Method of obtaining optically active alpha-arylalkinic acid or its pharmaceutically acceptable sodiu

专利摘要:
Pharmaceutically useful optically active a-arylalkanoic acids of the formula where Ar is aryl and R1 is alkyl or cycloalkyl or esters,ortho esters, or amides thereof are stereoselectively prepared by contacting a reagent of the formula Ar-MX, (Ar) 2M or ArM' where M is Cd, Cu(II), Mn(II), Mg or Zn, and M' is Cu(I) or Li, and X is halogen, with an optically active compound of the formula where Z is a leaving group and Y is halogen, acyloxy or where R' and R" are alkyl, aryl or with N are a heterocyclic group, to form the optically active ketone of the formula which is ketalized and rearranged to said acid, ester, ortho ester or amide. Alternatively, said ketone is reduced to the corresponding alkanol, which is rearranged to the a-arylalkanal. The alkanal so produced is converted to said acid by conventional methods.
公开号:SU1577694A3
申请号:SU823524059
申请日:1982-12-10
公开日:1990-07-07
发明作者:К.Шлемер Джордж
申请人:Синтекс Фармасьютикалс Интернэшнл Лимитед (Фирма)；
IPC主号:

专利说明:

The invention relates to an improved method for producing optically active oЈ-aryl-alkanoic acid of the formula
ch3
jp5r v-CH-COOH CH30 (I)
or its pharmaceutically acceptable narium salt or its C-C4 alkyl or C | -C4-hydroxyalkyl ester, which have biological activity and are used in medicine and agriculture.
The aim of the invention is to simplify the process.
This goal is achieved by treating a catalytic agent with an optically active compound of formula
ABOUT
 II
C-CH-CH3 Z
sngo
(Ii)
where —Z is hydroxy, acetoxy, halogen, or a group of the formula -, where R is C —C-alkyl, phenyl, unsubstituted or substituted by.-alkyl, obtained by reacting an organometallic compound of the formula
MX
or
CH30
(Ii) magnesium or
1 (III)
manganese
zinc;
chlorine or bromine, ski active compound
°
sns-sn-ci
Z
(Iv)
has the indicated meanings; halogen or group
/ -N
Xj
OR
in an inert solvent at a temperature of from 0 to -70 ° C, and either tri- (C1-C4 alkyl chloroformate and the compound of formula (II) are treated as the ketalizing agent in the presence of an acid catalyst in an alcohol solvent at a rate of
The reaction temperature is from 0 ° C to the reflux temperature of the reaction mixture, or a diatomic alcohol with 2 to 8 carbon atoms, and the compound of formula (II) is treated in an inert solvent at a temperature from 0 ° C to the reflux temperature of the reaction mixture, in order to charge ketal formulas
five
CH30
0
five
0
five
five
Where
N
0
five
0
C, -P-alkyl or R2 and R
taken together mean
Cr-Cd-alkylene; Z has the indicated meanings
or an alkali metal alkoxide is used as the ketalifying agent, and the corresponding ketal obtained in this case is reacted with the corresponding acid halide to obtain a compound of formula (V), and the rearrangement of the ketal by solvolysis in a protein or polar aprotic solvent in the presence of a base is carried out at 90 A) 50 ° С, or a lexe grouping of the ketal of formula (V) is carried out by treatment with an agent having an affinity for oxygen, in an aprotic solvent at teperature from a compound, to reflux temperature of the reaction mixture.
| Example 1, 120 g of (3) ethyl acetate and I20 g of triethylamine are dissolved in 500 ml of toluene with stirring, after which the solution is cooled to approximately 10-15 ° C. Then, 120 g of methanesulfonyl chloride is slowly added over a period of 5 hours while maintaining this temperature. The formation of triethyl amide hydrochloride is observed as a precipitate. The solution is then allowed to warm to 20 ° C, after which it is poured into water. The aqueous and organic layers were separated, and the organic layer was dried over magnesium sulfate and evaporated. The residue is distilled at about 110 ° C under a pressure of 2 mmHg to obtain 161 g of (S) - ethyl 2-methanesulfonyloxypropionate exhibiting optical rotation.
 ,
This compound exhibits
characteristic NMR spectrum, Ј; 1.28 (triplet, J-2,2); 1.57 (doublet, J-2,3);
3.12 4.23 (quartet, J-2.2); 5.12 (quartet, J-2,3).
Example 2 A solution of 75 g of (S) ethyl 2-methanesulfonyloxypropionate in 250 ml of methanol and 100 ml of water is cooled to approximately 15 ° C. A 40% aqueous solution of sodium hydroxide is slowly added to maintain the pH to 10.5. In view of the fact that the reaction proceeds with a sharp drop in pH, it is necessary to continue adding sodium hydroxide solution until the pH value starts to fall slowly or mostly remains constant. Thereafter, concentrated HC1 is added until a pH of 1.9 is reached. The methanol is then removed under reduced pressure and the remaining aqueous layer is extracted with methylene chloride. The resulting organic extract is evaporated to give 49 g of oily (3) -2-methanesulfonyloxypropionic acid with optical rotation G ° 0r5
 -53.3 °.
EXAMPLE 3 84.85 g of (5) -ethyl2-methanesulfonyloxypropion is dissolved in a solution of 180 ml of methanol and 80 ml of water. The solution thus obtained is cooled to -15 ° C. Then, to maintain a pH of about 10.5 or below, a 35% aqueous solution of NaOH is slowly added. Adding it is continued until the pH remains constant. Thereafter, concentrated HCl is added to acidify the solution to pH 1.8. Methanol is then collected under reduced pressure. The aqueous layer was extracted several times with ethyl acetate and the resulting organic extracts were dried under magnesium sulfate. Evaporation of the organic extract to dryness yielded 51 g of (5) -2-methanesulfonyl oxipropionic acid with optical rotation in methylene chloride cl, -54 °. This compound after crystallization from toluene has so pl. 72-75 ° C and characteristic NMR spectra, 0; 1.62 (doublet, J-2,3); 3.09, 5.11 (quartet, J-2,3).
Example 4. A mixture containing 40 g of (8) -2-methanesulfonyloxypropanoic acid, 32 g of thionyl chloride and one drop of dimethylAormamide is heated to approximately 50 ° C, at which gas evolution is observed. The mixture is slowly heated to 70 ° C, which is held for 1 hour. After over-, racing at 11 ° C under pressure
5 1Q 20
five
five
five
0
five
0
0
1.5 mmHg 31.2 g of (S) -2-methanesulfonyloxypropionyl chloride are obtained with optical rotation in methylene chloride OH 2t -36.9. The compound has
about
characteristic NMR spectra, 0: 1.68 (doublet, J-2,3); 3.15, 5.25 (quartet J-2.3).
Example 5: Proceed as described in Example 4, but using an equivalent amount of thionyl bromide, (S) -2-methanesulfonyloxypropionyl bromide is obtained.
Example 6. An addition, as indicated in Example 1, but using an equivalent amount p of toluene sulfonyl chloride, heating the mixture for 8 hours at 60 ° C and then, as indicated in Examples 3 and 4, gives (S) -2-p-toluenesulfonyloxypropionyl chloride . This compound exhibits optical rotation c (J2 -32 ° in chloroform and characteristic NMR spectra, S: 1.8 (trig, .plet, J-2.2); 1, A8 (doublet, J-2) ; 2.45, 4.13 (quartet, J-2.2); 4.96 (quartet, J-2); 7.28-8.03 (multiplet),
