CA1064943A - Optical resolution of 1-t-butylamino-2,3-dihydroxypropane - Google Patents
Optical resolution of 1-t-butylamino-2,3-dihydroxypropaneInfo
- Publication number
- CA1064943A CA1064943A CA241,257A CA241257A CA1064943A CA 1064943 A CA1064943 A CA 1064943A CA 241257 A CA241257 A CA 241257A CA 1064943 A CA1064943 A CA 1064943A
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- CA
- Canada
- Prior art keywords
- dihydroxypropane
- butylamino
- diastereoisomer
- acid
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
Abstract
Abstract of the Disclosure Process for resolving enantiomers of 1-t-butyl-amino-2,3-dihydroxypropane using a pyroglutamic acid or a tartaric acid as resolving agent. The enantiomers of 1-t-butylamino-2,3-dihydroxypropane are useful in preparing .beta.-adrenergic blocking agents.
Description
~6~L943 Background of the Invention The present invention involves a novel process for resolving mixtures of enantiomers of l-t-butylamino-~,3-dihydroxypropane from solution using a pyroglutamic acid or a tartaric acid as the resolving agent.
The sinister (S) enantiomer o~ l-t-butylamino-2,3-dihydroxypropane is especially useful in preparing the more active S-isomer of the 3-substituted-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole class of ~-adrenergic blocking agents. These ~-blocking agents and methods for their preparation are disclosed in U.S. 3,657,237 and U.S.
3,781,284. A method for preparing -the S-enantiomer oE l-t-butylamino-2,3-dihyd.roxypropane, as disclosed in U.S.
3l657,237, is by the reductive alkylation o:E a single enantiomer reactant namely D-glyceraldehyde or isopropylidene-D-glyceraldehyde. Whlle this method can be suitably used, 9~3 1 it requires the use of large quantities of æinc chloride and
The sinister (S) enantiomer o~ l-t-butylamino-2,3-dihydroxypropane is especially useful in preparing the more active S-isomer of the 3-substituted-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole class of ~-adrenergic blocking agents. These ~-blocking agents and methods for their preparation are disclosed in U.S. 3,657,237 and U.S.
3,781,284. A method for preparing -the S-enantiomer oE l-t-butylamino-2,3-dihyd.roxypropane, as disclosed in U.S.
3l657,237, is by the reductive alkylation o:E a single enantiomer reactant namely D-glyceraldehyde or isopropylidene-D-glyceraldehyde. Whlle this method can be suitably used, 9~3 1 it requires the use of large quantities of æinc chloride and
2 lead tetraacetate. This results in waste streams containing
3 large amounts of zinc and lead cations, which are objection-
4 able from an ecological standpoint. Removal of these cations from waste streams is very difficult and expensive.
6 An improved process for o~taining the enantiomers 7 o~ 1-t-butylamino-2,3-dihydroxypropane has been discovered.
8 This process involves resolution of mixtures of enantiomers 9 of 1-t-butylamino-2,3-dihydroxypropane from solution using a pyroglutamic acid or a tartaric acid as resolving agent. The 11 process does not result in any waste stream creating ecolog-12 ical problems.
14 Summary of the Invention 16 Process for resolving mixtures of enantiomers of 17 1-t-butylamino-2,3-dihydroxypropane which comprises treating 18 said mixture in solution with a pyroglutamic acid or a 19 tartaric aaid and recovering the novel diastereoisomer which separates. l'he single enantiomer i9 then recovered 21 ~rom the diastereoisomer by conven~ional technique~.
23 Description of the Preferred Embodiments A preferred embodiment of the present invention 26 is a process for resolving mixtures of enantiomers of 27 1-t-butylamino-2,3-dihydroxypropane which comprises treating 28 a solution of said mixture in a suitable solvent with an 29 agent selected from S-pyroglutamic acid, R-pyroglutamic acid, L-~+~-tartaric acid and D (-)-tartaric acid, separating, from . .
l 6~
l the solution, solid diastereoisomer which forms and recovering 2 from said diastereoisomer a single enantiomer of l-t-butyl-3 amino-2,3-dihydroxypropane.
