Method for producing optically pure monoesters of tartaric acid and optically active alkanolamines o

专利摘要:
The invention relates to derivatives of hydroxy acids, in particular monoesters of tartaric acid and alkanolamines of the general formula (1) A - C (OR,) - CH, j - - NHR, where A is 4 nitrophenyl-1, 1-naphtil three, 4 -indolyloxymethyl phenoxyl residue 4-R ,, 2-R -CgHj- -O-CBj-, where R is methoxyethyl, -NHK; K is alkanoyl C, -C, in which alkyl C, -C 7 or dicarbamoyl, in which alkyl C, -Cg; R4-H, CH, -C (0) -; RZ-, hydrogen or branched C, -C-alkyl; R, is the residue of a disubstituted (R, R) - or
公开号:SU1297723A3
申请号:SU843783004
申请日:1984-08-17
公开日:1987-03-15
发明作者:Линднер Вольфганг
申请人:Хеми Линц Аг (Фирма)；
IPC主号:

专利说明:

This invention relates to the preparation of optically pure novel monoesters of tartaric acid and optically active alkanolamines of the formula
A-C-CH2-T55H- OR

R.
where A is a 4-nitrophenyl, 1-naphthyl-hydroxymethyl or 4-indolyloxymethyl residue, or a substituted phenoxy residue of the formula
o-cis
II
Yats
 3
R / -
RO (
de iR is a methoxyethyl residue or a HN-acyl residue, wherein adyl means an alkanoyl residue containing 1-4 carbon atoms or a dialkylcarbamoyl residue in which the alkyl moiety contains 1 or 2 carbon atoms; hydrogen atom or residue
a hydrogen atom or a branched alkyl residue with 3 or 4 carbon atoms; the residue of a disubstituted (R, R) - or (8,8) -tartaric acid of the formula
noos son-soon
1 iIII
OR. OR
Pr imer2. 1.81 g (7 mmol) of the dried (K, 5) -propran6lol is dissolved in 20 ml of dicloromethane, mixed with room temperature. 3.02 g (14 mmol) of anhydride (R, R) - - (+) - 0,0-diacetal tartaric acid and stirred for 48 hours at room temperature. After removal of the solvent in vacuo, the residue is stirred at 40.degree. At room temperature.
moreover, Rj is an alkyl radical with 1-4 carbon atoms, a benzyl residue, p, p-dichlorovinyl residue, an alkanoyl residue with 1-5 carbon atoms, containing in some cases sewing with 16 mmol of NaHCOj, is dissolved as the substituent chlorine benzine in 50 ml of water, while falling
products for more easily obtaining optically pure forms of free alkanolamines.
Example 1. 25.9 g (0.1 mol) of dry (R, 5) -propranolol is dissolved in 20.0 g (0.105 mol) of p-toluenesulfonic acid in 300 ml of 1,2-dichloroethane at room temperature. The crystallization water of toluenesulfonic acid is removed by distillation. 32 ° 4 g (0.15 mol) of (R, R) - (+) - 0.0-diaceontinous anhydride is added to the filtered solution at room temperature and the mixture is stirred under reflux at 80 ° C for 24 hours.
0
five
removing the solvent in vacuo; the solid residue is dissolved in a 5% aqueous solution of NaHCOg and then acidified with 1N. hydrochloric acid to pH 2.5. An isomeric mixture of diastereomeric wine ester of (R, S) -propanolol- (R, R) -0.0-di-acetyl tartaric acid of the monoester precipitates; extracted with dichloromethane (3-100 ml). After removing the extraction agent, a residue is obtained (yield 38 g, 80% of the theoretical), which crystallizes in acetone.
Similarly, the reaction is carried out with (S, S) - (-) - O, 0-diacetyltricic anhydride as a reagent, and the corresponding isomeric mixture is also obtained in 80% yield.
Pr imer2. 1.81 g (7 mmol) of the dried (K, 5) -propran6lol is dissolved in 20 ml of dicloromethane, mixed with room temperature. 3.02 g (14 mmol) of anhydride (R, R) - - (+) - 0,0-diacetal tartaric acid and stirred for 48 hours at room temperature. After removal of the solvent in vacuo, the residue is stirred at room temperature with stirring.
0
stitched with 16 mmol of NaHCOj dissolved in 50 ml of water;
a soyl, toluoyl or phenadethyl residue, or their salts.
These compounds are convenient intermediates in the preparation of optically pure alkanolamines possessing pharmacological activity and, in particular, i-adrenergic blocking activity.
The aim of the invention is to develop a method for obtaining new optically pure ethers of optically active alkanolamines, the original pro
five
crystalline precipitate. It is sucked off, washed with water and get pure monoether (S) -propanolol- (R, R) - -0.0-diacetyl tartaric acid, which upon hydrolysis gives pure (more than 98%) (8) - (-) - propranolol. The solution contains a mixture of diastereomeric monoesters of (R) - and (8) -propranolol (R, R) -0.0-di-acetyl tartaric acid, which can be separated into optical isomers.
The output of monoether (C) -propranolol- - (R, R) -O, 0-diacetyltartic acid
3
is 0.7 g (42% of those theoretical.).