Example 7. Replacement of methanesulphonyl chloride in example 1 with the appropriate amount of benzenesulfonyl chloride and work first in example 1 with heating at 30–40 ° C for 5-6 h and then in examples 3 and 4, respectively, are obtained (8 ) -2-Benzenesulfonoxypropionyl chloride.
Example 8 Using the appropriate amount of (P) ethyl ethyl lactate and working as in Example 1 and then in Examples 2 and 4, (I) -2-methanesulfonyloxypropionyl chloride is obtained.
Example 9. 0g 2-bromo-6-metroxy-naphthalene, dissolved in 40 ml of tetrahydrofuran (THF), is slowly added to 3.6 g of metallic magnesium at the reflux temperature of THF (about 60-62 ° C). After the addition is complete, the mixture is stirred at reflux temperature for about 1 hour, after which excess magnesium is filtered. The result is a solution of Grignard compound ((6-methoxy-2-naphthyl) -bromide magnesium in TFH).
Example 10. A solution of (6-metroxy-2-naphthyl) magnesium bromide, prepared in Example 9, is slowly added to 8 g of (8) -2-methanesulonyloxy-propionyl chloride dissolved in 40 ml of THF, cooled to - iO ° C, and
maintain the temperature of the mixture at about
reactionary mixture
40 ° H
stir for another 1 h at this temperature, then it is poured into 200 ml of 5% hydrochloric acid. Then 100 ml of ethyl ether is added to the reaction mixture. The precipitate was filtered and washed with 30 ml of ice-cold ethyl ether to give 6.46 g of (8) -2-methanesulfonyloxy-1- (6-methoxy-2-naphthyl) -propan-1-one with a mp. 149-151 C and optical rotation in chloroform -33 °. This compound has characteristic NMR spectra in deuterium chloroform, b: 1.65 (doublet, J-2,1); 3.10, 3.9, 6.17 (quartet, J-2.1); 8.55-7.10 (multiplet).
Example 11. Using an equivalent amount of (8) -2-p-toluene sulfonyloxypropionyl chloride in the example of Example 10 with the coupling reaction at -78 ° C, receive (8) -1- (6-methoxy-2-per-methyl) - 2-p-toluene-sulfonyloxy-propane-1-one; mp. 117- 119 ° C, VJ25 + 24.2 ° in chloroform. (This compound has characteristic NMR spectra, S: 1.67 (doublet, J-2.2); 2.37, 3.98, 5.92 (quartet, J-2.2); 7.14-8 , 44 (multiplet),, Example 12. Using an equivalent amount of (8) -2-benzenesulfonyl-oxypropionyl chloride in the formulation of Example 10, (8) -2-benzene-sulfonyloxy-1- (6-methoxy-2- naphthyl) - propan-1-one
Example 13. Using an equivalent amount of (K) -2-methanesulfonyloxypropionyl chloride in the formulation of Example 10, (K.) t-2-methane sulfonyloxy-1- (6-methoxy-2-naphthyl) propane is obtained. 1-on.
Example 14. Apply an equivalent amount of (K) -2-p-toluenesulfonoxypropionyl chloride in the intake according to
Example 10, receive (K) -1- (6-meth-hydroxy-2-naphthyl) -2-p-toluenesulfonyl-g hydroxypropan-1-one.
Example 15 By using the appropriate amount of (K) -2-benolsulfonyloxypropionyl chloride in the method of Example 10, (K) -2-benzenesulfonyloxy-1- (6-methoxy-2-naphthyl) -propan-1-one is obtained
Example 16. A suspension of 4.6 g of (8) -2-methanesulfonyloxy-1- (6-labels si-2-naphthyl) -propan-1-one in 50 ml of methanol is treated with 50 g of trimethyl ortho formate and 2 g of concentrated sulfuric acid. The mixture is then heated to approximately 55 ° C and maintained at this temperature for 15 hours. The mixture is then cooled and poured into an aqueous solution of sodium bicarbonate and extracted with 120 ml of diethyl ether. The organic layer is then separated, dried over magnesium sulfate and filtered. By evaporation of the ether under reduced pressure, 4.8 g of (8) -1,1-dimethoxy-1- (6-methoxy-2-naphthyl) prop-2-yl-methanesulfonate are obtained with a mp of P2-115 ° C. , optical rotation of -23.9 ° (C-1, chloroform) and NMR spectra in deuterochloroform, 6: 9.0 (doublet, J-2); 6.85, 6.70, 6.61, 6.07, 4.89 (quartet, J-2); 1.99 2.88 (multiplet).
Example 17 To a solution of 7 g of sodium acetate D with 50 ml of acetic acid, 3 g of (8) -1,1-dimethoxy-1- (6-methoxy-2-naphthyl) prop-2-yl methanesulfonate is added. Then the resulting mixture is heated to 110 ° C for one and a half hours and poured into 300 ml of water. The resulting precipitate is filtered and washed with methanol to obtain (8) -methyl- 2- (6-methoxy-2-naphthyl) -propionate with m.p., P5-87 ° C and optical rotation of + 65.4 ° (C- 1, chloroform), The substance has an optical purity of about 92%.
Example 18. Using the appropriate amount of (8) -1- (6-meth-c and-2-naphthyl) -2-p-toluenes ulfonyl-hydroxypropan-1-one in example 16, you get (8) -1, -dimethoxy -1- (6-methoxy-2-naphthyl) -prop-2-yl-p-toluenesulfonate. By treating this substance as indicated in Example 17, (8) -methyl-2- (6-methoxy-2-naphthyl) propionate is obtained
Example 19. Applying the appropriate amount of (8) -2-benzenesulfonoxy-1- (6-metoxy-2-naphthyl) -propan-1-one in Example 16 and working, as indicated, is obtained (8) - 1,1-Dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-yl-benzenesulfonate. By working out this substance, as indicated in Example 17, (8) -methyl-2- (6-methoxy) - 2-naphthyl) -propionate.
Example 20. (K) -2-methanesulfonyloxy-1- (6-methoxy-2-naphthyl) -propan-1-one obtained in Example 13 is treated with a 1.5 M excess solution of sodium methoxide in methanol. The mixture is then stirred for 1 hour at room temperature, after which methanol in a rotary evaporator is distilled off at 50 ° C.
machine until 80% of the methanol is removed. The resulting reaction mixture is rapidly cooled in water and extracted with methylene chloride. The organic layer was then separated, dried over magnesium sulfate, and evaporated under reduced pressure to give (S) -l, 1-dimethoxy- (6-methoxy-2-naphthyl) propan-2-ol. This substance is then dissolved in methylene chloride containing triethylamine, the reaction mixture is cooled to / v5 ° C and one equivalent of methanesulfonyl chloride is slowly added with a temperature in the range of 5-10 ° C. After the addition of methanesulfonyl chloride is complete, the mixture is stirred for another half hour. The solution is then filtered to remove the triethylamine hydrochloride crystals, and the filtrate is poured into water. The organic layer is separated and dried over magnesium sulfate. After the organic layer is evaporated under reduced pressure, (S) -I, 1-dimethoxy- (6-methoxy-2-naphthyl) prop 2-yl-methanesulfonate is obtained. The substance is treated as indicated in Example 17, after which (8) -methyl-2- (6-methoxy-2-naphthyl) propionate ”is obtained
Example 21. Replacement of (8) -2-methanesulfonyloxypropionyl chloride in Example 10 with an equivalent amount of (S) -2-chloropropionyl chloride, (S) -2- bromopropionyl chloride, (K) -2-chloropropionyl chloride and (K) -2-bromopropionyl chloride respectively, and the work, as indicated in example 10, is obtained respectively: (8) -2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one; (5) .- 2-bromo- (6-methoxy-2-naphthyl) propan-1-one; (K) -2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one and (K) -2-bromo-1- (6-methoxy-2-naphthyl) -propan 1-on.
Example 22. (5) -2-chloro-1, 1-g-diethoxy-1- (6-m-tox-2-naphthyl) propane.
