CA1097662A - Process for preparing an optically active benzamide, the optically active benzamide so obtained, and pharmaceutical compositions containing it - Google Patents
Process for preparing an optically active benzamide, the optically active benzamide so obtained, and pharmaceutical compositions containing itInfo
- Publication number
- CA1097662A CA1097662A CA321,673A CA321673A CA1097662A CA 1097662 A CA1097662 A CA 1097662A CA 321673 A CA321673 A CA 321673A CA 1097662 A CA1097662 A CA 1097662A
- Authority
- CA
- Canada
- Prior art keywords
- ethyl
- levo
- methoxy
- sulphamoyl
- proline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title description 8
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- GNMSLDIYJOSUSW-LURJTMIESA-N N-acetyl-L-proline Chemical compound CC(=O)N1CCC[C@H]1C(O)=O GNMSLDIYJOSUSW-LURJTMIESA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 229940050176 methyl chloride Drugs 0.000 claims 1
- 230000021736 acetylation Effects 0.000 abstract description 3
- 238000006640 acetylation reaction Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- -1 amino compound Chemical class 0.000 abstract description 2
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract 1
- 230000000506 psychotropic effect Effects 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229960004940 sulpiride Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- SQAILWDRVDGLGY-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoic acid Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(O)=O SQAILWDRVDGLGY-UHFFFAOYSA-N 0.000 description 1
- KDNIOKSLVIGAAN-UHFFFAOYSA-N 2-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC=CC=C1C(O)=O KDNIOKSLVIGAAN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000490229 Eucephalus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101150007148 THI5 gene Proteins 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract:
Levorotatory N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide has increased psychotropic activity as compared with the dextrorotatory compound or racemate.
The compound is prepared by a synthetic route commencing with acetylation of levo-proline followed by reduction, chlorination and amination, and reaction of amino compound thereby obtained with ethyl-2-methoxy-5-sulphamoyl benzoate.
Levorotatory N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide has increased psychotropic activity as compared with the dextrorotatory compound or racemate.
The compound is prepared by a synthetic route commencing with acetylation of levo-proline followed by reduction, chlorination and amination, and reaction of amino compound thereby obtained with ethyl-2-methoxy-5-sulphamoyl benzoate.
Description
7~6;~
This invention relates to an optically active ben-zamide, the process for its preparation, and therapeutic compositions containing it.
; More precisely, the present invention relates to levorotatory N-(ethyl-2~pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide, the process for its preparation and therapeutic compositions which contain it as their active principle.
N-(L-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide of formula fEI2 l H2 CONH - CH - CH* CH
This invention relates to an optically active ben-zamide, the process for its preparation, and therapeutic compositions containing it.
; More precisely, the present invention relates to levorotatory N-(ethyl-2~pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide, the process for its preparation and therapeutic compositions which contain it as their active principle.
N-(L-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide of formula fEI2 l H2 CONH - CH - CH* CH
2 \ / 2 N
i~ ~ - OCH3 1~H5 H2NO2S - ~
has been known for some time, and has been available commer~
cially for some time under the common name of Sulpiride.
This compound has found widespread application in ` the neurological and psychiatric field, administered either along or in association with other known tranquillisers.
As can be seen from the stated formula, Sulpiride .
~ comprises one asymmetric carbon atom (indicated by an aster ~: :
isk), and is therefore a mixture of two optical antipodes.
It~has now been found that in reality the two opti-- caL antipodes present in the raceme Sulpiride have very :: :
different activity and toxicity values, such that they in practice constitute t~o different therapeutic substances.
More eXactly, ~t~has been found that levarotatory .: :
~ N~ ethyl-2-pyrrolidinomethyl)-2-methoxy-5 sulphamoyl ben-. ~ :
zamide is much more active than the dextrorotatory isomer, and ~ts toxicity is also much lower against all logical expectancy.
Having determined the high therapeutic quality of ~7~6;~
levarotatory N~ ethyl-2-pyrrolidinomethyl)-2-me~hoxy-5-sulphamol benzamide, the problem was posed of separating the raceme Sulpiride containing it, by an economical industrial process.