PRI me R 3. 2.34 g (10 mmol) (K, K) -0.0-diacetyl tartaric acid is suspended in 15 ml of dichloromethane and mixed with 1.72 g (10 mmol) of anhydrous toluenesulfonic acid. A solution of 1.3 g of (K, 3) -propranolol (5 mmol) in 10 ml of dichloromethane is added dropwise to them with stirring, and then a solution of 2.06 g of didiclohexyl carbodiimide in 15 ml of dichloromethane is added. The mixture is stirred for 24 hours at room temperature, then sucked off and the filtrate is washed twice with 15 and 10 ml of water. The organic phase is dried and the solvent is distilled off in vacuo; The residue is treated with an aqueous solution of NaHCOj. The filtered aqueous solution is acidified to pH 3 and the mixture of the diastereomeric pair of tartaric acid esters is extracted with dichloromethane, which is then concentrated and the residue is suspended in acetone. Further processing of the reaction product is carried out as in Example 1.
Similarly to this example, diastereomeric monoesters of (K5K) -0.0-diacetyl tartaric acid metoprolol can also be prepared.
Example4. 15g of the crystalline mass, consisting of the diametereomeric mixture obtained according to Example 1, is placed in the sleeve in the Soxhlet apparatus and extracted again with stirring with acetone. After 10 transfers with a single volume of 300 ml, pure monoester (S) -npo pranolol- (R, R) -O, O-diadetyl tartaric acid (fraction II) crystallizes out in the receiver, and pure monoester (R) - - - remains in the sleeves. propol anolol- (R, R) -0.0-diacetylvinic acid (fraction I).
Fraction 1: monoester (E) -proprano-LOL- (R, R) -O, 0-diacetyltartic acid yield 7 g; m.p. 96-198 ° C; And ° 13.5 ° (, 405 in DMSO), optical purity over 98%.
50
Fraction II: mono-ester of (B) -propranolol- (R, R) -O, 0-diacetyl tartaric acid; yield 5 g; m.p. 176-177 ° C;
546 + 33.3 ° (from 0.98 in DMSO), op- 55
The physical purity is over 98%.
3 g of a mixture of fractions I and II remain in the acetone mother liquor.
7,: h4
NMR is consistent with structure.
The tartaric acid monoesters obtained by converting (R, S) -npo-pranolol with (8.8) -0.0-diacetylvinna anhydride instead of (R, R) -0.0-diacetyltvinyrim anhydride are referred to as their solubility acc. extractability back to the indicated scheme, i.e. The residual mono ester is (3) -propranolol- (8.5) -0.0-diacetyl tartaric acid, a. the more easily extruded fraction is monoester (R) -propanolol- (S, S) -O, 0-diacetyl tartaric acid. This type of inverse properties of diastereomeric compounds are common and therefore also serve for all other derivatives (R, R) respectively. (S, S) -O, 0-diacetyltartaric acid and alkanolamines,
According to the chemical structure, the monoester of the alkanolamic acid forms internal salts, and hydrochlorides can also be obtained with strong acids, for example hydrochloric acid, also in anhydrous aprotic solvents.
Moreover, alkali and alkaline earth salts and carboxyl function can be obtained by equivalent addition of alkali or alkaline earth hydroxides.
Example 5. The separation of the mixture of diastereomeric monoethers (R) - and (S) -nponpaHO-lol- (R, R) -O, 0-diacetyltartaric acid obtained in Example I into optical antipodes is carried out using thin-layer chromatography:
DC-plate silica gel (Si 60, Megsk); solvent: acetone-isopropanol 1: 1; extent of occurrence of Bp cm.
R value oi 1.78
Fraction II 0.41 Fraction I 0.23
Example Analogously to Example 1, propranolol, metropolol, acetobutolol, pindolol, nor-propranolol, and nifenapol with (R, R) -0,0-dibenzoyl-tartaric anhydride are converted. The resulting diastereomeric mixture of mono-esters of (R, R) -O, 0-dibenzoyl tartaric acid is separated by Reversed-phase — HPLC.
Chromatographic separation system:
Column 250-4.6 mm, 1, packed with Spherisorb Rp 18.5 mm.
Esters (R) acc. J
TO
EXAMPLE 7 Analogously to Example 1, (K, 5) -propranolol is converted with (R, R) -O anhydride, 0-ditoluoyl tartaric acid anhydride and the diastereomeric mixture of effieves is separated through a Reversed phase — HPLC.
Chromatographic separation system: column and mobile phase as in Example 6, U. 7.1; Kg 2.98. h "
Example According to Example 1, (R, S) -propanolol is converted with (R, R) -0.0-dimethyl acid anhydride and separated through the Reversed phase - HPLC.
Chromatographic separation system: column as in Example 6; mobile phase: 2% ammonia pH 3.7) and MeOH 65:35; to 5.8;
Kg 8.7; s, 1.5.40
11 example9. 7g (26 mmol) of (R, S) -methyliol together with 4.4 g (27 mmol) of trichloroacetic acid was dissolved in 150 ml of 1,2-dichloroethane,. at room temperature. On a rotary evaporator, the azeotropic fraction (approximately 30 ml) is distilled off for dehydration. 18 g (53 mmol) of (R, R) -0.0-dibenzoyl tartaric anhydride was added to the remaining solution, the solution was heated to 80 ° C for 2 hours, after cooling it was filtered with excess reagent. The remaining solution is concentrated on a rotary evaporator to a dry residue. 50 ml of acetone and 100 ml of a 10% aqueous solution of NaHCO are added to the residue. A precipitate is formed which
50
Mobile phase: 2% acetic acid in double-distilled, set at pH 3.7 with W, and methanol 35:65.