A mixture of (5) -2-chloro-1- (6-methoxy-2-. Naphthyl) -propanone (10 g, 40.2 mmol), triethyl ortho formate (20 g. 135 mmol), sulfuric acid (0.4 g , 4.1 mmop) and 50 ml of absolute ethanol are heated at 45-58 ° C for 4 hours. After cooling, the resulting solution is poured into an aqueous solution of sodium carbonate and extracted with 70 ml of methylene chloride. The methylene chloride solution is dried over magnesium sulfate and the solvent is evaporated to obtain (S) -215
20
Jq 30
0
five
chloro-1,1-diethoxy-1- (6-methoxy-2-naphthyl) propane P as an oil.
(3) -2-chloro-1,1-dimethoxy-1 - (6-methoxy-2-naphthyl) propane.
A mixture of (5) -2-chloro-1t (6-methox-2-naphthyl) -propanone (10 g, 40.2 mmol) of trimethyl ortho formate (14.3 g, 135 mmol), sulfuric acid (0.4 g, 4.1 mmol) and 50 ml of methanol are heated at 45-48 ° C for 4 hours. After cooling, the resulting solution is poured into an aqueous solution of sodium carbonate and extracted with 70 ml of methylene chloride. The methylene chloride solution is dried over magnesium sulfate and the solvent is evaporated to give (8) -2-chloro-1,1-dimethoxy- 1 - (6-methoxy-2-naphthyl) propane as an oil.
(5) ethylene acetal-2-chloro-1- (6-methyl-2-naphthyl) -propan-1-one,
A mixture of (I) -2-chloro-1- (6-methoxy-2-naphthyl) propan-1-one (8 g, 32, 2 mmol), ethylene glycol (42 g, 677 mmol), monohydrate 25 p α-toluene sulfonic acid (1.3 g, 6.8 mmol) and toluene (65 ml) were heated under reflux and the layer of the NATIVE ethylene glycol solution was removed using a Dean-Stark separator. Ethylene glycol must be added to complete the reaction. Upon completion of the reaction, the reaction mixture is cooled and added to an aqueous solution of sodium carbonate with vigorous stirring. The layers are separated, and the toluene layer is dried over magnesium sulfate and evaporated to give (S) - ethylene glycol -2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one.
(5) -propylene acetal-2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one.
A mixture of (5) -2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one (South, 40, 2 mmol) of 1,3-propanediol (28 g, 368 mmol), p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol) and 85 ml of toluene are heated to reflux.
 Water is removed with a Dean-Stark type separator before obtaining the theory. ical amount. The reaction mixture is cooled and added to an aqueous solution of sodium carbonate with vigorous stirring. The layers are separated, and the toluene solution is dried over magnesium sulfate. Evaporation of the solution yields (S) -propylene acetal-2-chloro-1- (6-methoxy-2-naphthyl) propan-1-one. (S) l, 2-dimethylethylene acetal 2 chloro 1- (6-methoxy-2-naphthyl j-propane-β-one.
35
40
five
eleven
A mixture of (S) -2-chloro-1- (6-methoxy-2157769412
Example 24, (S) -l, 1-dimethocaphthyl) -propan-1-one (South, 40.2 mmol) si-1- (6-methoxy-2-naphthyl) -propan-2-2,3-butanediol (33.2 g, 368 mmol), ol. p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol) - and 85 ml of toluene
15
thirty
ol is heated to reflux. Water is removed with a Dean-Stark-type separator until a theoretical amount is obtained (approximately 8 hours). The reaction mixture was worked up as described in the previous example to obtain (S) -l, 2-dimethyl-ethylene acetal -2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one.
Using the same procedures, using the following amounts of bromoketone, one can -catalyze: (5) -2-bromo-1- (6-methoxy-2-naphthyl) -propan-1-one, (5) -2-bromo-1,1-di-20 methoxy- (6-methoxy-2-naphthyl) propane; bromeketon. (H, 8 g, 40.2 mmol); (3) -2-bromo-1,1-diethoxy- (6-methoxy-2-naphthyl) propane: bromoketone (11.8 g, 40.1 mmol); (8) ethylene acetal-2-25 bromo-1- (6-methoxy-2-naphthyl) propan-1-one: bromoketone (9.4 g, 32.2 mmol); (5) - -propylene acetal 2-bromo-1 - (6-methoxy-2-naphthyl) -propan-1-one: bromoketone (11.8 g, 40.2 mmol); (8) 2-bromo-1- (6-methoxy-2-naphthyl) -propan-1-one t1,2-dithylethylene acetal: bromoketone (11.8 g, 40.2 mmol).
i
Example 23. Optically active bromoketal or hlrrketal, prepared according to example 22, is dissolved in the indicated solvent and the required amount of catalyst is added. The reaction mixture is heated at the temperature indicated in the table for the indicated time in order to effect the rearrangement. The solution is cooled, and the amount, if appropriate, of the insoluble catalyst is filtered off. The resulting solution was washed with two portions of a 0.5 M aqueous solution of hydrochloric acid and water. The resulting solutions are dried over magnesium sulphate, filtered and evaporated to give crude (3) -aproxene esters, which can be hydrolyzed using known methods (acid hydrolysis).
Such rearrangement reactions can be carried out using chlorine chlorides,
35
40
45
50
55
(R) -2-chloro-1- (6-meth hydroxy-2-naphthyl) -propan-1-one (10 g, 40.2 mmol) and 150 ml of anhydrous methanol are introduced into the flask. This solution was kept at 2x C, and powdered sodium methoxide (4.6 g, 85 mmol) was slowly added as a solid, keeping the temperature at 25 ° C by cooling. After the addition is complete, the reaction mixture is stirred for 1 hour and poured into an aqueous solution of sodium carbonate. The organics are extracted with methylene chloride and dried over magnesium sulfate. As a result of heating the solvent, (I) - 1,1-dimethoxy-1 - (6-methoxy-2-naphthyl) propane - 2-ol with a specific angle of rotation VJ - 5.6 ° (СНгС1), so pl. 49-55 ° C.
Proceedings in the manner described, with the exception that 11.8 g of bromoketone is used, and (R -) - 2-bromo-1- (6-methoxy-2-naphthyl) propan-1-one is obtained.
Example 25. (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) -propan-2-ol is treated with a molar excess (up to l; 50%) of methanesulfonyl chloride in the presence of a molar excess of triethyl an amine (equal to a molar excess of methanesulfonyl chloride or higher) in methylene chloride to obtain (5) -1,1-dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-yl-methanesulfonate. The latter is converted into (S) -methyl-2- (6-methoxy-2-naphthyl) -propionate as in Example 17.
Example 26. (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) -propan-2-ol is treated with a molar excess of p-toluene sulfonyl chloride in the presence of a molar excess of triethyl. on a method similar to that described in example 25, to obtain (S) - 1,1-dimethoxy-2- (6-methoxy-2-naphthyl) - prop-2-yl-p-toluenesulfonate The latter is converted into (8) - methyl 2- (6-methoxy-2-naphthyl) -propionate according to the method similar to that described in Example 17.
Example 27. The process described in Example 26 is repeated, replacing p-toluene sulfo-nylchloride with benzene sulphonyl chloride, to obtain (S) -l, 1-dimetry 157769412
Example 24, (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) propan-2-ol.
0
five
0
0 5
five
0
five
0
five
(R) -2-chloro-1- (6-methyl-2-naphthyl) -propan-1-one (10 g, 40.2 mmol) and 150 ml of anhydrous methanol are introduced into the flask. This solution was kept at 2x C, and powdered sodium methoxide (4.6 g, 85 mmol) was slowly added as a solid, keeping the temperature at 25 ° C by cooling. After the addition is complete, the reaction mixture is stirred for 1 hour and poured into an aqueous solution of sodium carbonate. The organics are extracted with methylene chloride and dried over magnesium sulfate. As a result of heating the solvent, (I) - 1,1-dimethoxy-1 - (6-methoxy-2-naphthyl) propane - 2-ol with a specific angle of rotation VJ - 5.6 ° (СНгС1), so pl. 49-55 ° C.
