USRE28287E - Into optical antipodes - Google Patents
Into optical antipodes Download PDFInfo
- Publication number
- USRE28287E USRE28287E US28773472A USRE28287E US RE28287 E USRE28287 E US RE28287E US 28773472 A US28773472 A US 28773472A US RE28287 E USRE28287 E US RE28287E
- Authority
- US
- United States
- Prior art keywords
- ephedrine
- hemisuccinate
- racemic
- ethyl acetate
- hemisuccinates
- 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
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- 230000003287 optical effect Effects 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 63
- 150000003839 salts Chemical class 0.000 abstract description 24
- 235000019439 ethyl acetate Nutrition 0.000 abstract description 21
- 229940093499 ethyl acetate Drugs 0.000 abstract description 21
- 230000007928 solubilization Effects 0.000 abstract description 2
- 238000005063 solubilization Methods 0.000 abstract description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 38
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- 229960002179 ephedrine Drugs 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- -1 succinyloxy Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Definitions
- ABSTRACT OF THE DISCLOSURE Invention concerned with a process for the resolution into optical antipodes of racemic compounds comprised in the general formula G/NII-CO p gH wherein R is N0 Cl, F, Br, based on the sharply different solubility in ethylaeetate of the salts of the dextroforms and levo-forms with (+)ephedrine or ()ephedrine.
- 1,4-benzodiazepines constitute a class of drugs showing a remarkable psyeoactivity.
- racemic hemisuecinates may easily be prepared for example by esterifieation of the corresponding 3-hydroxy derivatives with succinic anhydride, preferably in the presence of pyridine or of other tertiary bases used in such an amount to act also as a reaction medium.
- the hemisuecinates besides showing, as said, a very valuable activity on the central nervous system, present the great advantage of being easily salified by neutralization with an equimolecular amount of an organic or inorganic base and thus transformed in water-soluble hemisuccinates; these aqueous solutions may be easily administered by parenteral route, what form of administration is not possible today with any other benzodiazepine.
- the process object of the present invention is based on the discovery that the salts of the (+)hemisuccinates and (-)hemisuccinates with (+)cphcdrine or ()ephedrine have a sharply different solubility in ethylacetatc. More precisely the salts formed by the (+)hernisuccinates of Formula I with ()ephedrine show a very low solubility in ethyl acetate, while the salts of the (--)hcinisuceinates with ()ephedrine are highly soluble in the same solvent. The solubility of the ()ephedrine (+)hemisuccinates in ethyl acetate is still remarkably lower in the presence of the salts ()ephedrine ()hemisuccinate.
- the two salts obtained show an opposite behaviour, with respect to the solubility in ethyl acetate, when compared with the salts of ()ephedrine; that is the salts of the (+)hemisuccinates with (+)ephedrine are highly soluble in ethyl acetate, while the salts of the ()hemisuccinates with (+)ephedrine are nearly insoluble in the same solvent.
- the hydrolysis is carried out with acetic acid which is suitable to act both as a solvent and as hydrolysing agent. Moreover, acetic acid does not cause any yellowing of the product, as mineral acids do.
- acetic acid does not cause any yellowing of the product, as mineral acids do.
- the pure (+)hemisuccinate crystallizes out, is dried and may be recrystallized from a suitable solvent such as for example acetic acid/water or ethyl-alcohol/water. In order to render the process economically more convenient. it is always preferred to recover the (-)hemisuccinate contained in the solution under the form of salt with ephedrine.
- the ()hemisuccinate which precipitates is dissolved in a solvent for example in ethyl alcohol, added with an excess of aqueous 4 N NaOH under stirring and kept still under stirring up to complete precipitation.
- the precipitate is dissolved with water and from the clear solution the racemic B-hydroxy compounds are precipitated by acidification, preferably with acetic acid.
- the racemic 3-hydroxy compound is esterified with succinic acid and as such recycled.
