Note: Descriptions are shown in the official language in which they were submitted.
20~39~
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER-PURE -
HYDROXYPROPIONALDEHYDE DERIVATIVES
R1-CH2-C~-C~o (I)
OR2
(57~ Abstract
A process for the production of enantiomer-pure a-
hydroxypropionaldehyde derivatives of general formula (I) is
described, in which R1 means substituent Q, which represents a
hydrocarbon radical optionally interrupted by oxygen atoms,
carbonyloxy groups, nitrogen atoms and/or resonance-stabilized
imido groups and/or thio groups and/or substituted by halogen
atoms or a grouping resulting by hydrolysis of Q containing
hydroxy groups, carbonyl groups or carboxyl groups, and R2
symbolizes an alkanesulfonyl group with up to 6 carbon atoms, a
trifluoromethanesulfonyl group, a benzenesulfonyl group or a p-
toluenesulfonyl group.
3 9 5
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER PURE -
HYDROXYPROPIONALDEHYDE DERIVATIVES
Rl-CH2-CH-CHO (I)
I
OR2
(57) Abstract
A process for the production of enantio~er pure a-
hydroxypropionaldehyde derivatives of general formula (I) is
described, in which R1 means su~stituent Q, which represents a
hydrocarbon radical optionally interrupted by oxygen atoms,
carbonyloxy groups, nitrogen atoms and/or resonance-stabilized
imido groups and/or thio groups and/or substituted by halogen
atoms or a grouping resulting by hydrolysis of Q containing
hydroxy groups, carbonyl groups or carboxyl groups, and R2
symbolizes an alkanesulfonyl group with up to 6 carbon atoms, a
trifluoromethanesulfonyl group, a benæenesulfonyl group or a p-
toluenesulfonyl group.
2 0 ~
Process for the Production of ~nantiomer-pure
~-Hydroxypropionaldehyde Derivatives
The invention relates to a process for the production of
enantiomer-pure ~-hydroxypropionaldehyde derivatives of general
formula I
Rl_cH2-cH-cHo (I),
OR2
in which
Rl means substituent Q, which represents a hydrocarbon
radical optionally interrupted by oxygen atoms, carbonyloxy
groups, nitrogen atoms and/or resonance-sta~ilized imido groups
and/or thio groups and/or substituted by halogen atoms or
a grouping resulting by hydrolysis of Q containing hydroxy
groups, carbonyl groups or carboxyl groups, and
R2 symbolizes an alkanesulfonyl group with up to 6 carbon
atoms, a trifluoromethanesulfonyl group,, a benzenesulfonyl group
or a p-toluenesulfonyl group, which is characterized in that the
oxirane rings of a 1,2,5,6-dianhydrohexitol derivative, of
general formula II or III
'CH ` H21 0
CH ; HC
R O-CH ~ 1~1) R30-1 H ( IIII,
H~-OR3 ~ HC-OR3
" HC CH
2 CH2
in which
- : " ' ' ~ '
.
20~39~
both substituents R3 together mean an alkylidene group with up to
6 carbon atoms or a benzylidene group,
are opened with an organometallic compound of general formula IV
QME (I~),
in which
Q has the above-mentioned meaning and
ME represents an alkali metal atom, a copper(I) atom or a
magnesium halide radical,
the formed compounds of general formula V or VI
CH2Q l H2q
HO-CH (V~ HC-OH (VI),
R~O-~H R301C-~
HC-OR3 HC-OR
HC-OH HO-CH
CH2Q CHzQ
in which
Q and R3 have the above-mentioned meanings,
are esterified with a compound of general formula VII or VIII
R2Cl (VII), R2-OR2 (VIII)~
in which R2 has the above-mentioned meaning, to compounds of
general formula IX or X .. -
1 2 Cl~
R -O-CH HC-OR
2 1 (IX) I 2 tX~
R O-CH R O-C-H
HC-OR3 H~COR3
CH-OR R2~1CH
CH20 CH2Q
in which
: .,,
2~39~
Q, R2 and R3 have the above-mentioned meaning, the latter
are hydrolyzed to compounds of general formula XI or XII
CH2R 1
~H2 1 (Xl ~ H-~ -OR2 (X~ I
HO-CH HC-OH
HC-OH
R2O-C11
HF OR2 CH2 1
CH~R 1
in which
Rl and R3 have the above-mentioned meanings, and the latter
are cleaved by periodic acid or lead tetraacetate.