Proceedings in the manner described, with the exception that 11.8 g of bromoketone is used, and (R -) - 2-bromo-1- (6-methoxy-2-naphthyl) propan-1-one is obtained.
Example 25. (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) -propan-2-ol is treated with a molar excess (up to l; 50%) of methanesulfonyl chloride in the presence of a molar excess of triethyl - an amine (equal molar excess of methanesulfonyl chloride or higher) in methylene chloride to obtain (5) -1,1-dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-yl-methanesulfonate. The latter is converted into (S) -methyl-2- (6-methoxy-2-naphthyl) -propionate as in Example 17.
Example 26. (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) propan-2-ol is treated with a molar excess of p-toluene sulfonyl chloride in the presence of a molar excess of triethylamine-. on a method similar to that described in example 25, to obtain (S) - 1,1-dimethoxy-2- (6-methoxy-2-naphthyl) - prop-2-yl-p-toluenesulfonate The latter is converted into (8) - methyl 2- (6-methoxy-2-naphthyl) -propionate according to the method similar to the method described in example 17.
Example 27. The process described in Example 26 was repeated, replacing p-toluenesulfonyl chloride with benzeneulfonyl chloride, to obtain (S) -l, 1-dimethoxy 1- (6-methoxy-2-naphthyl) -prop- 2-yl-benzenesulfonate. The latter is converted into (5) -methyl-2- (6-methoxy-2-naphthyl) propionate according to Example 17.
Example 28 A solution of 6 ml of anhydrous methylene chloride and 1.0 mmol of (S) -1,1-dimethoxy-1- (6-methoxy-2 naphthyl) prop-2-yl-p-toluenesulfonate is added dropwise. to a stirred mixture of 0.20 ml of iodotrimethylsilane and I drops of cyclohexene in 8 ml of anhydrous methylene chloride at room temperature under argon atmosphere. A mixture of pepolucha 22 g of a colorless liquid. NMR analysis confirms the identity of the desired product.
Preparation of 1 - (-) - oЈ-acetoxy-1 (b-methoxy-2-naphthyl) -propan-1-one.
14.8 g of 1 - (-) - oЈ-acetoxypropionyl chloride is dissolved in 90 ml of THF and cooled to -30 ° C. 70 ml of a 1.28 M THF solution prepared from 2-bromo-6-methoxy-naphthalene are added to this solution in TO over 4 hours. Upon completion of the addition, an additional 100 ml is added.
product can be obtained at yield 70
0
dyes and 70 ml of ethyl ether. The layers are stirred for 1 hour at room temperature. The J5 is separated, the solvent is evaporated, after which 10 ml of saturated semi-solid product are added. Pure whelp aqueous sodium bicarbonate. The organic and aqueous layers are separated. The organic layer is then further washed with 5 ml of 10% aqueous sodium thiosulfate, 5 ml of water, 5 ml of aqueous sodium bicarbonate and 5 ml of water. Orga20
and a melting range of 114-115 With recrystallization from methanol. The NMR shift studies indicate complete preservation of optical purity.
The baking layer is then dried with magnesium sulfate and, after evaporation of the solvent, (5) -methyl-2- (6-methoxy-2-naphthyl) propionate is obtained.
I Example 29. As in example 28, (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-or-p-. Toluene sulfonate is converted to (S) methyl -2- (6-methoxy-2-naphthyl) -propionate.
Example 30. As in Example 28, (S) -l, 1-dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-yl-benzene sulfonate is converted to (5) -methyl-2- (6-methoxy-2-naphthyl) propionate.
Example 31. Getting - (-) - Ot-acetoxypropionic acid.
50 ml (50%) of 1 - (-) - sodium lactate is diluted with 40 ml of water and cooled to 20-22 ° C. Then 40 g of acetic anhydride are added dropwise during the SC, stirring then at 20 ° C for another 1 hour. The resulting aqueous solution was extracted three times with methylene chloride in 150 ml portions. The ec-, strata are dried over magnesium sulphate and evaporated, the product is distilled at 190-НО ° С / 2 mm rost. Yield 90% 1 (26.5 g).
Preparation of 1 - (-) - s (gacetoxypropionyl chloride „
24.5 g of 1 - (- 3 - # - acetoxypropionic acid is treated with 25 g of thionyl chloride and 4 drops of DMF. The mixture is heated to 35 ° C and finally to 50 ° C until gas evolution ceases. The product is distilled at 110 C / 25 mm Hg,
receiving 22 g of a colorless liquid. NMR analysis confirms the identity of the desired product.
Preparation of 1 - (-) - oЈ-acetoxy-1 (b-methoxy-2-naphthyl) -propan-1-one.
14.8 g of 1 - (-) - oЈ-acetoxypropionyl chloride are dissolved in 90 ml of THF and cooled to -30 ° C. 70 ml of a 1.28 M THF solution prepared from 2-bromo-6-methoxy-naphthalene are added to this solution over 4 hours. At the end of the addition, another 100 ml is added to the product can be obtained in 70% yield
0
dyes and 70 ml of ethyl ether. The layers are separated, the solvent is evaporated to give a semi-solid product. Clean
and a melting range of 114-115 ° C by recrystallization from methanol. The NMR shift studies indicate complete preservation of optical purity.
Hydrolysis of acetate to - (-) - cЈ-hydroxy-1- (6-methoxy-2-naphthyl) -propan-1-one.
The above acetate in an amount of 18.2 g is dissolved in 70 ml of THF and 30 ml of water. Then at room temperature 4tl g of sodium hydroxide is slowly added, the reaction mixture is stirred for 5 hours at 25 ° C.
five
phases are separated. By evaporation of the solvent, an oil is obtained, which according to NMR spectroscopy is 1 - (-) -pi-hydroxy-1 - (6-methoxy 2-naphthyl) propan-1-one. Yield 95%.
Example 32. Obtaining 4-J (S) - Ci-2-hydroxy-1-oxopropyl-morpholine,
A three-neck flask with a capacity of 250 ml, containing a rotating magnetic stirrer, is equipped with a thermometer and distillation head, then purged with nitrogen. 100.00 g (0.8465 mol) of ethyl-L - (+) - lactate and 73.75 g (0.8465 mol) of morpholine are added. The mixture is heated for 30 hours at A5 ° C to remove ethanol, then heated for 24 hours at a temperature ranging from 124 to. 113.45 g of product is obtained by vacuum distillation as a very pale yellow.
0 oils with so kip. 147-175 ° C (large portion 162-170 ° C) at 20 mm Hg. The yield is 84.2%.
Preparation of 4-l (S) -0Ј-2 (1-ethoxyethoxy) -1-oxopropyl-morpholine.
A three-necked 250 ml flask containing a rotating magnetic stirrer is equipped with a thermometer and an addition funnel, then purging with nitrogen. Then add 2.5 mm.
(0.0325 mol) of trifluoroacetic acid and 81.11 g (0.5095 mol) of 4- (S) -2-hydroxy- (1-hydroxypropyl) 1-morpholine, followed by the addition of 20 ml of ethyl 4 ether to facilitate mixing. 58.5 ml (0.6117 mol) of ethyl vinyl ether are placed in an addition funnel, added at 80 ° F for 80 minutes. The mixture is stirred for an hour and a half at 17 ° C and again for an hour and a half at 25 ° C. The black-red mixture is diluted with 250 ml of methylene dichloride and then washed with saturated aqueous solution.
15