- (+)hemisuccinate and ()hemisuccinate can be carried out also through the salts with (-i-)cphedrine, by following nearly the above technique wilh only the obvious variations.
- this method is less convenient then that performed through the (-)ephedriue, due to the (+)cphedrine (-l-)hemisuccinate salt remaining in solution being removable only with lower yields and with a lower degree of purity.
- the filtrate (A) is set aside, to undergo successive recovery procedure.
- the salt (-)ephedrine (+)7-NO hemisuccinate is dissolved in 50 cc. of glacial acetic acid at 60 (1., added with hot water up to incipient crystallization, cooled and filtered. 4.25 g. of (+)7-NO -hemi succinate are obtained which, after recrystallization from ethyl alcohol/water show the following characteristics:
- This highly pure ester is ready to be used, as such or as salt, in the hterapeutic field.
- the filtrate (A) is evaporated under vacuum to dryness and the residue is taken up at 60 C., up to dissolution, with the smallest possible quantity of acetic acid.
- 4.1 g. of (-)7-NO hemisuccinate precipitate which are separated by filtration is dissolved in 100 cc. of ethyl alcohol.
- cc. of 4 N NaOH are added dropwise, after about 15 minutes stirring a precipitate is obtained, which is redissolved by addition of cc. water; the solution is acidified with acetic acid.
- EXAMPLE 2 10 g. of racemic 7-Cl-hemisuccinate are dissolved under stirring into cc. of hot ethyl acetate.
- the filtrate (A) is temporarily set aside.
- the salt ()ephedrine (+)7-Cl-hemisuccinate is dissolved in 50 cc. of glacial acetic acid at 70-80 C., added with hot water up to incipient crystallization, allowed to crystallize by cooling.
- This highly pure ester is ready to be used, as such or as sodium salt, in the therapeutic field.
- the filtrate (A) is added with 2 cc. glacial acetic acid, evaporated under vacuum to dryness and the residue is taken up, up to dissolution, with the smallest possible quantity of acetic acid, at 70-80 C.
- water and cooling 4.1 g. of (-)hemisuccinate precipitate which are separated by filtration and dissolved in 100 cc. of 95 ethyl alcohol. This solution is cooled and kept at 10 C., while adding dropwise 51 cc. of N NaOH.
- EXAMPLE 3 10 g. of racemic 7-Br-hemissuccinate are dissolved under stirring into 140 cc. of ethyl acetate.
- the tests per os have instead been performed dissolving the desired amount of product in 1.5 cc. of mixture (A) and then adding 3.5 cc. of a 510% aqueous solution of carboxymethyl cellulose. Also in this case the concentration is so regulated to have the right amount of drug in 5-10 cc./kg. of treated animal, which is the dose administered.
- the drugs of the invention were administered to healthy men. Moreover the various optical forms of the drugs, namely the dextrorotatory, levorotatory and racemic ones, were administered to the same individuals, spacing the administration of drugs of different optical activity of two weeks.
- R is N0 Cl, Br, F,
- optically active ephedrine is (-)ephedrine.
Abstract
1. PROCESS FOR THE RESOLUTION INTO OPTICAL ANTIPODES OF RACEMIC 3 - SUCCINYLOXY - 5 - PHENYL - 1,3 - DIHYDRO - 2H1,4-BENZODIAZEPINE-2-ONE DERIVATIVES I.E., THE COMPOUND OF THE FORMULA
2-(O=),3-(HOOC-CH2-CH2-COO-),5-(H5C6-),7-R-1,3-DIHYDRO-2H-
1,4-BENZODIAZEPINE
WHEREIN R IS NO2, CL, BR, F, THROUGH SELECTIVE SOLUBILIZATION IN ETHYLACETATE OF THEIR SALTS WITH OPTICALLY ACTIVE EPHERDINE.