is a mixture of monoesters of tartaric acid and (R) - and (5) -metoprolol. After filtering and washing the precipitate with water, the latter is suspended in 100 ml of acetone and filtered off again. It is a mixture of esters, the proportion of (R) -MeTonpol- (R, R) -0.0-dibenzoyl tartaric acid monoester (fraction A) prevails. (B) Meto-prolol ether (fraction B) is present in the acetone phase, which is concentrated to dryness.
The total yield of fraction A, together with fraction B, is 12.8 g (80% of the theoretical).
5 g of a mixture of fractions A and B are dissolved in 20 MP of acetone and fed to a preparative silica gel column (g content of 70-230 mesh silica gel), the mixture is eluted with acetone. Fraction B is eluted before fraction A and thus fraction B is cleanly picked in a good yield.
Fraction B: mono-ether (8) -methanol- (R, R) -O, 0-dibenzoyl tartaric acid. Yield 1.1 g; Wj -57.2 (s;
CHClg); optical purity over 98%. The NMR data are consistent with the structure.
Primer 10. Anhydride (R, R) - -0,0-dibenzoyl acid is converted according to the examples with acebucol. The resulting diastereomeric mixture of esters is separated using Reversed phase — HPLC.
Chromatographic separation system ..: mobile phase: 2% acetic acid in bidistillate
71
water set at pH 3.7 NH, and methanol 65:35; column like. in example 6, K JJ 9.55; Kg 20, ll; oi 2.1
Example 11. 18.15 g (0.05 mol of (K, 3) -eliprolol together with 9 g (0.055 mol) of trichloroacetic acid is dissolved in 100 ml of dichloromethane at room temperature, the mixture is then dried with magnesium sulfate. To the solution is added 17 g (0.079 mol) of anhydride (K, K) -0.0-diacestric acid and stirred at room temperature. After 90 min of reaction time, 50 ml of saturated aqueous NaHCOg is added to the organic solution and the mixture is vigorously stirred. is separated and the procedure is repeated once more. Then the organic phase is dried with magnesium sulphate and strong the mixture is stirred, the dichloromethane is separated in vacuo at room temperature, the residue is amorphous-solid, a mixture of monoesters of (R) - and (8) -celiprolol- (K, K) -0.0-diacetyl tartaric acid (fractions A and B) Yield: 29 g of the diastereomeric mixture (90% of the theoretical).
10 g of a mixture of diastereomers of fractions A and B are dissolved in 50 ml of acetone and injected onto a preparative silica gel column, which is filled with 500 g of Si 60 silica gel (230-400 mesh). A mixture of acetone and isopropanol (1: 1) is used as a solvent. Fraction B luites with fraction A before and so it is clear how to separate fraction B
with a good way out.
Yield: 2 g (40% of theory); a levorotatory monoester of a cel-prolol- (R, R) -O, 0-diacetyl tartaric acid; -41.3 ° (c 1.0; di-.
chloromethane); optical purity over 98%.
2.2 g of the mixed fraction as well as 2.4 g of fraction A are purified with 10% fraction B; 0.8 g (16% of theory) of fraction A; programada monoether goalprolol- (R, R) -O, 0-diacetylvinol
l 0O
acid. p +54.5 (, 0; dichloromethane-); optical purity over 98%.
Separation of a mixture of diastereomers using thin layer chromatography; Si 60 silica gel plate,
23 8
Fa, Merck (aluminum foil); solvent isopropaiol - acetone (1: 1)
,, fraction B 0.46
-R, value - p i / -
Ifraction, 16