4 The symbols S and R designa~e the sinister (S) and rectus (R) isomer configurations of enantiomers. These 6 designations refer to absolute spatial configurations in the 7 molecule. The symbols L and D, (-) and (~), l and d may also 8 be used to identify the different optical isomers. Combina-9 tions of the various symbols and designations may also be used to identiy optically active isomers.
ll The resolving agents which are used in the present 12 process are S-pyroglutamic acid, R-pyroglutamic acid, D ~-)-13 tartaric acid and L (+)-tartarlc acid. The resolution is 14 carried out in solution.
Useful organic solvents include di-Cl~C3-alkyl-16 ketones such as methylethylketone, diisobutylketone, methyl 17 isobutylketone and the like, C3-C5 alkanols such as amyl-18 alcohol, isobutanol and the like and Cl-C4 alkyl esters of 19 C2-C4 mono-alkanoic acids such as ethyl propionate, methyl-butyrate, tert-butyl acetate and the like. Small amounts of 21 water may ~,e admixed with these organic solvents.
22 When S-pyroglutamic acld is used as the resolving 23 agent, the preferred solvents are acetone, isopropanol or 24 mixtures of acetone or isopropanol with water. The solid ~5 dia~tereoi~omer which separates from this resolving agent/
26 solvent system contains the S-isomer form of the l-t-butyl-27 amino-2,3-dihydroxypropane as S-pyroglutamic acid S-l-t-28 butylamino-2,3-dihydroxypropane. When R-pyroglutamic acid 29 is the resol~ing agent, the diastereoisomer obtained is R-pyroglutamic acid R-l t-butylamino-2,3-dihydroxypropane.
1~6~9~3 1 When D(-)- or L (+)-tartaric acid is the resolving 2 agent, again the preferred solvents used are acetone, isopro-3 panol or isopropanol/water mixtures. A most preferred solvent 4 for this system is isopropanol containing water, and preferably about 10% by weight of H2O. In carrying out 6 the resolution with the L (+)-tartaric acid, the diastereo-7 isomer isomer which separates contains the R-form of the 8 1-t-butylamino-2,3-dihydroxypropane as L (+)-tartaric acid.
9 R-l-~butylamino-2,3-dihydroxypropane salt - with the D (-)-acid, the diastereoisomer which separates contains the S form 11 of the 1-t-butylamino-2,3-dihydroxypropane as D (-)-tartaric 12 acid S-l-t-butylamino-2,3-dihydroxypropane salt.
-13 The resolution process may be carried out at any 14 suitable temperature~ The resolution is generally accomplished at room temperature, although higher or lower 16 temperatures may be used. If desired, the mixture o 17 enantiomers and the resolving agent can be refluxed to 18 insure complete solution and proper contact of the enantiomers 19 and resolving agent. The refluxed solution is then cooled to room temperature or lower, generally with agitation, whereupon 21 the dias~ereoisomer separates.
2Z The present process i~ carried out at atmospheric 23 pressure. Super atmospheric pressure is not required.
24 The amount of resolving agent used may he varied.
Generally, between about 0.5 to 1 mole of resolving agent is 26 u~ed per mole o enantiomer mixture. Molar ratios of resolving 27 agent: enantiomer o 0.5:1 or lcl are particularly useful.
28 The single enantiomer of l-t-butylamino-2,3-dihydr-29 oxypropane is recovered from the separated diastereoisomer by conventional techniques. For example, the S-pyroglutamic 31 acid-S~t-butylamino-2,3-dihydroxypropane diastereoisomer can 32 be treated with asùitable base whereby the S-l-t-butylamino-_ D~ --1 2,3-dlhydroxypropane is freed ~rom the S-pyroglutamic a~Id.
2 The S-l-t-butylamino-2,3-dihydroxypropane can then be re-3 covered by extraction with a suitable solvent and the solvent 4 stripped to yield the desired S-l-t-butylamino-2,3-dihydroxy-propane. The neutralized S-pyroglutamic acid can be conven-6 tionally recovered from the remaining solution for re-use 7 as a resolving agent.
8 Another procedure for recovering the amine enan-9 tiomer from the separated diastereoisomer is to run a solution of the diastereoisomer through a suitable ion 11 exchange resin column and then elute the free l-t-butylamino-12 2,3-dihydroxypropane enantiomer.
13 The mixture of enantiomers which can be re~olved 14 by the present process contain S and R enantiomexs of l-t-butylamino-2,3-dihydroxypropane. These mixtures include (R,S) 16 racemic mixtures or modifications as well as mixtures rich 17 ln R or S enantiomer.