7694
ten
New acid and 400 ml of toluene are heated to reflux. The azeotrope of toluene, water and ethylene glycol is then removed. After cooling, water and ethylene glycol are separated and removed with a Dean-Starc separator. The reaction mixture is azeotropically dried for 5 hours, after which it is cooled. The cooled mixture is drunk in an excess of aqueous sodium bicarbonate. The toluene layer is separated and dried over magnesium sulfate.
Toluene is evaporated, and solid residue
sodium bicarbonate followed by drying and the current is stirred in methanol, filtered with anhydrous potassium carbonate. Due to vacuum distillation, 83.54 g of a yellow oil are obtained. 97- 104 ° C at 0.2-0.4 mm Hg, quickly becoming soft brown. By repeated distillation from potassium carbonate, 70.89 g of a pale yellow oil of the central fraction were obtained, b.p. 104-1 О6С 0.3 mm Hg „st. Yield 60.2%.
Preparation of 1 - (-) - Ј 6-hydroxy-1- (b-meth-hydroxy-2-naphthyl) -propan-1-one.
A 250-ml three-neck flask containing a magnetic rotating stirrer is equipped with a reflux and a (S) -1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxy-propane-α-ethylene acetal with optical rotation GoO1 +6 is obtained, 1 ° (, chloroform) and 20 characteristic NMR spectra in deutero-chloroform, about: 1.35 (doublet, J-2), 2.78, 3.83, 3.98-3.68 (multiplet); 4.28-4.0 (multiplet) J 4.98 (quartet, J-2); 8-7 (multiplet),
Example 34. 6.4 g of (5) -1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxypropane 1-one-ethylene acetal, 60 ml of 1,2-diethoxyethane, 50 ml of water are placed in a suitable autoclave. and 3 g of carbonate
25
lump and dropping funnel, then heating on calcium, mixture with stirring f
with simultaneous purging with nitrogen. The R flask was introduced to 20.00 g (0.0865 mol) of 4- (5) -2- (1-ethoxyethoxy) -1-oxoprop-morpholine and 70 ml of THF obtained by distillation with sodium. 60 ml of THF and 2-bromo-6-methoxynaphthalene Grignard in the amount of 1.2 M THF, 74.0 ml, 0.0888 mol are placed in an addition funnel. The flask is cooled in an ice bath and the Grignard solution is added for 55 minutes. The cooling bath is removed, the solution is allowed to slowly warm to 20 ° C over 45 minutes. The mixture is stirred for one and a half hours at 20–22 ° C, followed by the addition of 200 ml of 1 N hydrochloric acid at 20–25 ° C. While stirring for 2 hours, the mixture was extracted with toluene three times in 200 ml portions, the combined extracts were washed with brine, and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, 19.92 g of a crude product is obtained in the form of a reddish oil, which slowly cures at room temperature.
Example 33. A mixture of 90 g of ethylene glycol, 30 g of (5) -1- (6-methoxy-2-naphthyl) 2-methanesulfonyloxypropan-1-one, 6 g of p-toluenesulfonic monohydrate 40
It is heated at 120 ° C for 36 hours at 2.95 kg / cmg. It is then cooled and the calcium salts filtered off. Concentrated hydrochloric acid is added and the mixture is again heated in
 for 3 hours at 95 ° C. After that, 1,2-diethoxyethane is distilled off to obtain a solid, which is extracted with ethyl ether. The organic layer is extracted with aqueous sodium bicarbonate, after which the aqueous and organic layers are separated. The aqueous layer is acidified with hydrochloric acid and after filtration, (5) -2- (6-methoxy-2-naphthyl) -propionic acid is obtained, m.p., 147-1506 ° C and optical rotation + 62.2 ° in chloroform.
Example 35. Work as in Example 34 using dimethylformamide (DMF) instead of 1,2-dimethoxyethane.
 The resulting mixture is heated to 110 ° C under atmospheric pressure during the day. As a result of processing by preparative TLC, (8) -2-hydroxy-methyl-2- (6-methoxy 2-naphthyl) -propion 55 nat is obtained, which has a value of 72.5 and NMR spectra of deuterochlorine, f: 1.49 (doublet, J-2, 3) f 3.67 (multiply; 3,85, 3,89 (the quark is stirred in methanol, filter
and (S) -1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxy-propane-one-ethylene acetal with optical rotation GoO1 + 6.1 ° (, chloroform) and characteristic NMR spectra in deuterium - chloroform, o: 1.35 (doublet, J-2), 2.78, 3.83, 3.98-3.68 (multiplet); 4.28-4.0 (multiplet) J 4.98 (quartet, J-2); 8-7 (multiplet),
Example 34. 6.4 g of (5) -1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxypropane 1-one-ethylene acetal, 60 ml of 1,2-diethoxyethane, 50 ml of water are placed in a suitable autoclave. and 3 g of carbonate
 f
0
It is heated at 120 ° C for 36 hours at 2.95 kg / cmg. It is then cooled and the calcium salts filtered off. Concentrated hydrochloric acid is added and the mixture is again heated in
for 3 hours at 95 ° C. After that, 1,2-diethoxyethane is distilled off to obtain a solid, which is extracted with ethyl ether. The organic layer is extracted with aqueous sodium bicarbonate, after which the aqueous and organic layers are separated. The aqueous layer is acidified with hydrochloric acid and after filtration, (5) -2- (6-methoxy-2-naphthyl) -propionic acid is obtained, m.p., 147-1506 ° C and optical rotation + 62.2 ° in chloroform.
Example 35. Work as in Example 34 using dimethylformamide (DMF) instead of 1,2-dimethoxyethane.
 The resulting mixture is heated to 110 ° C under atmospheric pressure during the day. As a result of processing by preparative TLC, (8) -2-hydroxy-methyl-2- (6-methoxy 2-naphthyl) -propion5 nat is obtained, which has a value of 72.5 and NMR spectra of deuterochloroform, f: 1.49 (doublet, J-2,3) f 3.67 (new arm; 3.85, 3.89 (quart 7
Tet, J-2,3); 4.1 / (multiplet), 7.77-t 7.07 (multiplet).