, 87 (10-cm area) Spectroscopic data: H - -NllP / DMSO-dg as standard, 8 (EFM); Jarian XL 200. CH tartaric acid. Fraction A: S 4.93 and 4.86 ppm (7.5 Hz). Fractions B: 8 5.50 and 5.20 ppm (6.5 Hz).
EXAMPLE 12 18.4 g (50 mmol) of (R, 5) -celiprolol, together with 9 g (55 mmol) of trichloroacetic acid, are dissolved in 100 ml of dichloromethane at room temperature. The solution is dried with magnesium sulfate. After removal of the drying agent, 23.8 g (70 mmol) of (R, R) -OJO-dibenzoic tartaric anhydride was added and the solution was stirred at room temperature. After 2 hours, the excess reagent is filtered off with suction, the organic solution is shaken twice with 50 ml of a saturated aqueous NaHCO solution and washed with 50 ml of pure water. The remaining organic phase is dried over magnesium sulphate and concentrated to dryness at room temperature. A solid amorphous residue is obtained consisting of (R) -cooTB monoesters. (S) -Celiprolol-0,0-dibenzoyl tartaric acid.
Yield: 33 g of the diastereomeric mixture (90% of the theoretical) of fractions I and TI (according to HPLC analysis there are still small portions of the reagents).
10 g of a diastereomeric mixture from fractions I and II are dissolved in 50 ml of acetone and fed to a preparative silica gel column, which is filled with 500 g of Si 60 silica gel (230-400 mesh), and with a solvent acetone-isopropanol (18: 1) are separated into fractions I and II. Fraction II elutes with a fraction of I and thus
get fraction II with a good yield. I
Yield: 4.1 g (82% of theory) of fraction II of the levorotating monoether of celipolol- (R, R) -0.0-dibenzoyl-tartaric acid, which is contaminated with 10% of fraction I. It can be obtained by repeating column separation at equal to 3.5 g (70% of theoretical) fraction II.
N: -62.6 ° (c 1.0; dichloromethane); optical purity over 98%; H-NMR
(CDClg,) TMS as internal standard, S (PPM); Varian XL 200; (K, E) -quinic acid; X 5.56 and 5.45 ppm (dt 1 7 Hz).
Separation of the diastereomeric mixture using thin layer chromatography; Silica gel plate (aluminum foil) Si 60, Fa.Merck; The solvent isopropanol is acetone (18: 1).
fraction II 0.50
R, value -: -: - tgtltg
1fraction I 0.09
55 (distance traveled 11 cm)
By thin layer chromatography, can be monitored and controlled; fraction from the column.
EXAMPLE 13 9 g (25 mmol) of (K, 3) -celiprolol, together with 5 g (60 mmol) of trichloroacetic acid, are dissolved at room temperature in 100 ml of dichloromethane. The solution is dried with magnesium sulfate. After removal of the drying agent, 9 g (80 mmol) of anhydride is added. (S, S) -0.0-diacetyl tartaric acid and the solution is stirred at room temperature. After 90 minutes, the organic solution is shaken twice in a separatory funnel with 25 ml.
: aqueous saturated solution of NaHCOg and again washed with water. After drying the organic phase with magnesium sulfate, it is concentrated to dry residue. An amorphous powder is obtained consisting of mono-esters of (R) - and (S) - -seliprolol- (5.8) -0.0-diacetyltric acid (fractions A and B), Yield; 13 g of diastereomeric mixture (85% of theoretical value). This diastereomeric mixture can be analogously to example 1 divided into its optical anti-pitch, and in reverse
(R, R) -cooTB. (8.3) -0.0-diacyl, dialkyl, as well as dibenzylvinic acids and their anhydrides, used in various examples, were prepared according to known methods.