18 ~ The resolution process is relatively simple. It 19 lnvolves preparing a solution of the mixture of enantiomers of 1-t-butylamino-2,3-dihydroxypropane in one of the solvents 21 described above. ~he aoncentration oE the enantiomer mixture 22 in the solution can be varied. The resolving agent i9 then 23 add~d either directly or a~ a solution in one o~ the a~oresaid 24 solvents. After the solid diastereoisomer drops out of the solution, it is separated from the solution by any convenient 26 means e.g. by filtration, by centrifugration. This solid 27 diastereoisomer is then treated by conventional techniques 28 to recover the single enantiomer of 1-t-butylamino-2,3-29 dihydroxypropane. The remaining solution which is rich in the diastereoisomer containing the other enantiomer form of 31 1-t-butylamino-2,3-dihydroxypropane can also be treated to 32 recover this other enantiomer.
15563 :CA
~CI 6~3 1 As pointed out above, the enantiomers of l-t-butyl-2 amino-2,3-dihydroxypropane are useful in preparing ~-adrener-3 gic blocking agents,such ~s those described in U. S. 3,657,237.
4 The S-enantiomer of l-t butylamino-2,3-dihydroxypropane is especially useful for preparing the more active S-isomer of 6 the U. S. 3,657,237 ~-adrenergic blocking agents.
7 Following are examples which illustrate the 8 resolution process of the present invention.
~ ~ 15553 IA
~3D69~ 43 1 ExAMPLE 1 2 A. Preparation of R,S-l-t-butylamino-2,3-dihydroxypropane 3 A solution of R,S-glycidol (105 g; 1.42 moles) in 4 100 ml of isopropanol was added dropwise over one hour to a solution of t-butylamine ~197 g; 2~ 7 moles) in 200 m~
6 isopropanol while maintaining the tempera~ure between 46 -7 70C. The solution was aged a~ 70C. for one hour and the 8 excess t-butylamine was recovered by atmospheric distillation.
9 The distillation-was continued until the pot temperature reached 110C. Acetone (700 ml) was then added to the residue 11 ;and the~temperature of the final solution was adjusted to 12 40-45C. The yield of R,S-t-butylamino-2,3-dihydroxypropane 13 (R,S-glycolamine) was 88%.
B. Resolution of R,S-l-t-butylamino-2,3-dihydroxypropane 16 To the inal solution from (A) was added 83.0 g 17 (0.645 moles) of S-pyroglutamic acid (97% pure) and the 18 resultant sqlution mixture was refluxed, with stirring, for 19 1.5 hours. This solution was then cooled to room temperature over 2.5: hours, with stirring.
21 The S-pyroglutamic acid S-l-t-butylamino-2,3-22 dihydroxypropane diastereoisomer which separated from the 23 solution wa9 ~iltered o~ and wa~hed with 2x50 ml o~ acetone.
24 The yield of pure diastereoisomer was 130 g (33.5% based on the R,S-glycidol).
27 C. Regeneration of S-l-t-butylamine-2,3-dihydroxypropane 28 The S-l-t-butylamino-2,3-dihydroxypropane was 29 regenerated from the (~) diastereoisomer by dissolving the ~6~943 1 diastereoisomer in 200 ml of water and passing the solution 2 through a column of 350 ml of IR-120 ~H )~ IR-120 (H ) 3 is a gelular, strongly acidic, cation exchange resin marketed 4 by Rohm & Haas Company. The column was washed with water until a negative test for pyroglutamic acid was obtained.
6 S-pyroglutamic acid was recovered, in excess of 95% yield, by 7 concentrating to dryness, slurrying the residue with iso-8 propanol and filtering off the S-pyroglutamic acid.
9 The S-l-t-butylamino-2,3-dihydroxypropane was eluted from the IR-120 resin by washing with 5% ammonium 11 hydroxide solution. The eluate was concentrated to dryness 12 and the residue recrystallized from 150 ml of xylene to give 13 66.0 g of pure S-l-t-butylamino-2,3-dihydroxypropane. (31.7%
14 yield based on the weight o R,S-glycidol) 16 EX~MPLE 2 17 E~,S-t-butylamino-2,3-dihydroxypropane (5.88 g) and 18 S-pyroglutamic acid (2.70 g) were mixed in isopropanol 19 ~(20 ml) and heated on a steam bath until solution was complete.