2-(O=),3-(HOOC-CH2-CH2-COO-),5-(H5C6-),7-R-1,3-DIHYDRO-2H-
1,4-BENZODIAZEPINE
WHEREIN R IS NO2, CL, BR, F, THROUGH SELECTIVE SOLUBILIZATION IN ETHYLACETATE OF THEIR SALTS WITH OPTICALLY ACTIVE EPHERDINE.
Description
United States Patent 0 Matter enclosed in heavy brackets [II appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.
ABSTRACT OF THE DISCLOSURE Invention concerned with a process for the resolution into optical antipodes of racemic compounds comprised in the general formula G/NII-CO p gH wherein R is N0 Cl, F, Br, based on the sharply different solubility in ethylaeetate of the salts of the dextroforms and levo-forms with (+)ephedrine or ()ephedrine.
The present invention is concerned with a process for the resolution into optical antipodes of racemic compounds comprised in the general formula NH-CO CH-O c ocm-cm-C 0 OH R C=N eHs (I) wherein R is N0 Cl, F, Br.
In what follows, for the sake of simplicity, the compounds of Formula I will be identified with the terms 7-NO -hemisuccinate, 7-Br-hemisuccinate and so on.
It is known that the 1,4-benzodiazepines constitute a class of drugs showing a remarkable psyeoactivity.
Recently the racemic 7-Cl-hemisuccinate was studied and it was found endowed with a remarkably interesting activity, superior under some respects to that of notoriously valuable benzodiazepines such as ehlordiazepoxide. Such a result has been confirmed by the applicant also with the remaining hemisuceinates of Formula I.
The racemic hemisuecinates may easily be prepared for example by esterifieation of the corresponding 3-hydroxy derivatives with succinic anhydride, preferably in the presence of pyridine or of other tertiary bases used in such an amount to act also as a reaction medium.
The hemisuecinates, besides showing, as said, a very valuable activity on the central nervous system, present the great advantage of being easily salified by neutralization with an equimolecular amount of an organic or inorganic base and thus transformed in water-soluble hemisuccinates; these aqueous solutions may be easily administered by parenteral route, what form of administration is not possible today with any other benzodiazepine.
Re. 28,287 Reissued Dec. 31, 1974 The advantage of the treatment by injection resides in that a rather immediate therapeutic effect may be obtained. Particularly good results have been obtained with sodium hemissuecinates.
We have now found that of the two optically active isomers which constitute the racemic hemisuccinates of Formula I, the dextro rotatory form is by far more active than the levorotatory one.
It is immediately evident how advantageous it would be to eliminate the poorly active levo-form while obtaining in the pure state the highly active dextro-form which produces the same therapeutic effect at by far lower doses and thus with by far lower toxic eliects.
We have now found a process which allows the resolution of the racemic hemisuecinates of Formula I in a simple and economical manner leading to the dextrorotatory hemisuceinate in high yields; the levo-rotatory hemisuecinates may be also recovered in high yields, hydrolyzed to the racemic 3 hydroxy compounds, these again esterified to the racemic hemisuecinates and as such recycled.
The process object of the present invention is based on the discovery that the salts of the (+)hemisuccinates and (-)hemisuccinates with (+)cphcdrine or ()ephedrine have a sharply different solubility in ethylacetatc. More precisely the salts formed by the (+)hernisuccinates of Formula I with ()ephedrine show a very low solubility in ethyl acetate, while the salts of the (--)hcinisuceinates with ()ephedrine are highly soluble in the same solvent. The solubility of the ()ephedrine (+)hemisuccinates in ethyl acetate is still remarkably lower in the presence of the salts ()ephedrine ()hemisuccinate.
When the (+)ephedrine is used as salifying compound, the two salts obtained show an opposite behaviour, with respect to the solubility in ethyl acetate, when compared with the salts of ()ephedrine; that is the salts of the (+)hemisuccinates with (+)ephedrine are highly soluble in ethyl acetate, while the salts of the ()hemisuccinates with (+)ephedrine are nearly insoluble in the same solvent.
