during the process for the preparation of pantothenic acid to resolve the lactone in order to obtain the desired D()-optical isomer. The resolution of racemic pantolactone is required whether or not the process makes use of the intermediate pantamide. This heretofore has been accomplished by treating racemic pantolactone with l-brucine. The D()-isomer of the lactone is recovered as the brucine complex which by subsequent treatment with a base followed by relactonization with an acid frees the D -isomer.

In copending application Serial No. 742,979, Klein, Kapp and Griflith, filed concurrently herewith, a greatly improved procedure is disclosed and claimed for the preparation of D(--)-pantolactone from racemic pantamide. In brief, racemic pantamide in an inert solvent, preferably methanol, is treated with l-brucine at elevated temperatures. There is formed as reaction products a complex of D()-pantolactone and l-brucine and a complex of L(+)-pantolactone and l-brucine. Because of the difference in solubilities of these two complexes, the former may be precipitated from solution while the latter remains in solution. In this manner, the complex of the D()-pantolactone and l-brucine is recovered from which free D()-pantolactone may be obtained by treatment with a base followed by relactonization with an acid. The D(-)-pantolactone is thereby obtained in excellent yields and high purity. However, it must be realized that only a maximum yield of one-half mol of D()-pantolactone can be obtained from one mol of the starting material, racemic pantamide. This is because only the D(-) enantiomorph present in racemic pantamide is utilized to prepare D(-)-pantolactone since pantothenic acid or any derivative thereof obtained from L(+)-pantolactone lacks physiological activity.

Accordingly, it is an object of the present invention to obtain D()-u-hydroxy-fl,fl-dimethyl-y-butyrolactone in an improved and more direct manner than has been heretofore accomplished. It is a further object to obtain D( )-pantolactone in higher purity and larger yields when compared with prior art procedures. It is a more however, that the detailed description and the specific v examples do not limit the invention, but merely indicate the preferred embodiments thereof since various changes and modifications within the scope of the invention will become apparent to those skilled in the art.

The above and other objects have been unexpectedly accomplished in the following manner. Racemic pantamIde or racemic pantolactone in an inert solvent, preferably methanol, is treated with l-brucine and a racemization agent at elevated temperatures. There is formed as a reaction product, when either of said starting materials is utilized, a preponderance of a complex of D(--)-. pantolactone and l-brucine. The D(-)-pantolactone may then be recovered by treatment with a base followed by relactonization with an acid. Thus by following the procedure herein, excellent yields of highly pure D()- pantolactone may be obtained in yields approaching of theory, said yields being based upon all of the starting material i.e., racemic pantamide or racemic pantolactone.

According to theteachings of copending Serial No. 742,979 it is known to obtain D()-pantolactone directly from racemic pantamide. It is further known to resolve racemic pantolactone with l-brucine. Racemization of physiologically inactive pantolactone with variouslracemization agents or catalysts has also been taught by the art. However, it was unexpected to discover that L(+)-pantolactone contained in the L(+)-pantolactonel-brucine complex could be preferentially racemized to yield D(-)-pantolactone l-brucine complex leaving the l-brucine moiety unaffected. Moreover, D(-)-lactone l-brucine complex already present plus that amount formed as a result of the above racemization surprisingly remains unaffected by the racemizing agent and this complex does not limit the extent of racemization of the L(+)-pantolactone l-brucine complex. Hence, racemization of L(+)-pantolactone l-brucine complex con-' tinues until virtually all of the starting material i.e., racemic pantamide or racemic pantolactone has been con verted into the desired diasterioisomeric D(--)-pantolactone l-brucine complex.