Example 36 A solution of 20.98 mmol of (5) -2-methanesulfonyloxypropionic acid, 20.95 mmol of triethylamine and 48 ml of anhydrous THF is prepared in a dry vessel under nitrogen atmosphere and cooled to -30 ° C. Then the solution is stirred at -30 ° C for 5 minutes, after which 231.23 mmol of trimethylacetyl chloride are added, resulting in a white precipitate. Then the mixture is heated to -20 ° C and stirred at this temperature for 30 minutes. The resulting white suspension is cooled to -70 ° C and 20.98 mmol of the Grignard reagent obtained from 2-bromo-b-methoxy-naphthalene in THF is added, for 1 hour the resulting mixture is stirred for 4 hours at -70 C and then heated to -20 ° C. Then it is poured into 150 ml of diluted HC1 and extracted with methylene chloride. The organic extracts are evaporated to dryness and the remaining substance is extracted with diethyl ether. The suspension thus obtained is filtered to obtain (S) -l- (6-methoxy-2-naphthyl) -2-methanesulfonyloxypropan-1-one t-mp. 150-154 ° C.
Example 37 A mixture of 47.2 mmol of lithium chloride and 21.3 mmol of manganese chloride in 50 ml of anhydrous THF was stirred at 25 ° C until a yellow solution formed. A Grignard reagent derived from 19.8 mmol of 6-methoxy-2-bromonaphthalene in THF is then added at -30 ° C. The mixture is stirred for 1.5 hours at -30 ° C and then for 20 minutes at 25 ° C. A solution of chloro- (6-methoxy-2-naphthyl) manganese at -20 ° C is added to 22.3 mmol of (5) -2-methanesulfonyloxypropionyl chloride in 30 ml of THF. The mixture is stirred for 1 hour at -20 ° C, then it is allowed to warm to 25 ° C and stirred for another 1 hour at this temperature. After that, the mixture is taken up in 150 ml of dilute aqueous HC1 and extracted with methylene chloride. The latter is evaporated under reduced pressure, after which ethyl ether is added. The ether slurry is filtered to give (8) -. 1- (6-met-hydroxy-2-naphthyl) -2-methanesulfonyloxypropan-1-one, m.p. 148-150 ° C.
Example 38. In a dry flask is placed 80.6 mmol of imidaeol and 50 ml of anhydrous THF. Then a solution of 40.3 mmol (S) -2 is added dropwise.
- - xC - and - - -
 ,
577694
18
ten
15
25
methanesulfonyloxypropionyl chloride in 50 ml of THF at room temperature during which a white solid begins to precipitate. The mixture is stirred at room temperature for 2.5 hours. The resulting white suspension is filtered to remove the imidazole hydrochloride. The filtrate containing 1- (2-methanesulonyloxypropionyl) -imidazole is cooled to -10 ° C in a nitrogen atmosphere and then 40.0 mmol of magnesium reagent is added dropwise at (-70) - (-60) C Grinra derived from 2-bromo-b-methoxynaphthalene in THF. The mixture is stirred for 40 minutes, then it is allowed to warm to 10 ° C, after which it is poured into 50 ml of diluted 2Q HCl. The mixture is extracted with methylene chloride, and the organic extracts are evaporated to dryness. The obtained solid is washed with ethyl ether and dried with. obtaining (S) -l- (6-methoxy-2-naphthyl) -2-methanesulfonyloxypropan-1-one with a value of X -29.2 in methylene chloride.
Example 39. In a dry vessel of appropriate size, load 20 g of magnesium shavings and 15 ml of anhydrous THF. The stirred mixture is heated to 50-60 ° C. and treated with a solution of 16.6 g of 2-bromo-6-methoxynaphthalene in 35 ml of anhydrous THF. Then the mixture is stirred for 1 h at 50-60 ° C. The resulting 35 solution of Grignard reagent is transferred to another dry vessel and cooled to 25 ° C. Then 4.8 g of powdered zinc chloride are added to the stirred solution of the Grignard reagent. 40 The temperature of the resulting mixture is increased to 45-50 ° C to obtain a solution containing di (6-methoxy-2-naphthyl) zinc.
Example 40. A solution of 5.7 g of 45 (5) -2-methanesulfonyloxypropionyl chloride in 94 ml of dry THF is cooled to -60 ° C with stirring. A solution of di- (b-methoxy-2-50 naphthyl) zinc obtained according to example 39 is then added over 4 hours. Upon completion of the addition process, the reaction mixture is heated to 25 ° C for 15 hours. The resulting mixture is added to a stirred mixture containing 30 ml of concentrated HCl and 55 to 200 ml of water. Then 50 ml of diethyl ether are added. The suspension thus obtained is filtered and dried30.
hoisted under reduced pressure at 40 ° C to obtain (S) -1- (6-methoxy19
15
2-naphthyl) -2-methanesulfonyloxy-1-one.
Example 41. A mixture of 3.07 g of (S) - 1,1-dimethoxy-1- (6-methoxy-2-naphthyl) -prop-2-yl-methanesulfonate, 1.0 g of calcium carbonate, 100 ml of DMF and 25 ml the waters are heated to 110 ° C and kept at this temperature for 5 hours. The mixture is then cooled and the insoluble components are removed by filtration. The filtrate is poured into excess water and the resulting solid is filtered off. As a result of the separation by chromatography, the obtained methyl 2- (6-methoxy-2-naphthyl) pro- pionate with a value of di, s + 77 ° in chloroform and an optical purity higher than 99%.
Example 42. The mixture obtained by adding 23 g of (8) -2- (6-methoxy-2-naphthyl) -propionic acid, prepared according to example 23, to 4 g of Nat) H in 500 ml of aqueous methanol, stirred for 3 hours at room temperature. temperature The mixture is then evaporated by G to give 2- (b-methoxy-2-naphthkgm-propionate sodium. Then this product is converted to toluene by centrifugation and washed with hexane before drying.
The resulting product melts at 255 ° C with decomposition. Its IR spectra show maxima at 1260, 1600, 1625, and 1725. The output is 95%, based on 5-2- (6-methoxy-2-naphthyl) -propionic acid.