Between the two alternatives of the process, that using the ()ephedrine in the preferred one, since to obtain the (+)hemisuceinates as a precipitate rather than as a solution, accounts for a higher purity of the desired product. In an indicative manner it may be said that the solubilities in ethyl acetate at 50 C. of the ()ephedrine salts of (+)hernisuccinates and of ()hernisuceinates of Formula I are nearly as follows:
M g./ cc. )ephedrine )hemisuccinate 1 )ephedrine )hemisuccinate 50 The solubility of the ()ephedrine (-|-)hemisuccinates in ethyl acetate is still lower in the presence of the salts )ephedrine )hernisuccinate.
Taking advantage of the characteristics of solubility in ethyl acetate of the salts with ()ephedrine of (+)hemisuecinates and (-)hemisuccinates of Formula I the following industrial process has been set up. The racemic hemisuccinates and the (-)ephedrine are made toreact in hot ethyl acetate, the amount of the solvent being proportionated in such a manner to be sure that the whole ()ephedrine ()hemisuecinate salt formed remains 1n solution. To operate with a salt concentration between 2 and 15% is generally appropriate. The most of the formed ()ephedrine (+)hemisuccinatc precipitates from the warm solution. With certain hemisuccinates and depending on the salt concentration adopted at the start, it is convenient to cool the reaction mixture to 10 C. with a water-ice bath to obtain a complete precipitation. The formed crystalline precipitate, consisting essentially of (--)ephedrine (+Jhemisuccinate, is filtered,
3 dissolved in a suitable solvent and hydrolyzed with an acid.
According to a preferred embodiment of the invention, the hydrolysis is carried out with acetic acid which is suitable to act both as a solvent and as hydrolysing agent. Moreover, acetic acid does not cause any yellowing of the product, as mineral acids do. By dilution with water up to incipient crystallization and successive cooling, the pure (+)hemisuccinate crystallizes out, is dried and may be recrystallized from a suitable solvent such as for example acetic acid/water or ethyl-alcohol/water. In order to render the process economically more convenient. it is always preferred to recover the (-)hemisuccinate contained in the solution under the form of salt with ephedrine.
To perform such a recovery, the following procedure is adopted: the solution wherefrom the crystals of (-)ephedrine (+)hemisuccinate have been removed, is evaporated under vacuum up to dryness. The residue is dissolved with acetic acid (preferably at 5060 C.) and taken up with water to incipient crystallization.
The ()hemisuccinate which precipitates, is dissolved in a solvent for example in ethyl alcohol, added with an excess of aqueous 4 N NaOH under stirring and kept still under stirring up to complete precipitation. The precipitate is dissolved with water and from the clear solution the racemic B-hydroxy compounds are precipitated by acidification, preferably with acetic acid. The racemic 3-hydroxy compound is esterified with succinic acid and as such recycled.
As initially said, the separation of (+)hemisuccinate and ()hemisuccinate can be carried out also through the salts with (-i-)cphedrine, by following nearly the above technique wilh only the obvious variations.
However, as said, this method is less convenient then that performed through the (-)ephedriue, due to the (+)cphedrine (-l-)hemisuccinate salt remaining in solution being removable only with lower yields and with a lower degree of purity.
In order to better describe the separation object of the present invention, illustrative but not limitativ examples are reported hereinafter.
EXAMPLE 1 l g. of racemic 7-NO -hemisuccinate are dissolved under stirring and relluxing into 250 cc. of ethyl acetate. To this solution 4.2 g. of (-)ephedrine dissolved in 20 cc. of ethyl acetate are added dropwise. A remarkable amount of crystals precipitates within a few seconds. Heating is discontinued and the mixture is allowed to cool under stirring up to 5060 C. At this temperature the mass of precipitated crystals is filtered, washed with ethyl acetate and dried. 6.75 g. of (-)ephedrine (+)7-NO hemisuccinate are obtained.