However, all attempts made to resolve the raceme Sulpiride have either been totally negative or have at the most led only to the isolation of small quantities of the levarotatory isomer~
It was therefore absolutely impossible to base an industrial process on these methods of resolution.
An industrial process has now been discovered, and constitutes the object of the present invention, which star-ting rom a raw material available commercially at low cost, enables very pure levarotatory N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide to be obtained at very high yields, using a very simple and economical process.
The new process of the present invention is repre-sented diagrammatically by the following reaction sequence~
1) ~ 1 acetylation ~ J -COOH
N N
H (levo) CO
20 2) reduction r~
-COOH ~ ~ J -CH2OH
N N
: CH3 ¦levo) CH3 (levo) ` ~ : -
i~ ~ - OCH3 1~H5 H2NO2S - ~
has been known for some time, and has been available commer~
cially for some time under the common name of Sulpiride.
This compound has found widespread application in ` the neurological and psychiatric field, administered either along or in association with other known tranquillisers.
As can be seen from the stated formula, Sulpiride .
~ comprises one asymmetric carbon atom (indicated by an aster ~: :
isk), and is therefore a mixture of two optical antipodes.
It~has now been found that in reality the two opti-- caL antipodes present in the raceme Sulpiride have very :: :
different activity and toxicity values, such that they in practice constitute t~o different therapeutic substances.
More eXactly, ~t~has been found that levarotatory .: :
~ N~ ethyl-2-pyrrolidinomethyl)-2-methoxy-5 sulphamoyl ben-. ~ :
zamide is much more active than the dextrorotatory isomer, and ~ts toxicity is also much lower against all logical expectancy.
Having determined the high therapeutic quality of ~7~6;~
levarotatory N~ ethyl-2-pyrrolidinomethyl)-2-me~hoxy-5-sulphamol benzamide, the problem was posed of separating the raceme Sulpiride containing it, by an economical industrial process.
However, all attempts made to resolve the raceme Sulpiride have either been totally negative or have at the most led only to the isolation of small quantities of the levarotatory isomer~
It was therefore absolutely impossible to base an industrial process on these methods of resolution.
An industrial process has now been discovered, and constitutes the object of the present invention, which star-ting rom a raw material available commercially at low cost, enables very pure levarotatory N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide to be obtained at very high yields, using a very simple and economical process.
The new process of the present invention is repre-sented diagrammatically by the following reaction sequence~
1) ~ 1 acetylation ~ J -COOH
N N
H (levo) CO
20 2) reduction r~
-COOH ~ ~ J -CH2OH
N N
: CH3 ¦levo) CH3 (levo) ` ~ : -
3) r ¦ chlorination¦ NH~
-CH2OH ~ ~ ~ -CH2cl ~ ~ -CH2NH2 1 2 (levo) ¦ (levo) I tlevo) .
~76~i~
-CH2OH ~ ~ ~ -CH2cl ~ ~ -CH2NH2 1 2 (levo) ¦ (levo) I tlevo) .
~76~i~
4 ) CO-OR
CH2 -NH2 + H2N2 ~J - ROH
1H3 ( levo) CO - NH -- CH 2 ~ ~ , J
N
J ¦ (levo) H2NO~S - ~ . CH3 It has in fact bsen surprisingly found that star-ting with levarotatory proline, which is a natural product available commercially at low cost, it is possible to subject it to a series of chemical transformations to obtain levaro-tatory N-ethyl-2-aminomethyl-pyrrolidine, without there ~ being any racemisation or inversion of optical activity of : the product during the process steps.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine obtained as the final product of these chemical transforma-~`~ tions:of proline can be reacted with an ester of 2-methoxy-S-sulphamoyl benzoic acid:under suitable conditions, to obtain N~ ethyl-2-pyrrolidino-methyl~-2-methoxy-5-sulphamoyl ben-~ zamide, thi5 being done under r~ther drastic:conditions of .~; temperature, time and mechanical homogenization of the mass, :
to obtain the final levarotatory pxoduct with nearly quanti-tative yields.