The solution was cooled to 50C and seeded with the pure S-21 pyroglutamic acid S-l-t-butylamino-2,3-dihydroxypropane salt.
22 The mixture was then allowed to cool 910wly to room 23 temperature with stirring over about a two hour period. The 24 slurry wa~ cooled at 0.5C ~or one hour and ~ ered to give 4.03 g (73~) of the S-pyroglutamic acid S-I-t-butylamino-26 2,3-dihydroxypropane diastereoisomer, having a melting point 27 o~ 140-143C; [a]~ = (-) 21.9 (CH30E~). Recrystallization 28 rom 3.5 volumes o boiling isopropanol yave a 91.5~ yield 29 of the pure diastereoisomer melting at 143-146; [a]D= -23.4 (C=2 in CH30H).
9~3 1 Pure S-l-t-butylamino-2,3-dihydroxypropane was 2 recovered from the pure diastereoisomer by dissolving 3 the diastereoisomer in excess 50~ aqueous NaOH solution 4 and extracting the S-l-t-butylamino-2,3-dihydroxypropane with ether. The ether extract was dried over magnesium 6 sulfate and filtered. The product obtained was pure 7 S-1-_-butylamino-2,3-dihydroxypropa~e characterized by a 8 melting point of 83-85C and [a] D= t-) 30 (lN ~ICl).
9 Alternately, the S-l-t-butylamino-2,3-dihydroxy-propane was recovered by dissolving the diastereoisomer 11 in 10 ml of water and using the ion exchange resin (IR-120) 12 procedure of Example 1 (C).
-A mixture of L (~)-tartaric acid (35.0 g) and 16 R,S-t-butylamino-2,3-dihydroxypropane (34.4 g) were dissolved 17 in 500 ml of hot 90~ isopropanol/10% water. The solution was 18 slowly cooled to room temperature over four hours with 19 stirring. The L (+)-tartaric acid R-l-t-butylamino-2,3-dihydroxypropane diastereoisomer which separated was filtered.
21 The yield was 45.6 g of the diastereoisomer havlng a 22 melting point of 85C and ~a]D= ~9 5 . r~WO additional 23 recr~stallizations rom aqueous isopropanol gav~ substantiall~
24 pure L (~)-tartaric acid-R-1-t-butylamino-2,3-dihydroxypropane diastereoisomer, having a melting point of 94-~6C and [a] D=
26 ~1g.9, (C-2 in lNHCl).
27 The pure R-l-t-bu~ylamino-2,3-dihydroxypropane 28 was recovered from the diastereoisomer by substantially the 29 same procedure as described in Examples 1 and 2.
Claims to the invention follow.
6 An improved process for o~taining the enantiomers 7 o~ 1-t-butylamino-2,3-dihydroxypropane has been discovered.
8 This process involves resolution of mixtures of enantiomers 9 of 1-t-butylamino-2,3-dihydroxypropane from solution using a pyroglutamic acid or a tartaric acid as resolving agent. The 11 process does not result in any waste stream creating ecolog-12 ical problems.
14 Summary of the Invention 16 Process for resolving mixtures of enantiomers of 17 1-t-butylamino-2,3-dihydroxypropane which comprises treating 18 said mixture in solution with a pyroglutamic acid or a 19 tartaric aaid and recovering the novel diastereoisomer which separates. l'he single enantiomer i9 then recovered 21 ~rom the diastereoisomer by conven~ional technique~.
23 Description of the Preferred Embodiments A preferred embodiment of the present invention 26 is a process for resolving mixtures of enantiomers of 27 1-t-butylamino-2,3-dihydroxypropane which comprises treating 28 a solution of said mixture in a suitable solvent with an 29 agent selected from S-pyroglutamic acid, R-pyroglutamic acid, L-~+~-tartaric acid and D (-)-tartaric acid, separating, from . .
l 6~
l the solution, solid diastereoisomer which forms and recovering 2 from said diastereoisomer a single enantiomer of l-t-butyl-3 amino-2,3-dihydroxypropane.