five
0 5 0
0
five
telnosti. Fraction B, which is eluted before Fraction A, is a converting monoether of target prolol- (S, S) -0.0-diacetyl tartaric acid, and is an isomer, namely, a left handed monoester of target prolol- (S, S) -O, O-diacetyl tartaric acid.
Fraction B of Example 11 and Fraction B of this Example are enantiotropic (as well as Fractions A and A), i.e. they show the same chromatographic properties in non-chiral chromatographic systems. Separation by column chromatography and conditions as in Example 11. I.
Yield: 1.9 g (38% of theoretical) fraction B of the target rotation monoether of objective (S, S) -0.0-diacetyl tartaric acid.
ty t ol
W = 40.9 ° (c 1.0; dichloromethane).
Thin-layer chromatographic separation of a diastereomeric mixture: silica gel plate (Alu folie) Si 60, FafMerck solvent isopropanol - acetone (1: 1); 11 cm distance traveled
 . - fraction В 0.46, then,
R. The value is - about -yy, about /, about 7.
± Fraction AO, ID
Example 14. From the p-blockers below, similarly to examples 1-3, as well as 11 and 12, receive monoethers of (R, R) -0.0-diethyl tartaric acid. The separation followed through the Reversed-phase - HFLC.
Chromatography system for separation: a column as in Example 6; mobile phase: 0.1 M phosphoric acid, aqueous WJ set at pH 3.6, and MeOH 50:50.
TO
eleven
Example 15. Similarly, the example, ru 11 (K, 8) -celiprolol turn
with anhydride (K, E) -0.0-di (p-dichloro-vinyl) -tartaric acid. Separation follows through the Reversed phase — HPLC,
Chromatography system for separation: a column as in Example 6; mobile phase: 0.1 M phosphoric acid, using aqueous concentrated NH, adjusted to pH 3.6, and MeOH 40:60.
to; 1.58; Kg 2.63; about 1.66.
Example 16: By analogy with Example 1, (K, 8) -propranolol is reacted with (E, K) -0.0-diacetyl tartaric acid, after which the resulting isomeric mixture of diasteresomeric monoesters ( R) - n (S) -npo-pranolol and (K, K) -0.0-diacetyltartic acid is treated. When conducting separate interactions, solvents and acids were used as protective groups (see Table 1),
When using di: ethyl ether as a solvent and as a result of its subsequent removal, (2) (2) is obtained
(2) (10)
Acetone (3)
Acetonitrile (3)
Acetonitripe (3)
Tetrahydrofuran (15)
977Z3-12
whether a viscous residue that forms a melt. In this melt. Interaction proceeds with a yield of more than 85%.
5 Example17. By analogy with example 1, (R, B) -propranolol is reacted with the substituted (R, R) -0.0-β-tartaric anhydride specified in Table 2, with 1,2-dichloro used as the W solvent. -; ethane, and trichloroacetic acid is used as a protective group. The separation of the isomeric mixture of the diastereomeric J5 monoesters of propranolol and (R, R) -0.0-disubstituted tartaric acids formed by the analogy with Example 6 via the Reversed phase — HPLC.
Chromatographic separation system 20:
Column 250-4.0 mm, 1, D. Polygo-sil Rp 18.7 microns; mobile phase: a) 2% acetic acid in bidistilled water, adjusted to pH 3.7 with ammonia (pH 50) and ammonia; B) the same components as willow) (30:70 ratio).
Table 1
vinegar
acid
(3)
3
3
50 50
75 80
(3)
50
70