:
A description is gLven hereinafter in detail of the :~ ~0 individual stag s of the process according to the present ~: invention: ;;
: 1. The levarotatory proline i6 acetylated in solution with a suitable acetylating substance such as acetyl chloride or acetic anhydride. The acetylation is:preferably carried ; -3-~7~
out in an aqueous solution with a strong excess of acetic anhydride.
The reaction is exothermic.
The levorotatory acetyl-proline precipitates by cooling and is separated by filtration.
A very pure crystalline product is obtained in a yield of around 90%.
2. The levorotatory acetyl-proline undergoes reduction with a reducing system which acts simultaneously, under the same conditions, on the acetyl and carboxyl groups. Good results are obtained by using metal hydrides in an organic solvent.
Particularly good yields, of around 60% are obtai-; ned with LiAlH4 in tetrahydrofuran.
The reduction is carried out under reflux, and theproduct is separated b~ precipitating the unreacted acetyl-proline from the reaction mixture by means of an alkaline '~ base.
The levorotatory N--ethyl-2-pyrrolidino methanol is ,separated from the filtrate by dietillation under vacuum.
3. The levorotatory N-ethyl-2-pyrrolidino methanol is transformed into the corresponding 2-methyl amine by firstlv substltuting the hydroxyl with an active chlorine atom, and then reacting~thechlorine atom, and then reacting the chloride with ammonia~
The chlorine derivative of the alcohol can be pre-pared using any suitabLe reactant system.
Preferably, the reaction is conducted with thionyl ----chloride in an anhydrous chlorinated organic solvent such as CHC13 , CC14 , CH2C12 , between ambient temperature and 60C.
The thionyl chloride can be used either in the stoichiometric ratio or in slight excess.
..... ........... .....~ ,- , ~ , ''' ~'a7~
When the reaction has terminated, the solvent is eliminated and the residue is reacted with methanolic or ethanolic ammonia at ambient temperature.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine which has Eormed is separated, with yields of around 50%, by eliminating the alcoholic solvent, dissolving it in an alka-line aqueous solution and extracting it from the aqueous solution by a suitable organic solvent, preferably ethyl ether.
4. The levorotatory N-ethyl-2-aminomethyl-pyrrolidine is reacted with an ester of 2-methoxy-5-sulphamoyl benzoic acid in the absence of solven~ at a temperature of 80-90C, this temperature being maintained without adding external heat because of the exothermic nature of the reaction, and ; using for mixing the reactants a Z mixer, this being criti-cally necessary for carrying out the reaction (Spanish Patent 428,341).
Very pure levorotatory N-(l-ethyl-2-pyrrolidino methyl)-2-methoxy-5-sulphamoyl benzamide i5 obtained by cry-stallisation from the reaction mass using a suitable solvent, preferably ethanol, giving yields of 90-95%.
Alternatively, stages 3 and 4 described above can be carried out in succession in the same reactor, without separating the intermediate amine. In this case, after ~li-minating the alcohol and unreacted ammonia by evaporation, ~ the residue is mixed directly with the ester of 2-methoxy-5-`~ sulphamoyl benzoic acid, in the absence of solvents, and using a Z mixer for mixing purposes.
The levorotatory N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide obtained by the process of the present invention has the following characteristics:
M.P. - 186-188C (n.c.) ~C1D = -68.5 (C = 1% in DMF) Purity = 99. 5%
CH2 -NH2 + H2N2 ~J - ROH
1H3 ( levo) CO - NH -- CH 2 ~ ~ , J
N
J ¦ (levo) H2NO~S - ~ . CH3 It has in fact bsen surprisingly found that star-ting with levarotatory proline, which is a natural product available commercially at low cost, it is possible to subject it to a series of chemical transformations to obtain levaro-tatory N-ethyl-2-aminomethyl-pyrrolidine, without there ~ being any racemisation or inversion of optical activity of : the product during the process steps.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine obtained as the final product of these chemical transforma-~`~ tions:of proline can be reacted with an ester of 2-methoxy-S-sulphamoyl benzoic acid:under suitable conditions, to obtain N~ ethyl-2-pyrrolidino-methyl~-2-methoxy-5-sulphamoyl ben-~ zamide, thi5 being done under r~ther drastic:conditions of .~; temperature, time and mechanical homogenization of the mass, :
to obtain the final levarotatory pxoduct with nearly quanti-tative yields.