4 The symbols S and R designa~e the sinister (S) and rectus (R) isomer configurations of enantiomers. These 6 designations refer to absolute spatial configurations in the 7 molecule. The symbols L and D, (-) and (~), l and d may also 8 be used to identify the different optical isomers. Combina-9 tions of the various symbols and designations may also be used to identiy optically active isomers.
ll The resolving agents which are used in the present 12 process are S-pyroglutamic acid, R-pyroglutamic acid, D ~-)-13 tartaric acid and L (+)-tartarlc acid. The resolution is 14 carried out in solution.
Useful organic solvents include di-Cl~C3-alkyl-16 ketones such as methylethylketone, diisobutylketone, methyl 17 isobutylketone and the like, C3-C5 alkanols such as amyl-18 alcohol, isobutanol and the like and Cl-C4 alkyl esters of 19 C2-C4 mono-alkanoic acids such as ethyl propionate, methyl-butyrate, tert-butyl acetate and the like. Small amounts of 21 water may ~,e admixed with these organic solvents.
22 When S-pyroglutamic acld is used as the resolving 23 agent, the preferred solvents are acetone, isopropanol or 24 mixtures of acetone or isopropanol with water. The solid ~5 dia~tereoi~omer which separates from this resolving agent/
26 solvent system contains the S-isomer form of the l-t-butyl-27 amino-2,3-dihydroxypropane as S-pyroglutamic acid S-l-t-28 butylamino-2,3-dihydroxypropane. When R-pyroglutamic acid 29 is the resol~ing agent, the diastereoisomer obtained is R-pyroglutamic acid R-l t-butylamino-2,3-dihydroxypropane.
1~6~9~3 1 When D(-)- or L (+)-tartaric acid is the resolving 2 agent, again the preferred solvents used are acetone, isopro-3 panol or isopropanol/water mixtures. A most preferred solvent 4 for this system is isopropanol containing water, and preferably about 10% by weight of H2O. In carrying out 6 the resolution with the L (+)-tartaric acid, the diastereo-7 isomer isomer which separates contains the R-form of the 8 1-t-butylamino-2,3-dihydroxypropane as L (+)-tartaric acid.
9 R-l-~butylamino-2,3-dihydroxypropane salt - with the D (-)-acid, the diastereoisomer which separates contains the S form 11 of the 1-t-butylamino-2,3-dihydroxypropane as D (-)-tartaric 12 acid S-l-t-butylamino-2,3-dihydroxypropane salt.
-13 The resolution process may be carried out at any 14 suitable temperature~ The resolution is generally accomplished at room temperature, although higher or lower 16 temperatures may be used. If desired, the mixture o 17 enantiomers and the resolving agent can be refluxed to 18 insure complete solution and proper contact of the enantiomers 19 and resolving agent. The refluxed solution is then cooled to room temperature or lower, generally with agitation, whereupon 21 the dias~ereoisomer separates.
2Z The present process i~ carried out at atmospheric 23 pressure. Super atmospheric pressure is not required.
24 The amount of resolving agent used may he varied.
Generally, between about 0.5 to 1 mole of resolving agent is 26 u~ed per mole o enantiomer mixture. Molar ratios of resolving 27 agent: enantiomer o 0.5:1 or lcl are particularly useful.
28 The single enantiomer of l-t-butylamino-2,3-dihydr-29 oxypropane is recovered from the separated diastereoisomer by conventional techniques. For example, the S-pyroglutamic 31 acid-S~t-butylamino-2,3-dihydroxypropane diastereoisomer can 32 be treated with asùitable base whereby the S-l-t-butylamino-_ D~ --1 2,3-dlhydroxypropane is freed ~rom the S-pyroglutamic a~Id.
2 The S-l-t-butylamino-2,3-dihydroxypropane can then be re-3 covered by extraction with a suitable solvent and the solvent 4 stripped to yield the desired S-l-t-butylamino-2,3-dihydroxy-propane. The neutralized S-pyroglutamic acid can be conven-6 tionally recovered from the remaining solution for re-use 7 as a resolving agent.
8 Another procedure for recovering the amine enan-9 tiomer from the separated diastereoisomer is to run a solution of the diastereoisomer through a suitable ion 11 exchange resin column and then elute the free l-t-butylamino-12 2,3-dihydroxypropane enantiomer.