The invention relatas, moreover, to the use of the thus
produced enantiomer-pure ~-hydroxypropionaldehyde derivatives of
general formula I for the synthesis of enantiomer-pure ~-
hydroxypropionic acid derivatives of general formula XIII
Rl-CH CH~COOH (XIII),
OR2
in which
Rl and R2 have the above-mentioned meaning and their esters,
for synthesis of enantiomer-pure ~-azidopropionic acid
derivatives of general formula XIV
Rl-CE~-CH-COOH t XIV),
N3
in which
Rl has the meaning mentioned in claim 1 and their esters, as
well as for synthesis of enantiomer-pure ~-amino acid derivatives
., : :
: .
, ' :. . ":
2 ~ 9 ~
of general formula XV
Rl-CH2 -CH--COOH ( XV),
NH2
in which
Rl has the meaning mentioned in claim l and their esters.
It is known that the synthesis of enantiomer-pure amino
acids often is quite expensive, this is especially the case when
"unnatural amino acids," i.e., (R)-amino acids or (S)-amino
acids, which do not occur in nature, are produced. But there
exists a demand for the most diverse "unnatural amino acids," for
the latter are used, for example, to produce modifications of
pharmacologically effective peptides.
As an example of such modified peptides, the LHRH
antagonists can be mentioned. (J~ J. Nastor et al.; Annual
Reports in Medicinal Chem., 23, 1988, 211-220).
This invention basically relates to a relatively simple
synthesis of enantiomer-pure amino acids or enantiomer-pure ~-
azidoamino acids also very suitable for peptide syntheses. It
further has the advantage that it is very universally applicable
and makes possibla the syntheses of the most varied "unnatural
amino acids."
As initial compounds, preferably 1,2,5,6-dianhydro-3,4-O
isopropylidene-D-mannitol of formula II [R3 =, C(CH3)2] or
1,2,5,6-dianhydro-3,4-0-isopropylidene-L-iditol of formula III
[R3 = ` C(CH2)3] is used for the procass according to the
invention. Both substances can be produced in a simple way from
D-mannitol (Chem. Ber. 92, 1959, 2506 ff; Tetrahadron Letters 26,
2~3~
1985, 319 ff). It is possible, of course, to use as initial
compounds also 1,2,5,6-dianhydrohexitol derivatives of general
formulas II or III, which have other protective groups such as
the isopropylidene radical in 3- and 4-position; such protective
groups are~ for example, the methylene group, the ethylidene
group, the 3,3-pentylidene group or the benzylidene group. But
the synthesis of such compounds is generally more expensive than
that of the isopropylidene compounds and their use as a rule
brings no advantages.
The oxirane rings of the 1,2,5,6-dianhydro derivatives of
general formulas II or III are opened with an organometallic
compound of general formula IV. These organometallic compounds
can be produced, for example, from the corresponding halogen
compounds of general formula XVI
QX (XVI),
in which Q has the above-mentioned meaning and X represe~ts a
halogen atom -~ preferably a chlorine atom, bromine atom or
iodine atom -- by reaction with lithium, butyllithium,
phenyllithium, sodium or magnesium, optionally by adding copper
(I) salts; also, their reaction with the oxiranes takes place in
a way known in the art [Methoden der organischen Chemie [Methods
of Organic Chemistry3 (Houben-Weyl) ~th edition, Georg Thieme
Verlag, DE-Stuttgart Volume XIII/1, 1~70, pages 87 ff and 255 ff
and Volume XIII/2a, 1973, pages 47 ff; ~etrahedron Letters 17,
1979, 1503 ff3.
It was already mentioned that substituent Q of the
organometallic compounds represents a hydrocarbon radical, which
2~39~
is optionally interrupted by oxygen atoms, carbonyloxy groups,
nitrogen atoms and/or resonance-stabilized imido groups and/or
substituted by halogen atoms. This hydrocarbon radical, which
preferably contains at most 20 carbon atoms and preferably at
most five hetero atoms, can be saturated or unsaturated, as well
as alicyclic, cyclic or mixed cyclic-alicyclic. The cyclic or
mixed cyclic-alicyclic hydrocarbons can be nonaromatic, aromatic
and/or heterocyclic ring systems or can contain the latter.