The advantages of such a procedure, wherein we are able in a single step to obtain directly from racemic pantamide or from racemic pantolactone extremely high yields of the D(-)-pantolactone l-brucine complex by treatment of said starting material with both a resolving agent and a racemization agent simultaneously are many fold and substantial. The productivity of each production unit is greatly increased, an objective toward whichall industries strive. Moreover, further economies are gained by the incorporation into a single operation the previously essential and separate steps of resolution and racemization. Heretofore a common feature of industrial resolution procedures involved first the resolution of racemic pantolactone with l-brucine. Thereafter, the physiologically inactive enantiomorph, L(+)-pantolactone, was recovered from its brucine complex by means of alkali extraction which removed the pantolactone as the sodium salt in the presence of an organic solvent which dissolved the brucine. Then, the pantoate was relactonized with acid, followed by the steps of neutralization, extraction, drying, etc. Finally, the L(+)-pantolactone was subjected to various more or less involved racemization procedures, many of which called for distillation techniques or extraction techniques for recovery of the racemized pantolactone. Thus, the present invention eliminates previously necessary materials and prc- Patented Jan. 10,

viously necessary steps. The present invention will also bring about more satisfactory working conditions through reduction in the handling of materials which are always a potential health and safety hazard, in particular, the alkaloid brucine.

The quantity of l-brucine utilized in the reaction may be from about 1.0 to 1.1 mols of l-brucine per mol of racemic pantamide or racemic pantolactone. Generally it is preferred to employ about a 5% to excess e.g., 1.1 mols of l-brucine. It is true that this quantity of 1- brucine is considerably in excess of the quantity utilized in copending Serial No. 742,979. However, because a much larger yield of D()-pantolactone l-brucine complex is obtained, the cost of the larger quantities of 1- brucine called for herein becomes relatively insignificant. Although reaction is preferably brought about at the reflux temperature of the reaction mixture other temperatures of from about 40 C. up to the reflux temperature may be used. Of course, the lower the temperature, the longer the reaction time will be. Generally, the reaction time will be from about 3 hours to 48 hours. At reflux temperature, a preferred reaction time of from about 16 to 22 hours is used when racemic pantamide is the starting material. When racemic pantolactone is the starting material, at reflux temperature, the reaction time is preferably from about 3 to 8 hours. In other words, a longer time for the process is needed when racemic pantamide is the starting material.

The selection of a solvent may be made from any number of liquid organic materials which are inert with respect to the reactants i.e., the racemic starting materials and the l-brucine and the racemization agents. The racemic pantamide or racemic pantolactone and l-brucine may be dissolved or suspended in the solvent. Suitable solvents are methanol, isopropanol, ethanol, etc. It is preferred that the solvent and in fact the entire reaction mixture be free from water. The quantity of solvent employed is usually from about 2.5 to 5 parts thereof per part by weight of l-brucine used.

Concerning the racemization agent we prefer to use from about 3% to 26% by weight based upon the weight of racemic pantamide or racemic pantolactone. However, best yields are obtained when the racemization agent is present in an amount of from about 10% to 20% by weight of said racemic pantamide or racemic pantolactone. Suitable racemization agents have been found to be alkali metal and alkaline earth metal alcoholates in which the alcohol portion has been derived from a lower aliphatic alcohol containing from 1 to about 4 carbon atoms. Such alcoholates are e.g., sodium methoxide, sodium ethoxide, sodium isopropoxide, magnesium methoxide, and magnesium isopropoxide. Also useful as racemization agents are the following: aluminum isopropoxide; alkali metal silicates, e.g., sodium silicate, sodium orthosilicate, sodium metasilicate, potassium silicate, potassium tetrasilicate and alkali metal carbonates such as sodium carbonate and potassium carbonate.

It it is desired to racemize the complex of L(+)-pantolactone l-brucine alone, any of the preceding racemizing agents may be used. They may be present in an amount of from 3% to 26% by weight based upon the weight of the lactone moiety of the complex. Temperatures of from about 40 C. up to the reflux temperature may be used and the reaction time may be from 3 to 48 hours. In other words, reaction conditions will correspond to those used when both resolution and racemization are carried out upon racemic pantolactone or racemic pentamide.

For a fuller understanding of the nature and objects of the invention, reference may be made to the following examples which are given merely to illustrate the invention and are not to be constructed in a limiting sense. The percent yields where reported are based upon the total quantity of starting material i.e., racemic pantamide or racemic pantolactone.

4 Example] This example is included to demonstrate the unexpected racemization of L(+)-pantolactone l-brucine complex to D('+)-pantolactone l-brucine complex.