:
A description is gLven hereinafter in detail of the :~ ~0 individual stag s of the process according to the present ~: invention: ;;
: 1. The levarotatory proline i6 acetylated in solution with a suitable acetylating substance such as acetyl chloride or acetic anhydride. The acetylation is:preferably carried ; -3-~7~
out in an aqueous solution with a strong excess of acetic anhydride.
The reaction is exothermic.
The levorotatory acetyl-proline precipitates by cooling and is separated by filtration.
A very pure crystalline product is obtained in a yield of around 90%.
2. The levorotatory acetyl-proline undergoes reduction with a reducing system which acts simultaneously, under the same conditions, on the acetyl and carboxyl groups. Good results are obtained by using metal hydrides in an organic solvent.
Particularly good yields, of around 60% are obtai-; ned with LiAlH4 in tetrahydrofuran.
The reduction is carried out under reflux, and theproduct is separated b~ precipitating the unreacted acetyl-proline from the reaction mixture by means of an alkaline '~ base.
The levorotatory N--ethyl-2-pyrrolidino methanol is ,separated from the filtrate by dietillation under vacuum.
3. The levorotatory N-ethyl-2-pyrrolidino methanol is transformed into the corresponding 2-methyl amine by firstlv substltuting the hydroxyl with an active chlorine atom, and then reacting~thechlorine atom, and then reacting the chloride with ammonia~
The chlorine derivative of the alcohol can be pre-pared using any suitabLe reactant system.
Preferably, the reaction is conducted with thionyl ----chloride in an anhydrous chlorinated organic solvent such as CHC13 , CC14 , CH2C12 , between ambient temperature and 60C.
The thionyl chloride can be used either in the stoichiometric ratio or in slight excess.
..... ........... .....~ ,- , ~ , ''' ~'a7~
When the reaction has terminated, the solvent is eliminated and the residue is reacted with methanolic or ethanolic ammonia at ambient temperature.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine which has Eormed is separated, with yields of around 50%, by eliminating the alcoholic solvent, dissolving it in an alka-line aqueous solution and extracting it from the aqueous solution by a suitable organic solvent, preferably ethyl ether.
4. The levorotatory N-ethyl-2-aminomethyl-pyrrolidine is reacted with an ester of 2-methoxy-5-sulphamoyl benzoic acid in the absence of solven~ at a temperature of 80-90C, this temperature being maintained without adding external heat because of the exothermic nature of the reaction, and ; using for mixing the reactants a Z mixer, this being criti-cally necessary for carrying out the reaction (Spanish Patent 428,341).
Very pure levorotatory N-(l-ethyl-2-pyrrolidino methyl)-2-methoxy-5-sulphamoyl benzamide i5 obtained by cry-stallisation from the reaction mass using a suitable solvent, preferably ethanol, giving yields of 90-95%.
Alternatively, stages 3 and 4 described above can be carried out in succession in the same reactor, without separating the intermediate amine. In this case, after ~li-minating the alcohol and unreacted ammonia by evaporation, ~ the residue is mixed directly with the ester of 2-methoxy-5-`~ sulphamoyl benzoic acid, in the absence of solvents, and using a Z mixer for mixing purposes.
The levorotatory N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide obtained by the process of the present invention has the following characteristics:
M.P. - 186-188C (n.c.) ~C1D = -68.5 (C = 1% in DMF) Purity = 99. 5%
-5-. . .
7~62 IR See Fig. 1 which shows the superimposed spectra for the product obtained by the process in four stages and by the process in three stages.
TLC over silica gel 60 F 254 Eluent isopropanol : methano] : ammonia, conc. 8:1:1 Detector: UV 254 or Drayendorff Rf = 0.40 approx.
The new product can be administered orally mixed with the normal pharmaceutical diluents such as lactose, mag-nesium stearate etc., to form capsules or tablets.
It can also be administered parenterally in an aque-ous solution in the form of a salt, for example a sulphate.