Hydrocarbons, which are interrupted by oxygen atoms, are,
for example, those which contain ether groups ~such as the
methoxy group, tert-butyloxy group, benzyloxy group or the 2-
tetrahydropyranyloxy group). Such ethers can optionally be used
to synthesize substances which contain hydroxy groups. Other
hydrocarbons, which are interrupted by oxygen atoms, are, for
example, those which contain furan rings, tetrahydrofuran rings,
pyran rings or 1,3-dioxolane rings. The latter can optionally be
used to synthesize substances which contain carbonyl groups.
It is possible to synthesize compounds, whose hydrocarbon
radical is interrupted by carbonyloxy groups, in satisfactory
yield only in exceptional cases; in this connection, see, for
example, Tetrahedron Letters 27, 1986, 4161 ff). If it is
desired to synthesize substances whose hydrocarbon radical R1 is
substituted by a carboxyl group, the latter can be brought about,
for example, by starting from halogen compounds which contain a
4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group (J. Am. Chem.
Soc., 92, 1970, 6644 and 6646).
20~9~
Hydrocarbons Q, which are interrupt~d by nitrogen atoms,
are, for example, those which contain dialkylamino groups, such
as the dimethylamino groups, pyrrolino groups (Houben-Weyl, 4th
edition, Volume XVII, ls74, page 293) or dibenzylamino groups.
The latter can, for example, be used to synthesize substances
which contain primary amino groups. Hydrocarbons of this type
are, on the other hand, also those which contain N-alkyl or N-
benzyl-substituted imido groups.
The aromatic N-heterocycles or hydrocarbons, which contain
such N-heterocycles, are also included in the radicals of this
type.
Radicals Q, which contain resonance-stabilized imido groups
or thio groups, are the pyrrolyl and thienyl radicals and those
hydrocarbons which contain pyrrole rings or thiophene rings. If
the imido group in the compounds does not prove sufficiently
resonance-stabilized, it can be protected before the production
of the organometallic compounds, for example, by benzylation or
tosylation.
As suitable radicals Q, for example, there can be mentioned:
Straight-chain or branched alkyl groups, cycloalkyi groups
or cycloalkyl-alkyl groups with up to 20 carbon atoms, such as
the methyl group, the ethyl group, the 1-methylethyl group, the
propyl group, the butyl group, the 1-methyl-propyl group or the
l,l-dimethylethyl group, the cyclopropyl group, the cyclopentyl
group, the cyclohexyl group and the cyclopropylpropyl group.
Alkyl groups with up to 8 carbon atoms, which are
substituted by benzyloxy groups and/or dibenzylamino groups, such
as the benzyloxymethyl group, the dibenzylamino-methyl group, the
2-benzyloxy-ethyl group, the 2-dibenzylaminoethyl group, the 3-
dibenzylamino-propyl group and the 2-benzyloxy-3-dibenzylamino-
propyl group.
Alkyl groups with up to 8 carbon atoms, which are
substituted by a 4,4-dimethyl-4,5-didehydro-1~3-oxazol-2-yl
group, such as, for example, the (4~4-dimethyl-4,5-dihydro-1,3-
oxazol-2-yl)-methyl group or the 3-(4,4-dimethyl-4,5-dihydro-1,3-
oxazol-2-yl)-3-dibenzylamino-propyl group.
Phenyl groups, l-naphthyl groups or 2-naphthyl groups, which
can be substituted by lower alkyl groups with up to 4 carbon
atoms (for example, methyl, ethyl, 1-methylethyl or 1,1-
dimethylethyl), trifluoromethyl groups, lower alkoxy groups with
up to 4 carbon atoms (for example, methoxy or tert-butyloxy),
halogen atoms (preferably fluorine or chlorine atoms), 4,4-
dimethyl-4,5-dihydro-1,3-oxazol-2-yl groups, oxathiazole groups,
lower dialkylamino groups with up to 4 carbon atoms in each alkyl
group, such as the dimethylamino group and/or dibenzylamino
groups. Such groups are, for example, the phenyl radical, the p-
chlorophenyl radical, the 4-benzyloxyphenyl radical, the 4-
trifluoromethylphenyl radical, the 4-dimethylaminophenyl radical
or the 2-naphthyl radical.