26 grams of L(+)-pantolactone (0.2 mol) were dissolved in 185 ml. of methanol and thereafter admixed with 78.8 grams of l-brucine. This mixture was refluxed for 3 hours and allowed to stand overnight. In this manner, the brucine complex was formed. The solution was then treated with 5.4 grams of sodium methoxide (0.1 mol) and refluxed. A precipitate of D(-)-pantolactone l-brucine complex began to form in about 10 minutes. Refiuxing was continued for 3 hours during which time the complex continued to precipitate out thereby forming a slurry. Thereafter, the slurry was cooled to room temperature, centrifuged and dried. In this manner, 71.5 grams of D()-pantolactone l-brucine complex (68% of theory) were obtained having a melting point at 202 to 205 C. A second crop of complex weighing 14.26 grams and melting at 177 to 179 C. was obtained from the mother liquor.

Example II 26 grams of racemic pantolactone (0.2 mol) and 1.1 grams of sodium methoxide (0.02 mol) contained in 30 ml. of methanol, were added to 78.8 grams of l-brucine (0.2 mol) contained in 156 ml. of methanol. The resulting mixture was refluxed for 2 /2 hours and allowed to stand at room temperature overnight. After centrifuging, washing with methanol and drying, 65.4 grams of D()- pantolactone l-brucine (62% of theory based upon all of the racemic pantolactone) melting at 203 to 206 C. were obtained. Upon chilling the mother liquor, 13.46 grams of additional complex melting at to 177 C. were obtained.

D(-)-pantolactone was obtained from the complex in the following manner. The 65.4 grams of complex obtained above were treated with 65 ml. of chloroform and 5.35 grams of sodium hydroxide contained in 35 ml. of water for one hour at room temperature. The aqueous layer was extracted 6 times with 20 ml. portions of chloroform in order to remove the brucine. The sodium pantoate contained in the aqueous layer was relactonized by treatment with 11 ml. of concentrated hydrochloric acid. Extraction of the crude D(-)-panto1actone yielded 15.29 grams. This material was then recrystallized from 7 ml. of methyl isobutyl ketone and 7 ml. hexane thereby yielding 9.77 grams of D()-pantolactone (37% of theory). The ((1) was 44.8.

Example 111 To 65 grams of racemic pantolactone (0.5 mol) contained in 60 ml. of methanol, 2.75 grams of sodium methoxide were added. The resulting solution was then added to 197 grams of l-brucine (0.5 mol) contained in 390 ml. of methanol. After 16 hours of refluxing, the reac tion mixture was cooled down and 161.4 grams of D()- pantolactone 1-brucine complex (61.5% of theory) were recovered. The complex melted at 202 to 207 C. Chilling the mother liquor to -12 C. yielded an additional 47.4 grams of complex melting at 169 to 173 C.

Example IV 66.5 grams of 97.6% pure racemic pantolactone (0.5 mol) contained in 40 ml. of dry methanol were added during the course of /2 hour to a refluxing solution of 200 grams of l-brucine (0.5 mol) and 12 grams of sodium methoxide (0.22 mol) in 400 ml. of methanol. Refiuxing was carried out for 3 hours with stirring. Thereafter, the slurry was cooled to room temperature, centrifuged and dried. In this manner, grams of D()- pantolactone 1'-brucine complex (70% of theory based on all of the racemic lactone) were obtained having a melting point of 201 to 204 C. A second crop from Example V This example is directed to a variation of our process in which racemic pantolactone is first resolved by treatment with l-brucine. The remaining L(+)-pantolactone l-brucine complex is subsequently racemized in a manner similar to Example I. This variant may also be applied when the starting material is racemic pantamide.