In order to facilitate the reproduction of the pro- -cess according to the present invention, one practical embo-diment is described hereinafter by way of non-limiting example only.
EXAMPLE
; 1. Preparation of the levo N-acetyl-proline.
11.5 kg of levo-proline are dissolved in 30 1 of water, and 21.5 kg of acetic anhydride are added to the solution under agitation~
! The temperature rises spontaneously, and the mix-ture is allowed to stand under agitation Eor a further 20-30 minutes.
The reactor is then cooled to a temperature of 0-4C and is left to stand until the crystalline mass completely separates (about 12 hours). It is filtered, the precipitate is washed with iced water and dried. A further 10 kg of product are recovered from the mother liquor after adding a ; 30 little isopropanol.
A total of 15 kg of levo N-acetyl-proline are obtained, having a M.P. of 89C and a yield of 95~.
7~62 IR See Fig. 1 which shows the superimposed spectra for the product obtained by the process in four stages and by the process in three stages.
TLC over silica gel 60 F 254 Eluent isopropanol : methano] : ammonia, conc. 8:1:1 Detector: UV 254 or Drayendorff Rf = 0.40 approx.
The new product can be administered orally mixed with the normal pharmaceutical diluents such as lactose, mag-nesium stearate etc., to form capsules or tablets.
It can also be administered parenterally in an aque-ous solution in the form of a salt, for example a sulphate.
In order to facilitate the reproduction of the pro- -cess according to the present invention, one practical embo-diment is described hereinafter by way of non-limiting example only.
EXAMPLE
; 1. Preparation of the levo N-acetyl-proline.
11.5 kg of levo-proline are dissolved in 30 1 of water, and 21.5 kg of acetic anhydride are added to the solution under agitation~
! The temperature rises spontaneously, and the mix-ture is allowed to stand under agitation Eor a further 20-30 minutes.
The reactor is then cooled to a temperature of 0-4C and is left to stand until the crystalline mass completely separates (about 12 hours). It is filtered, the precipitate is washed with iced water and dried. A further 10 kg of product are recovered from the mother liquor after adding a ; 30 little isopropanol.
A total of 15 kg of levo N-acetyl-proline are obtained, having a M.P. of 89C and a yield of 95~.
-6 t~
Percentage Anaylsis;
Calculated Found C 53.49 53.35 H 7.06 7.00 N 8.90 8.95 2. Preparation of the levo N-ethyl-2-pyrrolidino methanol.
15 kg of N-acetyl-proline are added to a solution containing 14.25 kg of LiAlH4 in 500 litres of tetrahydro-furan. The solution is heated under reflux for 24 hours.
After this time it is cooled to 0C, then 100 lit-res of tetrahydrofuran containing about 4% of water and 12 litres of 20~ NaOH are added.
The precipitate formed is filtered, the tetrahydro-furan is evaporated and the residue is distilled under vacuum.
9 kg of N-ethyl-2-pyrrolidino methanol are obtained, having a B.P. of 80C/16 mm and a ~ield of 75~.
Percentage Anaylsis: -Calculated Found C 65.07 ~ 64.95 H 11.70 11.72 N 10.84 10.80 ~ 3. Preparation of the levo N-(l-ethyl-2-pyrroli-dinomethyl~-2-methoxy-5-sulphamoyl benzamide.
; 9 kg of levo~N-ethyl-2-pyrrolidinomethanol are dissolved in 200 1 of CH~C12, and 6 kg of thionyl chloride are dripped into this~solution under cold conditions. The solution is agitated for 6 hours at ambient temperature and then for Z hours under boiling, and is evaporated to dryness.
The Gily residue is taken up in ethanol saturated with ammo-~, , nia, and the mixture is kept under agitation at ambient temperature for one night. The alcohol and ammonia are then evaporated under vacuum.
Percentage Anaylsis;
Calculated Found C 53.49 53.35 H 7.06 7.00 N 8.90 8.95 2. Preparation of the levo N-ethyl-2-pyrrolidino methanol.
15 kg of N-acetyl-proline are added to a solution containing 14.25 kg of LiAlH4 in 500 litres of tetrahydro-furan. The solution is heated under reflux for 24 hours.