50
85
but )
but )
B)
B)
B)
B)
B)
table 2
2.2
3-, 3
1.85
6.3
eleven
1.74
1.82
3.36
1.85
1.18
1.82
1.54
1.82 2.82 1.55
9
1.95
3.45
1.77
1.11
2.44
2.2
17
(s 0.534; dichloroethane), 25 c
I2) 7V ,. G that
royl tartaric acid
Anhydride (R, R) - -0.0-diphenylacetyl-tartaric acid
Anhydride (R, R) - -0.0-ditrimethyl-acetyl tartaric acid
R, R-di-0-tert-Ivic acid anhydride is prepared by the following method.
14 h ill i
W 546 51.2
(from 0.506;
dichloroethane)
W "-39.7 °
(from 0.494; dichloroethane)
ten
11 t (ieHU .-- /, | h Ul i COMP -PPTTOCH Mperature with the German nic TOTon Bands 98% l with yields 85% of t.oretimrsk (1 - 8.32 ps (from 1.0 in 95% ). °
Optically pure alkanolamines of formula 111 can also be prepared in such a way that the mixture of diastereomeric tartaric monoesters of formula I is subjected to stereospecific (pH controlled) hydrolysis or stereospecific enzymatic hydrolysis. However, the path through the section
The optically pure monoesters of vin-10 g of (R, R) -BHH-jjj hydrochloric acid dimethyl ester are mixed in 140 ml of ethylene glycol dimethyl ether in a flask to work under pressure with 40 ml of isobutane and 3 ml of concentrated sulfuric acid, after which the mixture Hold at shaking for 48 hours at room temperature. After neutralizing the mixture with a dilute solution of potassium hydroxide
acids of formula I are preferred. since the optically pure tartaric monoesters of formula 1 are particularly convenient as starting materials for optically production.
20 pure forms of free alkanolamines, since they have very different chemical and physical properties. This difference allows us to simply divide them into
extraction is carried out with ether and the product is recrystallized from petroleum ether.
5 g of the resulting bisether (mp. 68 ° C) is heated in 80 ml of 50% di methylsulfoxide with 3 g of hydroxide capi for 3 hours at 100 ° C. After acidification, extraction is carried out with ether, the solution is washed with water, and after drying, it is mixed with an equimolar amount of dicyclohexylcarbodiimide. After 2 hours of stirring at room temperature, the resulting dicyclohexylmode is separated off. Using other alkanolamine derivatives — optically active amides — also reduces the yield and
the chevines, the ether is distilled off in vacuum, after which the residue is recrystallized to a degree of racemization over cuei from n-hexane. Pure anhydrous conditions for the decomposition of amides are obtained. The pvd (R, R) -0.0-di-tert-butyl tartaric acid cfoiJI g is +107.3 (with 0.996; dichloroethane).
EXAMPLE 18 The hydrolytic cleavage of (R) -propanolol- (R, R) - -0.0-diacetyl tartaric acid monoether is carried out with a methanolic solution of sodium hydroxide at room temperature, the reaction time is 1 hour. Pure (R) - (+) - Priborolol
LOL
 MD + 8.33 ° (with 1.0 in ethanol
95%) with 98% optical purity and 88% yield. In the same way, for example, S-propranolol can be obtained from (S) -propranolol- (R, R) -O, 0-diacetyl-tartaric acid monoether by treating methanol hydrochloric acid difference from amides; the use of this method leads to the compound easily solvolitically uncoupling 45 under mild conditions.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining optically pure 50 monoesters of tartaric acid and optics of active alkanolamines of the general formula G
55
A-C-CHe-NH-Ro
ORj
) 7V ,. G that
14 h ill i
ten