133 grams of 97.6% pure racemic pantolactone (1.0 mol) contained in 40 ml. of dry methanol, which was prepared by distilling over sodium methoxide, were added during 20 minutes to a refluxing solution of 200 grams (0.5 mol) of l-brucine contained in 400 ml. of dry methanol. After minutes of refluxing the resulting slurry was cooled and centrifuged. In this manner 252 grams of crude D(-)-pantolactone l-brucine complex (48% of theory based on all of the racemic pantolactone) were obtained. The complex melted at 201 to 204 C. This material was redigested with 375 ml. of methanol for /2 hour at reflux temperature, cooled and filtered to yield 232 grams of purified complex (44% of theory based on all of the racemic lactone) melting at 203 to 206 C. The original mother liquor was combined with the mother liquor from the redigested crude complex and treated anew with 100 grams of l-brucine (0.25 mol) contained in 200 ml. of dry methanol. 250 ml. of the methanol were distilled ofl? and the residue treated with 8 grams of sodium methoxide contained in 50 ml. of methanol at reflux temperature for 3 hours. In this manner a second portion of complex weighing 120 grams (22.9% of theory) was filtered ofi. It melted at 196 to 201 C. Redigestion of this material with methanol yielded 99 grams (19% of theory) melting at 200 to 203 C. To the combined mother liquors were added 100 grams of l-brucine dissolved in 200 ml. of methanol. This solution was concentrated to 300 ml. and refortified with 5 grams of sodium methoxide contained in 50 ml. of methanol. After 6 hours of reflux, the resulting slurry was cooled and filtered from which was obtained a third crop of D()-pantolactone l-brucine complex weighing 47 grams and melting at 186 to 196 C. Redigestion of this complex with methanol resulted in 22.7 grams of partially purified complex melting at 199 to 205 C. which amounted to 4.3% of theory. Hence, the total quantity of D()pantolactone l-brucine complex isolated was 353.7 grams which was 67% of theory based upon all of the racemic lactone.

This complex was split by treatment with 360 ml. of chloroform and 31.6 grams of sodium hydroxide contained in 220 ml. of water for one hour at room temperature. The aqueous layer containing sodium pantoate was extracted with chloroform to remove all of the 1- brucine, relactonized with hydrochloric acid and finally extracted with isopropyl acetate. 79.6 grams of crude D(--)-pantolactone were thus obtained. The crude D( )-pantolactone was recrystallized from a solution of 40 ml. methyl isobutyl ketone and 40 ml. hexane to yield 53.0 grams of D()-pantolactone (40.7% of theory) having a (a) =-48.6.

Example VI 400 ml. of methanol, 197 grams of l-brucine (0.5 mol) and 17.7 grams (0.1 mol) of aluminum isopropoxide were refluxed for 3 hours. Thereafter 67.5 grams of 97.5% pure (0.5 mol) racemic pantolactone contained in 20 ml. of methanol were added. Refluxing was then continued for 3 hours. After cooling and filtration, 196.7 grams of D(-)-pantolactone l-brucine complex melting at 198 to 203 C. were recovered. Redigestion of the complex with 200 ml. of methanol yielded 195.6 grams of purified complex which amounted to 61% of theory based upon all of the racemic lactone starting material.

Example VII 2.4 grams of magnesium turnings (0.1 mol) were con verted to magnesium methoxide by refluxing overnight with 390 ml. of methanol. To the resulting magnesium methoxide in methanol, 197 grams of l-brucine (0.5

mol) were added and refluxing carried out. After three hours of refluxing, 66.5 grams of 97.6% pure racemic.

pantolactone contained in 40 ml. of methanol were added. After an additional 3 hours of refluxing, the resulting slurry was cooled and filtered thereby yielding 200.9 grams of crude D(-)pantolactone l-brucine complex melting at 197 to 205 C. The complex was purified by redigestion with 200 ml. of methanol. Upon recrystallization from the methanol, 154.9 grams of purified complex (59% of theory) were recovered having a melting point of 201 to 204 C.

Example VIII 8.0 parts by weight of l-brucine were refluxed with crude D(-)-pantolactone l-brucine complex were recovered. The complex melted at 201 to 204 C. Upon redigestion with 11 parts by volume of dry methanol, 7.3 parts by weight of complex were obtained melting at 201 to 204 C. Although this new melting point would indicate very little purification, considerable color was removed. The purified complex was split by treatment with 7.2 parts by volume of chloroform and a solution of 0.63 part by weight of sodium hydroxide dissolved in 4.4 parts by volume of water. The aqueous layer was extracted with 5 portions of 2.4 parts by volume chloroform and subsequently relactonized with 1.5 parts by volume of 37% by weight aqueous solution of hydrochloric acid. This aqueous layer was neutralized to a pH of 5 with ammonium hydroxide and extracted twice with 2.2 parts by volume portions of isopropyl acetate and then with 5 portions of 1.6 parts by volume isopropyl acetate. The extracts were combined and evaporated.