Heterocyclic groups, such as, for example, the 2-pyridyl
radical, the 3-pyridyl radical, the 2-thienyl radical, the N-
benzyl-3-nidolyl radical, the N-benzyl-2-imidazolyl radical, the
~-carbolin-6-yl radical, the pyrrolinomethyl radical, the 2-(N-
pyrrolino)-ethyl radical, the tetrazolyl xadical, the 2-oxa-
9 2~3~5
chloro-1,3-dihydro-1-methyl 5-phenyl-2H-1,4-benzoduazepin-3-yl
radical, the oxathiazolyl radical or the pteridinyl radical.
The compounds of formula V or VI formed by reaction of
organometallic compounds QM~ with 1,2,5,6-dianhydrohexitol
derivatives are converted by reaction with a compound of formula
VII or VIII to the substances of formula IX or X~ For this
reaction, preferably methanesulfonic acid chloride is used as a
compound of formula VII, but it is basically also possible to use
other alkanesulfonic acid chlorides or anhydrides,
trifluoromethanesulfonic acid anhydride, benzenesulfonic acid
chloride or p-toluenesulfonic acid chloride. This reaction is
performed under conditions known in the art, preferably in the
presence of tert-amines, such as triethylamine or pyridine.
Then, the 1,3-dioxolane rings of the compounds of formulas
IX or X are cleaved in a way known in the art by acid hydrolysis.
For this reaction, strong acids, such as hydrochloric acid,
sulfuric acid, methanesulfonic acid or t:rifluoroacetic acid, are
suitable. As solvent, for this reaction, for example, water,
lower alcohols (such as methanol, ethanol or isopropanol) or
aqueous lower alcohols and the like are used. In the case of
this hydrolysis, easily saponifiable groups of substituent Q
(such as tetrahydropyranyl radicals, 1,3-dioxolane groups or
ester groups) can also be cleaved, and corresponding radicals Rl
substituted by hydroxy groups, oxo groups and/or carbonyl groups
are obtained.
The thus obtained compounds of general formula XI or XII are
cleaved in a way known in the art by periodic acid or lead
.
. " .~ , . ..
" ",1: ,
tetraacetate (see Luis F. Fieser and Mary Fieser: Reagents for
Organic Synthesis; John Wiley ~ Sons, Inc., New York et al.; Vol
1 to 14 under the keywords: lead tetraacetate, periodates and
periodic acid). Thus, the oxidation can be performed, for
example, by periodic acid in a lower ether (such as, diethyl
ether, diisopropyl ether, dioxane or tetrahydrofuran) as solvent.
The oxidation by lead tetraacetate can be brought about, for
example, by using acetic acid or benzene as solvent.
Since the formed enantiomer-pure a-hydroxypropionaldehyde
derivatives of general formula I have only a low stability, it is
suita~le to further process the latter immediately. Thus, the
aldehydes, Eor example, can be reduced to the corresponding
alcohols or converted by reductive amination to the corresponding
amino compounds. On the other hand, the aldehydes can be
oxidized also by oxidation for example, by chromic acid or
potassium permanganate to the enantiomer-pure a-hydroxypropionic
acid derivatives of general formula XI:[I. The latter can be
converted in a way known in the art to their esters (preferably
alkyl ester with at most 6 C atoms in the alkyl radical, such as,
for example, methyl ester, ethyl ester or tert-butyl ester or
also benzyl ester). The thus obtained esters can be converted by
reaction with sodium azide to the corresponding esters of the
enantiomer-pure a-azidopropionic acid derivatives of general
formula XIV, which on their part can be reduced, for example, to
the ~-amino acid derivatives of general formula XV.~
~ o avoid a racemate formation, the individual reaction steps
are performed at the lowest possible temperature, in a neutral
11 20~9~
medium and shortest possible reaction time. The suitable
reaction conditions are determined as usual by preliminary tests.
The following embodiment is used to explain in more detail
the process according to the invention and to use the process
pxoducts obtained according to the invention.
` - :'
~.
' 12 2~3~
Example 1
a) 244 mg of magnesium ~10 mmol) in 3 ml of absolute
tetrahydrofuran is introduced in a three-necked flask flushed
with argon. With stirring, 1/20 of a solution of 2 g (10 mmol)
of 2-naphthyl bromide in 16 ml of absolute tetrahydrofuran is
added. The Grignard solution reacts quickly with greenish-yellow
discoloratiorl; the residual 2-naphthyl bromide solution is added
so that the reaction remains at boiling. After the addition,
almost all the magnesium is dissolved and the solution is
refluxed with stirring for another 2 hours. Then, the solution
is decanted in a dropping funnel (under argon~.