The filtrate (A) is set aside, to undergo successive recovery procedure. The salt (-)ephedrine (+)7-NO hemisuccinate is dissolved in 50 cc. of glacial acetic acid at 60 (1., added with hot water up to incipient crystallization, cooled and filtered. 4.25 g. of (+)7-NO -hemi succinate are obtained which, after recrystallization from ethyl alcohol/water show the following characteristics:
Analysis of (+)7-NO hemisuccinate-2H O Calculated Found C 52. 65 52. 74 ll 4. 38 4. N ll. 70 U. 74
This highly pure ester is ready to be used, as such or as salt, in the hterapeutic field.
The filtrate (A) is evaporated under vacuum to dryness and the residue is taken up at 60 C., up to dissolution, with the smallest possible quantity of acetic acid. By addition of water and cooling 4.1 g. of (-)7-NO hemisuccinate precipitate which are separated by filtration is dissolved in 100 cc. of ethyl alcohol. To this solution 12.5 cc. of 4 N NaOH are added dropwise, after about 15 minutes stirring a precipitate is obtained, which is redissolved by addition of cc. water; the solution is acidified with acetic acid.
The crystalline precipitate is filtered and recrystallized from dioxane. 2.6 g. of racemic 7-NO -3-oxy-5-phenyll,4-dihydro-2H-1,4-benzodiazepine-2-one are obtained ready for esterification with succinic acid and recycling.
EXAMPLE 2 10 g. of racemic 7-Cl-hemisuccinate are dissolved under stirring into cc. of hot ethyl acetate.
To this solution, 4.3 g. of (-)ephedrine dissolved in 20 cc. of ethyl acetate are added dropwise.
A remarkable amount of crystals precipitates within a few seconds. Heating is discontinued and the mixture is allowed to cool under stirring. When the room temperature is reached the mixture is further cooled to 10 C. with water-ice and at this temperature kept over one hour. The mass of precipitated crystals is filtered, washed with anhydrous ethyl acetate and dried. 6.75 grams of (-)ephedrine (+)7 C1 hemisuccinate are obtained showing the following characteristics:
The filtrate (A) is temporarily set aside.
The salt ()ephedrine (+)7-Cl-hemisuccinate is dissolved in 50 cc. of glacial acetic acid at 70-80 C., added with hot water up to incipient crystallization, allowed to crystallize by cooling.
4.25 g. of )7-Cl-hemisuccinate are filtered out which, after recrystallization from ethyl acetate/hexane, show the following characteristics;
This highly pure ester is ready to be used, as such or as sodium salt, in the therapeutic field.
The filtrate (A) is added with 2 cc. glacial acetic acid, evaporated under vacuum to dryness and the residue is taken up, up to dissolution, with the smallest possible quantity of acetic acid, at 70-80 C. By addition of water and cooling 4.1 g. of (-)hemisuccinate precipitate which are separated by filtration and dissolved in 100 cc. of 95 ethyl alcohol. This solution is cooled and kept at 10 C., while adding dropwise 51 cc. of N NaOH.
After about 15 minutes stirring, a precipitate is obtained which is filtered otf and dissolved in a mixture water-ethyl alcohol 50:50. The solution is acidified with acetic acid.
The crystalline precipitate is filtered and recrystallized from dioxane-water. 2.6 g. of racemic 7-chloro-3-oxy-5- phenyl-1,4-dihydro-2H-l,4-benzodiazepine-2-one are obtained, ready for esterification and thus recycling.
EXAMPLE 3 10 g. of racemic 7-Br-hemissuccinate are dissolved under stirring into 140 cc. of ethyl acetate.
To this solution, 3.8 g. of (-)ephedrine dissolved in 20 cc. of ethyl acetate are added dropwise.
