CA2065395A1 - Process for producing enantiomer-pure .alpha.-hydroxylproponioaldehyde derivatives - Google Patents
Process for producing enantiomer-pure .alpha.-hydroxylproponioaldehyde derivativesInfo
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- CA2065395A1 CA2065395A1 CA 2065395 CA2065395A CA2065395A1 CA 2065395 A1 CA2065395 A1 CA 2065395A1 CA 2065395 CA2065395 CA 2065395 CA 2065395 A CA2065395 A CA 2065395A CA 2065395 A1 CA2065395 A1 CA 2065395A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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Abstract
Abstract A process for the production of enantiomer-pure .alpha.-hydroxypropionaldehyde derivatives of general formula I
(I),
(I),
Description
20~39~
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER-PURE -HYDROXYPROPIONALDEHYDE DERIVATIVES
R1-CH2-C~-C~o (I) (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.
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER PURE -HYDROXYPROPIONALDEHYDE DERIVATIVES
Rl-CH2-CH-CHO (I) I
(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.
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER-PURE -HYDROXYPROPIONALDEHYDE DERIVATIVES
R1-CH2-C~-C~o (I) (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.
Published:
With international search report.
(54) Title: PROCESS FOR THE PRODUCTION OF ENANTIOMER PURE -HYDROXYPROPIONALDEHYDE DERIVATIVES
Rl-CH2-CH-CHO (I) I
(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), 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
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-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
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
~H2 1 (Xl ~ H-~ -OR2 (X~ I
HO-CH HC-OH
HC-OH
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), 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), 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), 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 , .
,
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), 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
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-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
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
~H2 1 (Xl ~ H-~ -OR2 (X~ I
HO-CH HC-OH
HC-OH
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), 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), 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), 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 , .
,
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS-
1. Process for the production of enantiomer-pure .alpha.-hydroxypropionaldehyde derivatives of general formula I
(I), 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, which is characterized in that the oxirane rings of a 1,2,5,6-dianhydrohexitol derivative, of general formula II or III
(II) (III), in which 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 (IV), 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
HO-CH
HC-OH (VI), (V) in which Q and R3 have the above-mentioned meanings, are esterified with a compound of genercll 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
(IX) (X) in which Q, R2 and R3 have the above-mentioned meaning, the latter are hydrolyzed to compounds of general formula XI or XII
(XI) (XII) in which R1 and R3 have the above-mentioned meanings, and the latter are cleaved by periodic acid or lead tetraacetate.
(I), 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, which is characterized in that the oxirane rings of a 1,2,5,6-dianhydrohexitol derivative, of general formula II or III
(II) (III), in which 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 (IV), 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
HO-CH
HC-OH (VI), (V) in which Q and R3 have the above-mentioned meanings, are esterified with a compound of genercll 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
(IX) (X) in which Q, R2 and R3 have the above-mentioned meaning, the latter are hydrolyzed to compounds of general formula XI or XII
(XI) (XII) in which R1 and R3 have the above-mentioned meanings, and the latter are cleaved by periodic acid or lead tetraacetate.
2. Use of enantiomer-pure .alpha.-hydroxypropionaldehyde derivatives of general formula I produced according to claim 1 for the synthesis of enantiomer-pure .alpha.-hydroxypropionic acid derivatives of general formula XIII
(XIII), in which R1 and R2 have the meaning mentioned in claim 1 and their esters.
(XIII), in which R1 and R2 have the meaning mentioned in claim 1 and their esters.
3. Use of enantiomer-pure .alpha.-hydroxypropionaldehyde derivatives of general formula I produced according to claim 1 for the synthesis of enantiomer-pure .alpha.-azidopropionic acid derivatives of general formula XIV
(XIV), in which R1 has the meaning mentioned in claim 1 and their esters.
(XIV), in which R1 has the meaning mentioned in claim 1 and their esters.
4. Use of enantiomer-pure .alpha.-hydroxypropionaldehyde derivatives of general formula I produced according to claim 1 for the synthesis of enantiomer-pure .alpha.-amino acid derivatives of general formula XV
(XV), in which R1 has the meaning mentioned in claim 1 and their esters.
(XV), in which R1 has the meaning mentioned in claim 1 and their esters.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4020349.2 | 1990-06-23 | ||
| DE19904020349 DE4020349A1 (en) | 1990-06-23 | 1990-06-23 | METHOD FOR PRODUCING ENANTIOMERIC PURE (ALPHA) HYDROXYPROPIONALDEHYDE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065395A1 true CA2065395A1 (en) | 1991-12-24 |
Family
ID=6409108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2065395 Abandoned CA2065395A1 (en) | 1990-06-23 | 1991-06-05 | Process for producing enantiomer-pure .alpha.-hydroxylproponioaldehyde derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0487667A1 (en) |
| JP (1) | JPH05502678A (en) |
| AU (1) | AU7971891A (en) |
| CA (1) | CA2065395A1 (en) |
| DE (1) | DE4020349A1 (en) |
| WO (1) | WO1992000275A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5688994A (en) | 1992-12-16 | 1994-07-04 | University Of Melbourne, The | Developmental regulation in anther tissue of plants |
-
1990
- 1990-06-23 DE DE19904020349 patent/DE4020349A1/en not_active Withdrawn
-
1991
- 1991-06-05 JP JP50951191A patent/JPH05502678A/en active Pending
- 1991-06-05 AU AU79718/91A patent/AU7971891A/en not_active Abandoned
- 1991-06-05 EP EP19910910293 patent/EP0487667A1/en not_active Withdrawn
- 1991-06-05 WO PCT/DE1991/000485 patent/WO1992000275A1/en not_active Application Discontinuation
- 1991-06-05 CA CA 2065395 patent/CA2065395A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05502678A (en) | 1993-05-13 |
| DE4020349A1 (en) | 1992-01-02 |
| WO1992000275A1 (en) | 1992-01-09 |
| AU7971891A (en) | 1992-01-23 |
| EP0487667A1 (en) | 1992-06-03 |
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