The 2-naphthylmagnesium bromide solution is slowly instilled
in 0.15 g (1 mmol) of anhydrous coppertI) bromide in 4 ml of
tetrahydrofuran at -30C with stirring and under argonO After 5
minutes at -30C, 0.4 g (2.2 mmol) of 1,2,5,6-dianhydro-3,4-0-
isopropylidene-L-iditol in absolute tetrahydrofuran i9 instilled.
The mixture is allowed to thaw to 0C and stirred for 2 hours at
this temperature~ Then, it is present as a white, di~ficult-to-
stir mass with green streaks. It is worked up as usual, and the
copper salts remain in the aqueous phase with a deep blue color.
After the working up, 1,5-didesoxy-1,6-di-(2-naphthyl)-3,4-
isopropylidene-L-iditol is obtained as crude product in a yield
of about 90%.
[a]22D = +34.6 (c = 0.8 in dichloromethane)
13 ~6~3~
b) 2.11 g (4.77 mmol) of the crude product is dissolved
with stirring in 40 ml of pyridine. At oc, 0.78 ml (1.1 eq~ of
mesyl chloride in dry pyridine, as well as a micro-spatula tip
full of 4-dimethylamino-pyridine are slowly added. The
yellowish-discolored solution is allowed to thaw while it is
stirred for 16 hours. Then, it is mixed carefully with some
water and the pyridine is removed in a vacuum at not more than
60C. The residue is mixed with water and extracted with ~ther.
The ether phases are washed with dilute hydrochloric acid, sodium
bicarbonate solution and some water, then the solvent is drawn
off and the resiclue is dried in a high vacuum for several hours.
1,6-Didesoxy-1,6-di-(2-naphthyl)-3,4-O-isopropylidene-2,5-0-
dimesyl-L-iditol is obtained as a foamy, solidified caramel-
colored mass. The yield in crude product is 2.7 g (95%), the
melting point of the crude mixture is at 75C.
[a]~2D = -22.3 (c = 1 in dichloromethane)
c) 4.65 g (7.8 mmol) of the obtained dimesylate is
dissolved in 35 ml of trifluoroacetic acid and 1 ml of water (7
eq) at 0C and stirred for 4 hours at this temperature. After
removal of the solvent in a vacuum, 4.3 g (99% of theory) of
crude mass is obtained, which is chromatographed on a silica gel
column with hexane/ethyl acetate, and the feedstock first moves
as a yellowish fraction through the column. 3.7 g (84% of
theory) of 1,6-didesoxy-1,6-dinaphthyl-2,5-di-0-mesyl-L-iditol of
melting point 75C (from chloroform) is produced.
[~]22D = -~4-7 (c = 0.7 in dichloromethane)
14 2 ~ 9 ~
d) 0.9 g (1.6 mmol) of the obtained product is dissolved in
8 ml of absolute tetrahydrofuran with stirring. Anhydrousness is
not absolutely necessary, since water results. 0.4 g (1.1 eq) of
periodic acid is added with water cooling, which first is
completely dissolved. After a few minutes, crystalline iodic
acid precipitates. The heterogeneous mixture is stirred for 3
hours at room temperature, then it is filtered and rinsed with a
little ether. In this case, a white precipitate results in the
filtrate, which is removed by shaking out with water. Then, the
water phase is acidic, the ether/tetrahydrofuran phase is
neutral. The solvent is briefly dried on magnesium sulfate and
drawn off at no more than 30C in a vacuum.
The (S)-2-methylsulfonyloxy-3-(2-naphthyl)-propionaldehyde
obtained as crude product is immediately further processed:
The yellow oily xesidue (1.6 mmol of aldehyde) in 10 to 11
ml of t-butanol heated to 30C is dissolved with stirring. 7 ml
of a 1.25 molar aqueous sodium dihydrogenphosphate solution is
added to it and the resulting solution is adjusted with several
drops of phosphoric acid to a pH of 6 to 6.5. 11 ml of saturated
(1 mol) potassium permanganate solution is added to it at room
temperature and with vigorous stirring. After 10 minutes, the
reaction is completed and is stopped by adding so much saturated
aqueous sodium sulfite solution that the solution loses the
violet potassium permanganate coloring and becomes brown
(manganese dioxide). Conditions that are too basic have to be
avoided. It is ad~usted to a pH of 3 to 4 with ice-cold dilute
(2n) hydrochloric acid and the colloidal manganese dioxide is
, .