11 t (ieHU .-- /, | h Ul i COMP -PPTTOCH Mperature with the German nic TOTon Bands 98% l with yields 85% of t.oretimrsk (1 - 8.32 ps (from 1.0 in 95% ). °
Optically pure alkanolamines of formula 111 can also be prepared in such a way that the mixture of diastereomeric tartaric monoesters of formula I is subjected to stereospecific (pH controlled) hydrolysis or stereospecific enzymatic hydrolysis. However, the path through separation of the optically pure monoesters of the wiened acid of formula I is preferable, since the optically pure tartaric acid monoethers of formula 1 are particularly convenient as starting materials for optically producing.
20 pure forms of free alkanolamines, since they have very different chemical and physical properties. This difference allows them to be easily divided into
25 optically pure compounds by selective crystallization, extraction or chromatography.
In contrast to this method, the use of salt formation of racemic alkanolamines with other optically active acids, for example with L-glutamic acid (by a known method), leads to compounds whose separation requires many
35 crystallization steps, which is not profitable and reduces the yield,
The use of other alkanolamine derivatives - optically active amides - also reduces the yield and eliminates the degree of racemization beyond the harsh conditions of the breakdown of amides, V
It expresses the degree of racemization of cuei harsh amide decomposition conditions,
Unlike amides, the use of this method leads to compounds that are easily solvolitically uncoupling 45 under mild conditions.
Invention Formula
The method of obtaining optically pure 50 monoesters of tartaric acid and optically active alkanolamines of General formula G
55
A-C-CHe-NH-Ro
ORj
where A is 4-nitrophenic, 1-naphthyl-hydroxymethyl or 4-indolyl-1-methyl. residue or substituted phenoxyl residue of general formula 11
K.CH UO-CH;
 Yats
de R- - methoxyethyl residue or
W
15
the residue HN-aurih, wherein acyl represents an alkanoyl residue containing 1 to 4 carbon atoms, or a dialkylcarbamoyl residue in which the alkyl moiety contains 1 or 2 carbon atoms;
RJ is a hydrogen atom or residue
R is a hydrogen atom or a branched alkyl residue with 3 or 4 carbon atoms;
R is the residue of dis-substituted (R, R) - 25 or (S, S) -tartaric acid of formula 111
20
HOOS - CH - CH - CO f I ORy OR
moreover, Rj is an alkyl radical with 1-4 carbon atoms, a benzyl residue, D, / -dichlorovinyl residue, an alkanoyl residue with 1-5 carbon atoms Editor M. Kelemesh
Compiled by L, Joffe
Tehred M. Khodanich Proofreader L. Patay
Order 800/64 Circulation 372Subscription
VNISh State Committee of the USSR
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
yes, containing in some cases a chlorine atom, a benzoyl, toluoyl or phenacetyl residue as a substituent,
or their salts, characterized in that the mixture of optical antipodes of the formula IVA-CH-CHo-l H-Ro
Ibg
HE
15
20
where A and RJ have the indicated meanings and aM4 | iorpynna can be protected, reacted in the melt or in an aprotic solvent with a di-substituted (R, R) - or (8,8-tartaric acid of the formula V
Noos-CH-CH-COOH
OR5 OR5
 where Rj has the indicated values or with its anhydride, provided that a condensing agent is used when reacting with the free acid, the resulting mixture of diastereomeric tartaric acid monoethers of the formula I is separated, the protective group is removed if necessary and the desired product is isolated as free compound or salt.

