Note: Descriptions are shown in the official language in which they were submitted.
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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,
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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.
13
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~.
22
23 Description of the Preferred Embodiments
24
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
. .
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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.
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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-
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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.
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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.
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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%.
14
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).
26
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
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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).
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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).
13
14 EXAMPLE 3
-
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.