parts by volume of methyl isobutyl ketone and 875 parts by volume of hexane yielded 1.39 parts by weight of D(-)-pantolactone (53.5% of theory) having a Example IX 26 grams of L(+)-pantolactone dissolved in 30 ml.

of methanol were added to a solution of grams of 1- brucine dissolved in 250 ml. of methanol. After 15 minutes of reflux, 4 grams of sodium silicate which were pro-dried at 106 C. were added to the solution. Refluxing was continued for 23 hours. A precipitate began to form about 4 hours after the silicate addition. After refluxing, the slurry Was cooled to 40 C., centrifuged and dried. In this manner, 45.5 grams of D()-pantolactone l-brucine complex melting at 199 to 202 C. were recovered. This weight has been corrected for the Weight of the sodium silicate which was collected with the product since it is insoluble in methanol.

Example X a 26 grams of L(+)-pantolactone dissolved in 30 ml. of methanol were added to 80 grams of l-brucine dissolved in 220 ml. of methanol. The resulting solution was refluxed for 15 minutes. Thereafter 4 grams of potassium= carbonate were added and refluxing continued. The almost clear solution began to precipitate white crystalline 1.8 parts by; weight of crude D()-pantolactone were recovered. Recrystallization of this material from a solution of 875 v of D()-pantolactone l-brucine complex melting at 201 to 205 C. were recovered.

Example XI 29.4 grams of racemic pantamide, 80 grams of 1- brucine and 150 ml. of methanol were refluxed together for minutes. Thereafter 5.4 grams of sodium methoxide dissolved in 50 ml. of methanol were added to the refluxing materials and refluxing was continued for 23 hours. Precipitation began in about /2 hour after the addition of sodium methoxide. The slurry, after refluxing was discontinued, was cooled down to 40 C., centrifuged, washed with methanol and dried. In this manner 71.5 grams of D()-pantolactone l-brucine complex were recovered which amounted to 68% of theory based upon all of the starting material, namely, racemic pantamide.

Having thus described our invention, what we claim as new and desire to secure by Letters Patent is:

1. A process for obtaining D()-ahydroxy-fl,B-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other l-brucine and a racemic material selected from the group consisting of racemic 01,7 dihydroxy 13,5 dimethylbutyramide and racemic a-hydroxy-flp-dimethyl-y-butyrolactone in the presence of from about 3% to about 26% by weight of said racemic material of a racemization agent in methanol, recovering from the resulting reaction product a complex of l-brucine D(-)-a-hydroxy-fi,;3-dimethyl- 'y-butyrolactone and freeing from said complex said D()-a-hydroxy-Bfi-dimethyl- -butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

2. A process for obtaining D(--)-a-hydroxy-p,p-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other from about 1 to 1.1 mols of l-brucine and one mol of a racemic material selected from the group consisting of racemic a,'y-dihydroxy-dfl-dimethyl butyramide and racemic a-hydroxy- 13,;9-dimethyl-' -butyrolactone in the presence of from about 3% to about 26% by weight of said racemic material of a racemization agent in methanol, recovering from the resulting reaction product a complex of l-brucine D(-)-a-hydroxy- 3,fi-dirnethyl'y-butyrolactone and freeing from said complex said D(-)-u-hydroxy-B,fi-dimethyl- 'y-butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

3. A process for obtaining D()-a-hydroxy-B fl-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other at a temperature of from about 40 C. up to the reflux temperature of the reaction mixture, a mixture of from about 1 to 1.1 mols of l-brucine and one mol of a racemic material selected from the group consisting of u,' -dihydroxy-fl,pdimethyl butyramide and racemic a-hydroXy-fi,B-dirnethyl- 'y-butyrolactone in the presence of from about 3% to about 26% by weight of said racemic material of a racemization agent in methanol, recovering from the resulting reaction product a complex of l-brucine D(--)- a-hydroxy-pfi-dimethyl- -butyrolactone and freeing from said complex said D(--)-u-hydroxy-B,B-dimethyl-y-butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