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

GB2036744A|1980-07-02|Eburnane derivatives

---

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---

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---

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---

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---

SU396326A1|1973-08-29|METHOD OF OBTAINING M-SULPHENYL SUBSTITUTED CARBAMINIC ACID ESTERS

---

Yoshikawa et al.1989|Pahutoxin: synthesis and determination of its absolute configuration

---

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---

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---

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---

Liang et al.2016|Efficient Synthesis of Glycosylated Matijin‐Su Derivatives via Ultrasonic Irradiation

同族专利:

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公开号 | 公开日

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FI843148A0|1984-08-10|

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IL72634D0|1984-11-30|

---

FI84910B|1991-10-31|

---

DK395884D0|1984-08-17|

---

IL72634A|1987-12-20|

---

AU3176284A|1985-02-21|

---

EP0135162A3|1986-04-16|

---

NO159083C|1988-11-30|

---

CS271307B2|1990-09-12|

---

EP0135162B1|1990-04-04|

---

EP0145840A1|1985-06-26|

---

FI843148A|1985-02-20|

---

FI84910C|1992-02-10|

---

YU45646B|1992-07-20|

---

AT51614T|1990-04-15|

---

AT26974T|1987-05-15|

---

HU193587B|1987-10-28|

---

NO159083B|1988-08-22|

---

DE3330005A1|1985-02-28|

---

AU573242B2|1988-06-02|

---

ZA846225B|1985-03-27|

---

RO91183A|1987-07-30|

---

GR82176B|1984-12-13|

---

DK395884A|1985-02-20|

---

RO91183B|1987-07-31|

---

PL146074B1|1988-12-31|

---

EP0145840B1|1987-05-06|

---

JPS6048954A|1985-03-16|

---

DE3463500D1|1987-06-11|

---

NO843285L|1985-02-20|

---

CA1239646A|1988-07-26|

---

DD231068A1|1985-12-18|

---

ES535243A0|1985-10-16|

---

PT79044B|1986-08-12|

---

HUT34949A|1985-05-28|

---

YU142784A|1988-04-30|

---

PT79044A|1984-09-01|

---

PL249228A1|1985-05-21|

---

DK151892A|1992-12-18|

---

ES8601098A1|1985-10-16|

---

CS625184A2|1989-04-14|

---

EP0135162A2|1985-03-27|

---

US4652672A|1987-03-24|

---

DE3481839D1|1990-05-10|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

NL300886A|1962-11-23|

---

US3541130A|1967-02-06|1970-11-17|Boehringer Sohn Ingelheim|1--2-hydroxy-3-tert.-butylamine propanes|

---

CH635573A5|1977-03-24|1983-04-15|Sandoz Ag|Process for preparing novel 1,2-dihydroxypropane derivatives|

---

GB8315495D0|1983-06-06|1983-07-13|Sumitomo Chemical Co|Fungicidal aniline derivatives|EP0355583B1|1988-08-10|1995-01-25|Otsuka Pharmaceutical Co., Ltd.|Cardiotonics|

---

US5198448A|1988-08-10|1993-03-30|Otsuka Pharmaceutical Company, Limited|Cardiotonics|

---

AU5546490A|1989-04-24|1990-11-16|Wilhelm Fleischhacker|Enantiomer-free 1,2-aminoalcohols acetalically protected on the oxygen, their production and use|

---

JPH0674243B2|1989-12-27|1994-09-21|ダイソー株式会社|Optically active atenolol salt with high optical purity and process for producing atenolol|

---

FI93833C|1992-05-14|1995-06-12|Orion Yhtymae Oy|Process for the preparation of propionic acid derivatives|

---

US20040259912A1|2001-09-28|2004-12-23|Takahiro Matsumoto|Benzine derivatives, process for preparing the same and use thereof|

---

JP2005104895A|2003-09-30|2005-04-21|Nippon Kayaku Co Ltd|Method for preparing optically active amino alcohol compound|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3330005A|DE3330005A1|1983-08-19|1983-08-19|TONIC ACID MONOESTERS OF OPTICALLY ACTIVE ALKANOLAMINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE|

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