权利要求:
Claims (1)
[1]
The proposed method, which is a stereoselective method, allows to obtain 2- (6-methoxy-2-naphthyl) -propionic acid in the form of the desired isomer, starting from the compound of formula (IV), a suitable configuration and thus simplify the process in comparison with the known method due to the exclusion of the separation step of the mixture of the R- and S-isomers by reverse dissolution. / "Claims of invention
The method of obtaining optically active / -arylalkanoic acid of the formula

H3
sn-soon
CH30
(I)
or its pharmaceutically acceptable nat. Rye salt, or its Cj-C-alkyl, 7
20
or C, -C4 hydroxyalkyl esters, by treating the 2-substituted 1- (6-methoxy-2-naphthyl) -propan-1-one with a ketalizing agent in an inert solvent at a temperature from 0 ° C to reflux temperature of the reaction mixture, rearranging the resulting thus, the corresponding ketal by solvolvine with a proton or polar aprotic solvent in the presence of a base at elevated temperature or by treatment with an agent that has an affinity for oxygen in an apro, a ton solvent, characterized in that ECCA, as 2-substituted 1- (6-methoxy-2-naphthyl) -propan-1-one, optically active soedi-.
Q formula Q
CN-CH3, (11, CH30 z
where Z is a hydroxy group, an acetoxy group, a halogen or a group of the formula —OS02R, where R is —C —C-alkyl, phenyl, unsubstituted or substituted by Cc-C, (., alkyl, obtained by reacting an organometallic compound
mh,
4 - I (C)
sngo sn3o / g (1W
where M is manganese (II), magnesium or
zinc;
X is chlorine or bromine,
with an optically active compound of the formula
five
0
five
H
0
ss-ss-sg
5Z
where Z has the indicated meanings; Y - halogen or group
(Iv)
x
or
/ -N
4J
in an inert solvent at a temperature of from 0 to -70 ° C, they take as a ketalizing agent.} Alkyl chloroformate and treatment of the compound of formula (II) in this case is carried out in the presence of an acid catalyst in an alcohol solvent, or diatomic alcohol with the number of carbon atoms 21577694
kind from 2 to 8 to obtain the corresponding ketal formula
 AD (V)
CH30
R4 and RJ are C -C-alkyl or R and R3 taken together represent C -Cg-alkylene, Z - has the indicated values.
22
or an alkali metal alkoxide is used as the ketalysis agent and the corresponding ketal obtained in this case is reacted with the corresponding acid anhydride to obtain the compound of formula (V), the ketal being rearranged by solvolysis at 90-150 ° C, and the treatment with an agent having affinity to oxygen, - at a temperature from room temperature to the reflux temperature of the reaction mixture.