4. A process for obtaining D()-a-hydroxy-fi,;3-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other at a temperature of from about 40 C. up to the reflux temperature of the reaction mixture, for about 3 to 48 hours a mixture of from about 1 to 1.1 mols of l-brucine and one mol of a racemic material selected from the group of racemic a-v-dihydroxy-flfi-dimethyl butyramide and racemic ahydroxy-[3,fi-dimethyl-'y-butyrolactone in the presence of from about 3% to about 26% by weight of said racemic material of a racemization agent in methanol, recovering from the resulting reaction product a complex of l-brucine D(-- -a-hydroxy-;3,f3-dimethyl-'y-butyrolactone and freeing from said complex said D(--)-a-hydroxy-p,fl-dimethyl-'y-butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

5. The process of claim 4 in which said racemic material is racemic a,'y-dihydroxy-fl,fl-dimethyl butyramide and the reaction is carried out for about 16 to 22 hours at the reflux temperature of the reaction mixture.

6. The process of claim 4 in which said racemic material is racemic a-hydroxy-fi,fl-dimethyl-'y-butyrolactone and the reaction is carried out for about 3 to 8 hours at the reflux temperature of the reaction mixture.

7. The process of claim 4 in which said racemization agent is present in an amount of from about 10% to 20% by weight of said racemic material.

8. The process of claim 4 in which said racemization agent is sodium methoxide.

9. The process of claim 4 in which said racemization agent is aluminum isopropoxide.

10. The process of claim 4 in which said racemization agent is magnesium isopropoxide.

11. A process for obtaining D(-)-a-hydroxy-fi,fl-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other from about 1 to 1.1 mols of l-brucine and a racemic material selected from the group consisting of racemic a, -dihydroxy-,B,fldimethyl butyramide and racemic a-hydroxy-B,Bdimethyl- 'y-butyrolactone in the presence of a racemization agent present in an amount of from about 3% to 26% by weight of said racemic material in the presence of methanol, recovering from the reaction mixture a complex of l-brucine D )-ot-hydroxy-5,54imethyl-y-butyrolactonc, reacting said complex with sodium hydroxide thereby forming D(+)-sodium pantoate and treating said D(+)- sodium pantoate with an acid thereby obtaining said D( -)-u-hydrow-3,5dimethyl-'y-butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

12. The process of claim 11 which said reaction is carried out at a temperature of about 40 C. upto the reflux temperature of the reaction mixture.

13. A process for obtaining D()-a-hydroxy-p,p-dimethyl-'y-butyrolactone which comprises the steps of bringing from about 1 to 1.1 mols of l-brucine and a racemic material selected from the group consisting of racemic a,v-dihydroxy-B,;3-dimethyl butyramide and racemic a-hydroxy-B,p-dimethyl-y-butyrolactone into contact with each other in methanol at a temperature of from about 40 C. up to the reflux temperature of the reaction mixture for a period of time from about 3 to 48 hours in the presence of from about 3% to 26% by weight of said racemic material of a racemization agent, recovering from the reaction mixture a complex of l brucine D( )-a-hydroxy-fi,fl-dimethyl-y-butyrolactone, reacting said complex with sodium hydroxide thereby forming D(+) sodium pantoate and treating said D(+) sodium pantoate with an acid thereby obtaining said,

D( )-a-hydroxy-p,B-dimethyl-ybutyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

14. The process of claim 13 in which said racemic material is racemic a,'y-dihydroxy-fi,fl-dimethy1 butyramide and the reaction is carried out for about 16 to 22 hours at the reflux temperature of the reaction mixture.

15. The process of claim 13 in which said racemic material is racemic a-hydroxy-mfl-dimethyl-y-butyrolactone and the reaction is carried out for about 3 to 8 hours at the reflux temperature of the reaction mixture.

16. The process of claim 13 in which racemization agent is present in an amount of from about to 20% by weight of said racemic material.