13 The mixture of enantiomers which can be re~olved 14 by the present process contain S and R enantiomexs of l-t-butylamino-2,3-dihydroxypropane. These mixtures include (R,S) 16 racemic mixtures or modifications as well as mixtures rich 17 ln R or S enantiomer.
18 ~ The resolution process is relatively simple. It 19 lnvolves preparing a solution of the mixture of enantiomers of 1-t-butylamino-2,3-dihydroxypropane in one of the solvents 21 described above. ~he aoncentration oE the enantiomer mixture 22 in the solution can be varied. The resolving agent i9 then 23 add~d either directly or a~ a solution in one o~ the a~oresaid 24 solvents. After the solid diastereoisomer drops out of the solution, it is separated from the solution by any convenient 26 means e.g. by filtration, by centrifugration. This solid 27 diastereoisomer is then treated by conventional techniques 28 to recover the single enantiomer of 1-t-butylamino-2,3-29 dihydroxypropane. The remaining solution which is rich in the diastereoisomer containing the other enantiomer form of 31 1-t-butylamino-2,3-dihydroxypropane can also be treated to 32 recover this other enantiomer.
15563 :CA
~CI 6~3 1 As pointed out above, the enantiomers of l-t-butyl-2 amino-2,3-dihydroxypropane are useful in preparing ~-adrener-3 gic blocking agents,such ~s those described in U. S. 3,657,237.
4 The S-enantiomer of l-t butylamino-2,3-dihydroxypropane is especially useful for preparing the more active S-isomer of 6 the U. S. 3,657,237 ~-adrenergic blocking agents.
7 Following are examples which illustrate the 8 resolution process of the present invention.
~ ~ 15553 IA
~3D69~ 43 1 ExAMPLE 1 2 A. Preparation of R,S-l-t-butylamino-2,3-dihydroxypropane 3 A solution of R,S-glycidol (105 g; 1.42 moles) in 4 100 ml of isopropanol was added dropwise over one hour to a solution of t-butylamine ~197 g; 2~ 7 moles) in 200 m~
6 isopropanol while maintaining the tempera~ure between 46 -7 70C. The solution was aged a~ 70C. for one hour and the 8 excess t-butylamine was recovered by atmospheric distillation.
9 The distillation-was continued until the pot temperature reached 110C. Acetone (700 ml) was then added to the residue 11 ;and the~temperature of the final solution was adjusted to 12 40-45C. The yield of R,S-t-butylamino-2,3-dihydroxypropane 13 (R,S-glycolamine) was 88%.
B. Resolution of R,S-l-t-butylamino-2,3-dihydroxypropane 16 To the inal solution from (A) was added 83.0 g 17 (0.645 moles) of S-pyroglutamic acid (97% pure) and the 18 resultant sqlution mixture was refluxed, with stirring, for 19 1.5 hours. This solution was then cooled to room temperature over 2.5: hours, with stirring.
21 The S-pyroglutamic acid S-l-t-butylamino-2,3-22 dihydroxypropane diastereoisomer which separated from the 23 solution wa9 ~iltered o~ and wa~hed with 2x50 ml o~ acetone.
24 The yield of pure diastereoisomer was 130 g (33.5% based on the R,S-glycidol).
27 C. Regeneration of S-l-t-butylamine-2,3-dihydroxypropane 28 The S-l-t-butylamino-2,3-dihydroxypropane was 29 regenerated from the (~) diastereoisomer by dissolving the ~6~943 1 diastereoisomer in 200 ml of water and passing the solution 2 through a column of 350 ml of IR-120 ~H )~ IR-120 (H ) 3 is a gelular, strongly acidic, cation exchange resin marketed 4 by Rohm & Haas Company. The column was washed with water until a negative test for pyroglutamic acid was obtained.
6 S-pyroglutamic acid was recovered, in excess of 95% yield, by 7 concentrating to dryness, slurrying the residue with iso-8 propanol and filtering off the S-pyroglutamic acid.
9 The S-l-t-butylamino-2,3-dihydroxypropane was eluted from the IR-120 resin by washing with 5% ammonium 11 hydroxide solution. The eluate was concentrated to dryness 12 and the residue recrystallized from 150 ml of xylene to give 13 66.0 g of pure S-l-t-butylamino-2,3-dihydroxypropane. (31.7%
14 yield based on the weight o R,S-glycidol) 16 EX~MPLE 2 17 E~,S-t-butylamino-2,3-dihydroxypropane (5.88 g) and 18 S-pyroglutamic acid (2.70 g) were mixed in isopropanol 19 ~(20 ml) and heated on a steam bath until solution was complete.