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同族专利:

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公开号 | 公开日

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DK461288D0|1988-08-17|

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FI901487A0|1990-03-26|

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EP0081993B1|1988-08-17|

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DD206372A5|1984-01-25|

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EP0081993A2|1983-06-22|

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AU560800B2|1987-04-16|

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IN156354B|1985-06-29|

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NO156650C|1987-10-28|

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DK461388D0|1988-08-17|

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JPH0354652B2|1991-08-20|

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HU191621B|1987-03-30|

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IE53922B1|1989-04-12|

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IL67455A|1992-09-06|

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PL142997B1|1987-12-31|

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DK461588D0|1988-08-17|

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FI824203L|1983-06-12|

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GR77059B|1984-09-05|

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NO156650B|1987-07-20|

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CA1259627A|1989-09-19|

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KR890000375B1|1989-03-15|

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KR840002764A|1984-07-16|

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PH20059A|1986-09-18|

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JPH02270840A|1990-11-05|

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PT75973B|1985-10-04|

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IT8224665D0|1982-12-10|

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PL239456A1|1984-03-12|

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AT36517T|1988-09-15|

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DE3278907D1|1988-09-22|

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PH20169A|1986-10-09|

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FI82680C|1991-04-10|

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DK461188A|1988-08-17|

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NO824175L|1983-06-13|

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ES518086A0|1984-12-16|

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ES8501732A1|1984-12-16|

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DK461288A|1988-08-17|

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EP0081993A3|1984-01-11|

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3637767A|1968-07-30|1972-01-25|Syntex Corp|2-propylene oxide and 5'-halo derivatives|

---

ES455064A1|1977-01-17|1978-02-01|Valles Quimica|Dextrorotatory methoxy-naphthyl-propionic acid - obtd. by resolving racemic methoxy-naphthyl-propanal with an oxalic acid amide hydrazide |

---

JPS54115358A|1978-02-25|1979-09-07|Daito Koeki|Manufacture of 226substituted naphthoo2yl propionic acid|

---

JPS623145B2|1978-07-27|1987-01-23|Ono Pharmaceutical Co|

---

JPS55130934A|1979-03-31|1980-10-11|Masao Sato|Ketone synthesis from grignard reagent and acid halide|

---

IT1212408B|1980-02-26|1989-11-22|Blaschim Spa|PROCESS FOR THE PRODUCTION OF SUBSTITUTED ALPHA ALCANOIC ACIDS.|

---

IE50898B1|1980-02-26|1986-08-06|Blaschim Spa|Process for preparing esters of 2--propionic acid via rearrangement of new ketals of 2-halo-1--propan-1-one|

---

IE53333B1|1980-09-11|1988-10-26|Syntex Pharma Int|Process for preparing alpha-aromatic group substituted alkanoic acids or esters thereof|

---

JPS5798232A|1980-11-10|1982-06-18|Sagami Chem Res Center|1--2-oxy-1-alkanone acetal|

---

IL65629A|1981-04-30|1987-08-31|Syntex Pharma Int|Preparation of alpha-arylalkanoic acids and esters and salts thereof|

---

JPH0255408B2|1981-06-15|1990-11-27|Shintetsukusu Pharm Intern Ltd|IE53333B1|1980-09-11|1988-10-26|Syntex Pharma Int|Process for preparing alpha-aromatic group substituted alkanoic acids or esters thereof|

---

IT1208109B|1983-11-23|1989-06-06|Alfa Chem Ital|PROCEDURE FOR THE OPTICAL RESOLUTION OF ARYLPROPIONIC ACIDS|

---

EP0151817B1|1984-02-02|1986-12-03|ZAMBON S.p.A.|Process for preparing alpha-arylalkanoic acids|

---

IT1173216B|1984-02-03|1987-06-18|Zambon Spa|PROCESS FOR THE PREPARATION OF ALPHA-HYDROXYARYL-ALCANOIC ACIDS|

---

IT1174084B|1984-05-10|1987-07-01|Blaschim Spa|PROCEDURE TO PREPARE NAPROXEN|

---

US4670586A|1984-09-12|1987-06-02|Nippon Chemicals Co., Ltd.|Method for the production of α-aryl-alkanoic acid|

---

IT1190362B|1985-05-30|1988-02-16|Zambon Spa|PREPARATION OF--KETONE AND ITS DERIVATIVES|

---

IT1188181B|1985-07-31|1988-01-07|Zambon Spa|PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE AND INTERMEDIATE CARBOXYLIC ACIDS|

---

IT1198237B|1986-12-23|1988-12-21|Zambon Spa|INTERMEDIATES FOR THE SYNTHESIS OF ORGANIC COMPOUNDS|

---

WO1989010350A1|1988-04-21|1989-11-02|Ici Australia Operations Proprietary Limited|Preparation of an epoxide|

---

EP0380316A3|1989-01-25|1990-11-28|Syntex Pharmaceuticals International Limited|Preparation of alpha-methylareneacetic acids|

---

IT1251958B|1991-10-18|1995-05-27|Zambon Spa|PROCESS FOR THE DEALOGENATION OF NAPHTHALENE DERIVATIVES|

---

JP3744060B2|1996-06-20|2006-02-08|ダイソー株式会社|Method for producing acyloxysulfonic acid ester derivative|

---

JPWO2003014056A1|2001-08-08|2004-11-25|鐘淵化学工業株式会社|Method for producing optically active 2-substituted carboxylic acid|

---

NZ531153A|2001-08-09|2005-10-28|Ono Pharmaceutical Co|Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient|

---

SK16482002A3|2002-11-20|2004-06-08|Slovakofarma, A. S.|Process for preparation of substituted 2-aryl alkane acids derivatives|

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CN106496092B|2016-08-30|2019-03-29|江苏宇田医药有限公司|It is a kind of for synthesizing the preparation method of the intermediate of silodosin|

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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US32967281A| true| 1981-12-11|1981-12-11|

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