Following the identical procedure described in the preceding example, 4.5 g. of (+)7-Br-hernisuccinate are obtained which, after recrystallization from ethyl acetatc/ hexane show the following characteristics:
Analysis.-Calculated for C ,,H N O Br (percent): C, 52.95; H, 3.48; N, 6.49. Found (percent): C, 53.20; H, 3.53; N, 6.51.
As initially said, the great importance of the process according to the invention resides in that it provides highly valuable pharmaceutical compounds.
The great advantage of using the (+)hernisuccinates instead of the racemics hemisuccinates is particularly evident when the elficacy indexes of these products are considered.
(c.=3% in In the following Table I, the efficacy indexes of the most important among the considered compounds, namely 7-Cl-hemisuccinate and 7-NO -hemisuccinate are given.
+=Test with 120 rngjkg. lntraperltoneally injected cardiazol, drug administered minutes ante.
++=Test with 200 rngJkg. intraperitoneally injected cardlazol, drug administered 30 minutes ante.
The tests by intraperitoneal or intravenous injection of 7-Cl-hemisuccinates have been performed dissolving the amount to be tested of racemic or (+)hemisuccinate in two drops of diethyl acetamide, then adding 6 cc. of a solvent mixture (A) consisting of:
parts by volume of propyleneglycol, 30 p. by v. of glycofurol and 5 p. by v. of benzyl alcohol. Finally 14 cc. of water are added. The concentration of the tested compound has been regulated to inject the product, both intraperitoneally or intravenously, at a dose of 5 ccJkg. of treated animal.
The tests per os have instead been performed dissolving the desired amount of product in 1.5 cc. of mixture (A) and then adding 3.5 cc. of a 510% aqueous solution of carboxymethyl cellulose. Also in this case the concentration is so regulated to have the right amount of drug in 5-10 cc./kg. of treated animal, which is the dose administered.
The tests with 7-NO -hemisuccinates have been performed by injecting 5 cc./kg, of a solution prepared dissolving the desired amount of product in 2 drops of diethylacetamide and then diluting to the desired volume with Sorenson buffer solution, having a pH 7.4.
The results obtained in pharmacology have been quite confirmed with the clinical tests.
In order to have data as reliable as possible, the drugs of the invention were administered to healthy men. Moreover the various optical forms of the drugs, namely the dextrorotatory, levorotatory and racemic ones, were administered to the same individuals, spacing the administration of drugs of different optical activity of two weeks.
For all the treated individuals a clear tranquilizing activity resulted only when the dextrorotatory 7-Cl-hemisuccinate and 7-NO -hemisuccinate were used. No effect at all was noticed with the racemic forms or with the levorotatory forms.
As another demonstration of efiicacy of the (+)hemisuccinates of the invention, their absorption and retention in the organism was tested in comparison with that of the racemates and of the levo-forms, by determining the amount of drug eliminated as glucoronate in urine after 24 and 48 hours.
The results obtained with the 7-Cl-hemisuccinates are summarized in the following Table II where the compound eliminated is expressed as a percentage of the drug injected in the organism, respectively (column 1) in the first 24 hours and (column 2) in the successive 24 hours from the administration.
The above data clearly show that the dextro-form is less eliminated by the organism, thus accounting for a stronger action.
What is claimed is:
1. Process for the resolution into optical antipodes of racemic 3 succinyloxy 5 phenyl 1,3 dihydro 2H- l,4-benzodiazepine-2-one derivatives i.e., the compound of the formula NH- C 0 c H-O C O CH CH C O O H C=N hat. (I)
wherein R is N0 Cl, Br, F,
through selective solubilization in ethylacetate of their salts with optically active ephedrine.
2. Process according to claim 1, wherein the optically active ephedrine is (-)ephedrine.
3. Process according to claim 1 wherein the racemic succinyloxy derivatives of Formula I and (-)ephedrine are made to react in boiling ethyl acetate.
4. Process according to claim 1, wherein an amount of ethyl acetate is used such as to have a salt concentration between 2 and 15%.