The solution was cooled to 50C and seeded with the pure S-21 pyroglutamic acid S-l-t-butylamino-2,3-dihydroxypropane salt.
22 The mixture was then allowed to cool 910wly to room 23 temperature with stirring over about a two hour period. The 24 slurry wa~ cooled at 0.5C ~or one hour and ~ ered to give 4.03 g (73~) of the S-pyroglutamic acid S-I-t-butylamino-26 2,3-dihydroxypropane diastereoisomer, having a melting point 27 o~ 140-143C; [a]~ = (-) 21.9 (CH30E~). Recrystallization 28 rom 3.5 volumes o boiling isopropanol yave a 91.5~ yield 29 of the pure diastereoisomer melting at 143-146; [a]D= -23.4 (C=2 in CH30H).
9~3 1 Pure S-l-t-butylamino-2,3-dihydroxypropane was 2 recovered from the pure diastereoisomer by dissolving 3 the diastereoisomer in excess 50~ aqueous NaOH solution 4 and extracting the S-l-t-butylamino-2,3-dihydroxypropane with ether. The ether extract was dried over magnesium 6 sulfate and filtered. The product obtained was pure 7 S-1-_-butylamino-2,3-dihydroxypropa~e characterized by a 8 melting point of 83-85C and [a] D= t-) 30 (lN ~ICl).
9 Alternately, the S-l-t-butylamino-2,3-dihydroxy-propane was recovered by dissolving the diastereoisomer 11 in 10 ml of water and using the ion exchange resin (IR-120) 12 procedure of Example 1 (C).
-A mixture of L (~)-tartaric acid (35.0 g) and 16 R,S-t-butylamino-2,3-dihydroxypropane (34.4 g) were dissolved 17 in 500 ml of hot 90~ isopropanol/10% water. The solution was 18 slowly cooled to room temperature over four hours with 19 stirring. The L (+)-tartaric acid R-l-t-butylamino-2,3-dihydroxypropane diastereoisomer which separated was filtered.
21 The yield was 45.6 g of the diastereoisomer havlng a 22 melting point of 85C and ~a]D= ~9 5 . r~WO additional 23 recr~stallizations rom aqueous isopropanol gav~ substantiall~
24 pure L (~)-tartaric acid-R-1-t-butylamino-2,3-dihydroxypropane diastereoisomer, having a melting point of 94-~6C and [a] D=
26 ~1g.9, (C-2 in lNHCl).
27 The pure R-l-t-bu~ylamino-2,3-dihydroxypropane 28 was recovered from the diastereoisomer by substantially the 29 same procedure as described in Examples 1 and 2.
Claims to the invention follow.
Claims (14)
1. Process for resolving mixture of enantiomers of 1-t-butylamino-2,3-dihydroxypropane which comprises treating a solution of said mixture in a suitable solvent with an agent selected from S-pyroglutamic acid, R-pyroglutamic acid, L-(+)-tartaric acid and D-(-)-tartaric acid, and separating from the solution the solid diastereoisomer which forms.
2. The process of Claim 1, wherein a single enantiomer of 1-t-butylamino-2,3-dihydroxypropane is recovered from the formed diastereoisomer.
3. The process of Claim 1, wherein said solvent is selected from acetone, isopropanol and isopropanol/water mixture.
4. The process of Claim 3, wherein said agent is L-(+)-tartaric acid and said single enantiomer is the R-form.
5. The process of Claim 4, wherein said solvent is isopropanol containing about 10% by weight water.
6. The process of Claim 3, wherein said agent is L-(+)-tartaric acid and the L-(+)-tartaric acid-R-1-t-butyl-amino-2,3-dihydroxypropane diastereoisomer is obtained.
7. The process of Claim 6, wherein said solvent is isopropanol containing about 10% by weight water.
8. The process of Claim 3, wherein said agent is S-pyroglutamic acid and said single enantiomer is the S-form.
9. The process of Claim 8, wherein said solvent is acetone.
10. The process of Claim 8, wherein said solvent is isopropanol.
11. The process of Claim 1, wherein said agent is S-pyroglutamic acid and there is formed the S-pyroglutamic acid-S-1-t-butylamino-2,3-dihydroxypropane diastereoisomer.