After this time it is cooled to 0C, then 100 lit-res of tetrahydrofuran containing about 4% of water and 12 litres of 20~ NaOH are added.
The precipitate formed is filtered, the tetrahydro-furan is evaporated and the residue is distilled under vacuum.
9 kg of N-ethyl-2-pyrrolidino methanol are obtained, having a B.P. of 80C/16 mm and a ~ield of 75~.
Percentage Anaylsis: -Calculated Found C 65.07 ~ 64.95 H 11.70 11.72 N 10.84 10.80 ~ 3. Preparation of the levo N-(l-ethyl-2-pyrroli-dinomethyl~-2-methoxy-5-sulphamoyl benzamide.
; 9 kg of levo~N-ethyl-2-pyrrolidinomethanol are dissolved in 200 1 of CH~C12, and 6 kg of thionyl chloride are dripped into this~solution under cold conditions. The solution is agitated for 6 hours at ambient temperature and then for Z hours under boiling, and is evaporated to dryness.
The Gily residue is taken up in ethanol saturated with ammo-~, , nia, and the mixture is kept under agitation at ambient temperature for one night. The alcohol and ammonia are then evaporated under vacuum.
-7-, ~76~2 The residue is taken up in a little water, NaOH
is dripped in and the mixture extracted with ethyl ether.
The ether phase is dried and evaporated.
The residue from the evaporation (about 5 kg) to-gether with 9 kg of ethyl-2-metho~y-5-sulphamoyl benzoate are ed into a Z mixer and the mixture is heated to 85C.
After a certain time, a crystalline powder begins to separate from the liquid mass. The reaction is exothermic and the tempera-ture is maintained spontaneously at 80-85C
without any further addition of heat. The reaction is com-plete in 8 hours.
The powder obtained is dissolved under cold condi-tions in 400 litres of water containing 4 litres of concen-trated hydrochloric acid, the solution is filtered and neu-tralized with sodium bicarbonate.
The crystalline powder obtained is recrystallized from ethanol.
11 kg of levo-N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide are obtained having a purity of 99.5% and a yield of 92% calculated on the ester.
The product obtained has the following characteris-tics:
M.P. = 186-188C
[~]D = 68.5 (c - 1% in DMF) Purity = 99.5%
Percentage Analysis:
- Calculated Found C 52.77 52.65 H 6.79 6.72 :~ 3~ N 12.30 12.20 ~ -8-
is dripped in and the mixture extracted with ethyl ether.
The ether phase is dried and evaporated.
The residue from the evaporation (about 5 kg) to-gether with 9 kg of ethyl-2-metho~y-5-sulphamoyl benzoate are ed into a Z mixer and the mixture is heated to 85C.
After a certain time, a crystalline powder begins to separate from the liquid mass. The reaction is exothermic and the tempera-ture is maintained spontaneously at 80-85C
without any further addition of heat. The reaction is com-plete in 8 hours.
The powder obtained is dissolved under cold condi-tions in 400 litres of water containing 4 litres of concen-trated hydrochloric acid, the solution is filtered and neu-tralized with sodium bicarbonate.
The crystalline powder obtained is recrystallized from ethanol.
11 kg of levo-N-(l-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide are obtained having a purity of 99.5% and a yield of 92% calculated on the ester.
The product obtained has the following characteris-tics:
M.P. = 186-188C
[~]D = 68.5 (c - 1% in DMF) Purity = 99.5%
Percentage Analysis:
- Calculated Found C 52.77 52.65 H 6.79 6.72 :~ 3~ N 12.30 12.20 ~ -8-
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing levo N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide, wherein levo-proline is acetylated, the levo N-acetyl-proline thus obtained is reduced with a metal hydride in an organic sol-vent, the levo N-ethyl-2-pyrrolidino methanol obtained is transformed into the corresponding chloride and then, by reaction with alcoholic ammonia, into levo N-ethyl-2-aminomethyl-pyrrolidine, which is reacted with ethyl-2-methoxy-5-sulphamoyl benzoate to give the levorotatory N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide.