5. Process according to claim 1, wherein a nearly quantitative precipitation of the salt with (-)ephedrine of (+)succinyloxy derivatives of Formula I, takes place between 50 and 10 C.
6. A compound of the formula References Cited The following references, cited by the Examiner, are of record in the patented file of this patent or the original patent.
UNITED STATES PATENTS 5/1969 Bell 260-239.3 D
OTHER REFERENCES Gilman Organic Chemistry, 2nd ed. (Wiley) (1943), pp. 254-264, in particular pp. 256-260.
HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl. X.R. 260-2393 D
Claims (1)
1. PROCESS FOR THE RESOLUTION INTO OPTICAL ANTIPODES OF RACEMIC 3 - SUCCINYLOXY - 5 - PHENYL - 1,3 - DIHYDRO - 2H1,4-BENZODIAZEPINE-2-ONE DERIVATIVES I.E., THE COMPOUND OF THE FORMULA
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB975970A GB1268783A (en) | 1969-04-08 | 1969-04-08 | Benzodiazepine derivatives |
GB1803469 | 1969-04-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE28287E true USRE28287E (en) | 1974-12-31 |
Family
ID=26243153
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US22673A Expired - Lifetime US3654267A (en) | 1969-04-08 | 1970-03-25 | Process for the resolution of racemic 3-succinyloxy - 5 -phenyl-1 3-dihydro-2h-1 4 - benzodiazepine - 2-one-derivatives into optical antipodes |
US28773472 Expired USRE28287E (en) | 1969-04-08 | 1972-09-11 | Into optical antipodes |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US22673A Expired - Lifetime US3654267A (en) | 1969-04-08 | 1970-03-25 | Process for the resolution of racemic 3-succinyloxy - 5 -phenyl-1 3-dihydro-2h-1 4 - benzodiazepine - 2-one-derivatives into optical antipodes |
Country Status (8)
Country | Link |
---|---|
US (2) | US3654267A (en) |
BE (1) | BE791988Q (en) |
CH (1) | CH533067A (en) |
DE (1) | DE2016810A1 (en) |
ES (1) | ES378296A1 (en) |
FR (1) | FR2068453B1 (en) |
NL (1) | NL7004846A (en) |
NO (1) | NO123760B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1292474A (en) * | 1970-06-25 | 1972-10-11 | Ravizza Spa | Benzodiazepine derivatives |
US3903276A (en) * | 1972-03-20 | 1975-09-02 | American Home Prod | N-carboxymethyl-N-substituted glycinate esters of 3-hydroxy-1,4-benzodiazepin-2-ones for inducing a calming effect |
-
0
- BE BE791988D patent/BE791988Q/en active
-
1970
- 1970-03-25 US US22673A patent/US3654267A/en not_active Expired - Lifetime
- 1970-04-03 NL NL7004846A patent/NL7004846A/xx unknown
- 1970-04-06 ES ES378296A patent/ES378296A1/en not_active Expired
- 1970-04-07 NO NO1275/70A patent/NO123760B/no unknown
- 1970-04-08 DE DE19702016810 patent/DE2016810A1/en active Pending
- 1970-04-08 CH CH519670A patent/CH533067A/en not_active IP Right Cessation
- 1970-04-08 FR FR7012692A patent/FR2068453B1/fr not_active Expired
-
1972
- 1972-09-11 US US28773472 patent/USRE28287E/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
FR2068453B1 (en) | 1974-05-24 |
US3654267A (en) | 1972-04-04 |
FR2068453A1 (en) | 1971-08-27 |
ES378296A1 (en) | 1973-02-01 |
NO123760B (en) | 1972-01-10 |
BE791988Q (en) | 1973-03-16 |
DE2016810A1 (en) | 1970-11-19 |
CH533067A (en) | 1973-01-31 |
NL7004846A (en) | 1970-10-12 |
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