12. The S-pyroglutamic acid?S-1-t-butylamino-2,3-dihydroxypropane or the L-(+)-tartaric acid-R-1-t-butylamino-2,3-dihydroxypropane, when prepared by the process defined in Claim 11 or 6 respectively or by an obvious chemical equiva-lent.
13. S-pyroglutamic acid?S-1-t-butylamino-2,3-dihydroxypropane, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.
14. L-(+)-tartaric acid?R-1-t-butylamino-2,3-dihydroxypropane, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53254774A | 1974-12-13 | 1974-12-13 | |
| US61594175A | 1975-09-25 | 1975-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064943A true CA1064943A (en) | 1979-10-23 |
Family
ID=27063872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA241,257A Expired CA1064943A (en) | 1974-12-13 | 1975-12-08 | Optical resolution of 1-t-butylamino-2,3-dihydroxypropane |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS51118711A (en) |
| AU (1) | AU510799B2 (en) |
| CA (1) | CA1064943A (en) |
| DE (1) | DE2556040C2 (en) |
| DK (1) | DK532575A (en) |
| FR (2) | FR2294151A1 (en) |
| GB (1) | GB1470030A (en) |
| IE (1) | IE42206B1 (en) |
| NL (1) | NL7513818A (en) |
| SE (1) | SE435499B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5931693A (en) * | 1982-08-13 | 1984-02-20 | Kanegafuchi Chem Ind Co Ltd | Preparation of optical active oxazolidinone derivative |
| JPH01149775A (en) * | 1987-12-07 | 1989-06-12 | Kawaken Fine Chem Co Ltd | Production of optically active 2-methylpiperazine |
| US5684159A (en) * | 1995-05-30 | 1997-11-04 | Rhone-Poulenc Rorer S.A. | L-tartaric acid salt of a (1R) diastereomer of a 2-azadihydroxybicyclo 2.2.1!heptane compound and the preparation of 2-azabicyclo 2.2.1!heptane compounds |
| IN187238B (en) * | 1995-06-30 | 2002-03-09 | Astra Ab | |
| WO2017165878A1 (en) * | 2016-03-25 | 2017-09-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2528267A (en) * | 1950-10-31 | Eobeet j | ||
| US3116332A (en) * | 1958-10-17 | 1963-12-31 | Du Pont | Resolution of racemic aminoisopropanol |
-
1975
- 1975-11-26 NL NL7513818A patent/NL7513818A/en active Search and Examination
- 1975-11-26 SE SE7513307A patent/SE435499B/en not_active IP Right Cessation
- 1975-11-26 DK DK532575A patent/DK532575A/en not_active Application Discontinuation
- 1975-12-03 AU AU87220/75A patent/AU510799B2/en not_active Expired
- 1975-12-08 CA CA241,257A patent/CA1064943A/en not_active Expired
- 1975-12-09 FR FR7537575A patent/FR2294151A1/en active Granted
- 1975-12-10 GB GB5063275A patent/GB1470030A/en not_active Expired
- 1975-12-11 IE IE2702/75A patent/IE42206B1/en unknown
- 1975-12-12 DE DE2556040A patent/DE2556040C2/en not_active Expired
- 1975-12-12 JP JP50147481A patent/JPS51118711A/en active Pending
-
1976
- 1976-05-04 FR FR7613241A patent/FR2303790A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| SE7513307L (en) | 1976-06-14 |
| JPS51118711A (en) | 1976-10-18 |
| GB1470030A (en) | 1977-04-14 |
| FR2303790B1 (en) | 1980-07-18 |
| FR2303790A1 (en) | 1976-10-08 |
| NL7513818A (en) | 1976-06-15 |
| SE435499B (en) | 1984-10-01 |
| DE2556040A1 (en) | 1976-06-16 |
| AU510799B2 (en) | 1980-07-17 |
| FR2294151B1 (en) | 1979-04-06 |
| DE2556040C2 (en) | 1986-05-07 |
| DK532575A (en) | 1976-06-14 |
| FR2294151A1 (en) | 1976-07-09 |
| IE42206L (en) | 1976-06-13 |
| IE42206B1 (en) | 1980-06-18 |
| AU8722075A (en) | 1977-06-09 |
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