2. A process as claimed in Claim 1, wherein the levo-proline is acetylated with acetic anhydride in aqueous solution.
3. A process as claimed in Claim 1, wherein the N-acetyl-proline is reduced to levo N-ethyl-2-pyrrolidinomethanol by heating under reflux with LiAlH4 in tetrahydrofuran.
4. A process as claimed in Claim 1, wherein the levo N-ethyl-2-pyrrolidino methanol is reacted with thionyl chloride in a chlorinated organic solvent under cold condi-tions to give the corresponding chloride.
5. A process as claimed in Claim 1, wherein the levo N-ethyl-2-pyrrolidino-methylchloride is reacted with ammonia to give the corresponding amine.
6. A process as claimed in Claim 1, wherein the levo N-ethyl-2-pyrrolidino-methylamine is reacted with ethyl 2-methoxy-5-sulphamoyl benzoate in the absence of solvent, at a temperature of 80-85°C, in a Z mixer.
7. Levorotatory N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulphamoyl benzamide having the following charac-teristics:
M.P. = 186° - 188°C
[.alpha.]?0° = 68.5 (1% in DMF) whenever prepared by a process as claimed in Claim 1.
M.P. = 186° - 188°C
[.alpha.]?0° = 68.5 (1% in DMF) whenever prepared by a process as claimed in Claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20295A/78 | 1978-02-16 | ||
| IT20295/78A IT1095415B (en) | 1978-02-16 | 1978-02-16 | PROCESS FOR THE PRODUCTION OF AN OPTICALLY ACTIVE BENZAMIDE, OPTICALLY ACTIVE BENZAMIDE SO OBTAINED AND COMPOSITIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097662A true CA1097662A (en) | 1981-03-17 |
Family
ID=11165504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA321,673A Expired CA1097662A (en) | 1978-02-16 | 1979-02-16 | Process for preparing an optically active benzamide, the optically active benzamide so obtained, and pharmaceutical compositions containing it |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS54130562A (en) |
| AT (1) | AT373870B (en) |
| CA (1) | CA1097662A (en) |
| CH (1) | CH639951A5 (en) |
| DE (1) | DE2903891A1 (en) |
| DK (1) | DK152752C (en) |
| EG (1) | EG14440A (en) |
| FR (1) | FR2417498A1 (en) |
| GB (1) | GB2014990B (en) |
| GR (1) | GR78220B (en) |
| IT (1) | IT1095415B (en) |
| MX (1) | MX5632E (en) |
| NL (1) | NL190845C (en) |
| SE (1) | SE430888B (en) |
| YU (1) | YU41145B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1141095B (en) * | 1980-11-27 | 1986-10-01 | Ravizza Spa | RESOLUTION PROCESS OF THE SULPYRID RACEMA |
| EP0088849A1 (en) * | 1982-03-11 | 1983-09-21 | Choay S.A. | Levorotatory compounds of N-substituted benzenesulphone amides, process for their preparation and pharmaceutical compositions containing them |
| SE8602339D0 (en) * | 1986-05-22 | 1986-05-22 | Astra Laekemedel Ab | AND EFFECTIVE STEREOCONSERVATIVE SYNTHESIS OF 1-SUBSTITUTED (S) - AND (R) -2-AMINOMETHYLPYRROLIDINES |
| DE4103451C2 (en) * | 1991-02-02 | 1994-08-25 | Hormosan Kwizda Gmbh | Uses of the active substance sulpiride in its R or S form |
| AU2002364553A1 (en) * | 2001-12-28 | 2003-07-15 | Farmaceutsko-Hemijska Industrija "Zdravlje" | A process for synthesis of heterocyclic aminoalkyl benzamides |
| ITMI20051943A1 (en) * | 2005-10-14 | 2007-04-15 | Procos Spa | ANANTIOMERIC RESOLUTION PROCESS OF 2-AMINOMETHYL-PYRROLIDINES 1-SUBSTITUTED FOR DAMAGE IN THE PRESENCE OF LIPASE |