17. The process of claim 16 in which said racemization agent is sodium methoxide.

18. The process of claim 16 in which said racemization agent is aluminum isopropoxide.

19. The process of claim 16 in which said racemization agent is magnesium isopropoxide.

20. A process for obtaining a complex of D()-ahydroxy-p,p-dimethyl-'y-butyrolactone and l-brucine which comprises bringing at temperatures of from 40 C. up to the reflux temperature of the reaction mixture, a complex of L(+)-a-hydroxy-p,fi-dimethyl-y-butyrolactone and l-brucine into contact with from about 3% to 26% by weight, based on the weight of said complex, of a racemization agent selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

21. The process of claim 20 in which said racemization agent is sodium methylate.

22. A process for obtaining D()-a-hydroxy-fl,fl-dimethyl-'y-butyrolactone which comprises the steps of bringing into contact with each other l-brucine and a racemic material selected from the group consisting of racemic om -dihydroxy-;3,/3-dimethyl butyramide and racemic u-hydroxy-p,p-dimethyl-y-butyrolactone in methanol thereby forming a complex of l-brucine D(-)-ahydroxy-pyp-dimethyl-'y-butyrolactone and a complex of l-brucine L -a-hydroxy-fl,fl dimethyl-'y-butyrolactone, separating the complex of l-brucine D()-a-hydroxy- 3,;3-dimethyl-y-butyrolactone, bringing into contact the remaining complex of l-brucine L(+)-a-hydroxy-fl,pdimethyl- -butyrolactone with from about 3% to about 26% by weight of said complex of a racemization agent thereby forming l-brucine D()-a-hydroxy-fi,fi-dimethyl- 'y-butyrolactone from said l-brucine L(+)-a-hydroxy- 5,B-dimethyl- -butyrolactone and thereafter freeing from said l-brucine D()-a-hydroxy-p,fi-dimethyl-y-butyrolactone and D()-a-hydroxy-p,,6-dimethyl-'y-butyrolactone, said racemization agent being selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates.

23. A process for obtaining a complex of D(-)-a-hydroxy-tw-dimethyl-y-butyrolactone and l-brucine which comprises bringing a complex of L(+)-a-hydroxy-p,pdimethyl- -butyrolactone and l-brucine into contact with a racemization agent selected from the group consisting of alkali metal and alkaline earth metal alcoholates in which the alcohol portion contains from one to about four carbon atoms, aluminum isopropoxide, alkali metal silicates and alkali metal carbonates, said racemization agent being present in an amount of about 3% to about 26% by weight of said complex.

References Cited in the file of this patent UNITED STATES PATENTS 2,377,390 Weijlard et a1. June 5, 1945 FOREIGN PATENTS 605,444 Great Britain July 23, 1948 626,498 Great Britain July 15, 1949 V v c UNITED STATES PATENT OFFICE CERTIFICATE CORRECTION Patent No. 2,967 869' January 10 1961 Charles O.- Beckmann et a1.

certified that error appears in the above numbered patie is hereby nd that the said Letters Patent should read as ent requiring correction a corrected below Celumn 3 line' 58 for "It" read If column 10 line 6 for "and" read said Signed and sealed this 12th day of September 1961 C SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents Attesting'Officer Y I USCOMM-DC

Claims (1)

1. A PROCESS FOR OBTAINING D(-)-A-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONE WHICH COMPRISES THE STEPS OF BRINGING INTO CONTACT WITH EACH OTHER 1-BRUCINE AND A RACEMIC MATERIAL SELECTED FROM THE GROUP CONSISTING OF RACEMIC A,Y - DIHYDROXY - B,B-DIMETHYLBUTYRAMIDE AND RACEMIC A-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONE IN THE PRESENCE OF FROM ABOUT 3% TO ABOUT 26% BY WEIGHT OF SAID RACEMIC MATERIAL OF A RACEMIZATION AGENT IN METHANOL, RECOVERING FROM THE RESULTING REACTION PRODUCT A COMPLEX OF 1-BRUCINE D(-)-A-HYDROXY-B,B-DIMETHYLY-BUTYROLACTONE AND FREEING FROM SAID COMPLEX SAID D(-)-A-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONE, SAID RACEMIZATION AGENT BEING SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL AND ALKALINE EARTH METAL ALCHOLATES IN WHICH THE ALCOHOL PORTION CONTAINS FROM ONE TO ABOUT FOUR CARBON ATOMS, ALUMINUM ISOPROPOXIDE, ALKALI METAL SILICATES AND ALKALI METAL CARBONATES.