' ' 15 2~65~
dissolved. The aqueous phase is shaken out three times with
ether. The combined organic phases are washed with water, dried
on magnesium sulfate and drawn off in a vacuum. The residue can
be recrystallized from methanol, and 0.72 g (76~ of theory) of
(S)-2-methylsulfonyloxy-3-(2-naphthyl)-propionic acid is add~d as
white crystals of melting point 88C.
a) An ethereal solution of diazomethane is instilled in a
solution of carboxylic acid (4 g, 13.6 mmol) in 50 ml of
methanol/water 10:1 with stirring until the solution is no longer
decolored, and the yellow coloring remains even after 5 minutes.
It is stirred until ~he N2 development is completed. The solvent
is drawn off in a vacuum not completely to dryness (water) and
the residue is dissolved in 70 ml of dichloromethane. Also, in
this stage, the reaction is not to be performed over 30C. The
organic phase is washed twice with sodium chloride solution and
once with water and dried on magnesium sulfate. The crude
substance is recrystallized from dichloromethane/ether and the
white fibrous crystals (melting point 103C) are washed with
pentane and dried in a high vacuum. The yield of S-(2-
methylsulfonyloxy-3-(2-naphthyl)-propionic acid methyl ester is
3.9 g of magnesium sulfate (94% of theory~.
~a]22D = 15.1 (c = 1.1 in dichloromethane)
f) 1.74 g (5.6 mmol) of methyl ester and 1 g (3 eq) of
sodium a~ide are added in 30 ml of dimethylformamide and the
suspension is stirred for 5 hours at room temperature. The
: .
16 2~3~
working up takes place according to ~tandard methods, and also in
this stage, the reaction generally is not performed over 30C.
The organic phase is drawn off in a vacuum and (R)-2-azido-3-(2-
naphthyl)-propionic acid methyl ester is dried as yellow, thin-
bodied oil for several hours with stirring in a high vacuum~
1.39 g (97% of theory) of azide is produced.
[~]22D - -~52~3 (c = 1.1 in dichloromethane~
g) 0.2 g of azidoester in 5 ml of methanol and 10 mg (5~ by
weight3 of palladium-barium sulfate catalyst are stirred under
hydrogen for 5 hours at standard pressure and room temperature.
Then, the azide has quantitatively reacted and the ~-aminoester
has formed. The content of the shaking vessel is filtered off on
celite (or else simply), rinsed with a lot of methanol and
concentrated by evaporation in a vacuum. The residue is taken up
in absolute ether and a well-dried hydrochloric acid stream is
guided through this solution. The 3-t2-naphthyl)-D-
alaninemethylester-hydrochloride immediately precipitates. The
solid is recrystallized from ethyl acetate, washed with hexane
and 1~4 g (65% of theory) of white crystals of the hydrochloride
of melting point 184C is produced.
[]22D = -10.6 (c = 1.16 in methanol)
Exam~le 2
Under the conditions of example 1 a-g, 3-(1-naphthyl)-D-
alaninemethylester-hydrochloride is produced but by using 1-
17 2 ~ 9 ~
naphthyl bromide. White crystals of melting point 184C (fromethyl acetate/methanol).
[~]22D = ~35 5 (methanol; c = 1)
Example 3
Under the conditions of example la-g, D-a-aminoenanthic acid
methyl ester-hydrochloride is produced but by using n-butyl
bromide. White crystals of melting point 130C (from methanol).
[~]22D = 24.1 (methanol; c = 1)
Example 4
Under the conditions of example la-g, 3-(9-phenanthrenyl)-D-
alaninemethylester-hydrochloride is produce~ but by using 9-
phenanthrenyl bromide. White powder of melting point 210C (from
dichloromethane/diethyl ether/HCl).
[~]22D = 24.9 (dimethylsulfoxide; c = 0.9)
Example 5
Under the conditions of la-g, 3-(4-chlorophenyl)-D-
alaninemethylester-hydrochloride is produced but by using 4-
chlorophenyl bromide. White powder of melting point 217C (from
diethyl ether/HCll.
[~]22D = -16.7 (methanol; c = 1
, .
,