| CL2012000874S1 (en) | 2012-01-31 | 2013-03-22 | Saverglass | Bottle with a tapered rectangular parallelepipedic body oriented vertically, with its narrowest part located at the lower end, it has all its curved edges, at its upper end it forms a rectangular surface with convex sides, which is joined to the bottle neck by means of slight slopes. |
| CN103772256B (en) * | 2012-10-24 | 2017-10-10 | 江苏天士力帝益药业有限公司 | A kind of preparation method of high-purity Sulpiride or its optical isomer |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3891671A (en) * | 1968-08-01 | 1975-06-24 | Ile De France | N-(2-pyrrolidyl or piperidyl alkyl)-4-hydroxy benzamides |
| CH605793A5 (en) * | 1974-03-05 | 1978-10-13 | Ile De France | |
| FR2394529A2 (en) * | 1977-06-13 | 1979-01-12 | Synthelabo | 2-METHOXY BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
| FR2393794A2 (en) * | 1977-06-06 | 1979-01-05 | Synthelabo | Therapeutic 2-methoxy benzamido methyl heterocycle(s) prepn. - from 2-methoxy benzoic ester(s) and amino methyl heterocycle(s) |
| IL52645A (en) * | 1976-08-05 | 1980-02-29 | Synthelabo | Optically active 1 substituted 2 aminomethyl pyrrolidines stereospecifics synthesis thereof and process for the preparation of optically active 2 methoxy n pyrrolidylmethyl benzamides |
| JPS5365875A (en) * | 1976-11-24 | 1978-06-12 | Teijin Ltd | Preparation of benzenesulfone amide derivs. |
-
1978
- 1978-02-16 IT IT20295/78A patent/IT1095415B/en active
-
1979
- 1979-02-01 DE DE19792903891 patent/DE2903891A1/en active Granted
- 1979-02-05 GB GB7903902A patent/GB2014990B/en not_active Expired
- 1979-02-08 FR FR7903216A patent/FR2417498A1/en active Granted
- 1979-02-12 YU YU308/79A patent/YU41145B/en unknown
- 1979-02-13 JP JP1441979A patent/JPS54130562A/en active Pending
- 1979-02-13 MX MX797713U patent/MX5632E/en unknown
- 1979-02-13 AT AT0110179A patent/AT373870B/en not_active IP Right Cessation
- 1979-02-14 CH CH142779A patent/CH639951A5/en not_active IP Right Cessation
- 1979-02-14 EG EG97/79A patent/EG14440A/en active
- 1979-02-15 DK DK066579A patent/DK152752C/en not_active IP Right Cessation
- 1979-02-15 GR GR58375A patent/GR78220B/el unknown
- 1979-02-15 SE SE7901337A patent/SE430888B/en not_active IP Right Cessation
- 1979-02-16 CA CA321,673A patent/CA1097662A/en not_active Expired
- 1979-02-16 NL NL7901251A patent/NL190845C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SE430888B (en) | 1983-12-19 |
| GB2014990A (en) | 1979-09-05 |
| SE7901337L (en) | 1979-08-17 |
| DK152752C (en) | 1988-09-26 |
| IT7820295A0 (en) | 1978-02-16 |
| GR78220B (en) | 1984-09-26 |
| NL190845B (en) | 1994-04-18 |
| DK66579A (en) | 1979-08-17 |
| MX5632E (en) | 1983-11-15 |
| CH639951A5 (en) | 1983-12-15 |
| YU30879A (en) | 1983-02-28 |
| DE2903891C2 (en) | 1992-02-06 |
| DE2903891A1 (en) | 1979-08-23 |
| NL190845C (en) | 1994-09-16 |
| YU41145B (en) | 1986-12-31 |
| ATA110179A (en) | 1983-07-15 |
| DK152752B (en) | 1988-05-09 |
| JPS54130562A (en) | 1979-10-09 |
| FR2417498B1 (en) | 1983-01-21 |
| AT373870B (en) | 1984-02-27 |
| NL7901251A (en) | 1979-08-20 |
| EG14440A (en) | 1984-03-31 |
| GB2014990B (en) | 1982-06-09 |
| FR2417498A1 (en) | 1979-09-14 |
| IT1095415B (en) | 1985-08-10 |
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