CH544775A - D-and l-isomers of 6h, 7h, cis-7-amino-3-aminomethyl cef -3 - Google Patents
D-and l-isomers of 6h, 7h, cis-7-amino-3-aminomethyl cef -3Info
- Publication number
- CH544775A CH544775A CH1334071A CH1334071A CH544775A CH 544775 A CH544775 A CH 544775A CH 1334071 A CH1334071 A CH 1334071A CH 1334071 A CH1334071 A CH 1334071A CH 544775 A CH544775 A CH 544775A
- Authority
- CH
- Switzerland
- Prior art keywords
- lactam
- aminomethyl
- acid
- carboxylic
- thiazine
- Prior art date
Links
- 229960001945 sparteine Drugs 0.000 claims abstract description 11
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- NLXPSEHDXHHCNM-UHFFFAOYSA-N 5-(aminomethyl)-3,4-dihydro-2H-1,3-thiazine-4-carboxylic acid Chemical compound NCC=1C(NCSC=1)C(=O)O NLXPSEHDXHHCNM-UHFFFAOYSA-N 0.000 claims description 19
- 150000003953 γ-lactams Chemical class 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- -1 alkyl radical Chemical class 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical class C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- JZPZIFOBEUPCKA-UHFFFAOYSA-N 2h-1,3-thiazine-4-carboxylic acid Chemical compound OC(=O)C1=NCSC=C1 JZPZIFOBEUPCKA-UHFFFAOYSA-N 0.000 claims description 4
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 150000002081 enamines Chemical class 0.000 claims description 2
- 229960002179 ephedrine Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 125000003441 thioacyl group Chemical group 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 2
- VGYDMOUMIQOMMU-UHFFFAOYSA-N 3,4-dihydro-2h-1,3-thiazine Chemical compound C1NCC=CS1 VGYDMOUMIQOMMU-UHFFFAOYSA-N 0.000 claims 1
- RHFFIPXCSYYCFE-UHFFFAOYSA-N 4,5-dioxopyrrolidine-3-carboxylic acid Chemical compound OC(=O)C1CNC(=O)C1=O RHFFIPXCSYYCFE-UHFFFAOYSA-N 0.000 claims 1
- MSTFRUQNYRRUKZ-UHFFFAOYSA-N 5,6-dihydro-2h-thiazine Chemical compound C1CC=CNS1 MSTFRUQNYRRUKZ-UHFFFAOYSA-N 0.000 claims 1
- 229930008564 C01BA04 - Sparteine Natural products 0.000 claims 1
- 238000006136 alcoholysis reaction Methods 0.000 claims 1
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 238000005902 aminomethylation reaction Methods 0.000 claims 1
- 150000005840 aryl radicals Chemical class 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 150000003573 thiols Chemical group 0.000 claims 1
- 238000005866 tritylation reaction Methods 0.000 claims 1
- 238000006642 detritylation reaction Methods 0.000 abstract description 2
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical class CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ASNCVAQMEWGGPS-UHFFFAOYSA-N 2-(aminomethyl)-3,4-dihydro-2H-1,3-thiazine-4-carboxylic acid Chemical compound NCC1SC=CC(N1)C(=O)O ASNCVAQMEWGGPS-UHFFFAOYSA-N 0.000 description 1
- VGKZBAMIYUHSMU-UHFFFAOYSA-N 4-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(NC(=O)N(CCCl)N=O)CC1 VGKZBAMIYUHSMU-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
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- H—ELECTRICITY
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- H01H9/18—Distinguishing marks on switches, e.g. for indicating switch location in the dark; Adaptation of switches to receive distinguishing marks
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- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
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- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur atoms
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- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/42—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by an araliphatic carboxylic acid
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- H01H13/50—Switches having rectilinearly-movable operating part or parts adapted for pushing or pulling in one direction only, e.g. push-button switch having a single operating member
- H01H13/52—Switches having rectilinearly-movable operating part or parts adapted for pushing or pulling in one direction only, e.g. push-button switch having a single operating member the contact returning to its original state immediately upon removal of operating force, e.g. bell-push switch
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- Cephalosporin Compounds (AREA)
Abstract
Title cpds. of formula (I): (where R2 is H, alkyl or aryl) are prepd. from trityl derivs. of formula (II) by (i) resolution of the 1-sparteine diastereoisomers; (ii) ring closure with dicyclohexylcarbodiimide; (iii) detritylation with HCl gas in MeNO2.
Description
On a décrit dans le brevet suisse N 515276 un procédé de pré paration de dérivés de la céphalosporine, racémiques ou optique- ment actifs, de formule générale:
EMI0001.0010
EMI0001.0011
EMI0001.0012
EMI0001.0013
dans laquelle <B>R'</B> et<B>R"</B> représentent des radicaux alcoyle ou aral- coyle ou forment ensemble le reste d'un hétérocycle, remplace dans ce composé le groupe amine substituée
EMI0001.0027
par un groupe thioacyle,
EMI0001.0029
EMI0001.0030
condense ce dernier avec une énamine de formule VII
EMI0001.0033
dans laquelle R représente un radical alcoyle inférieur ou un radi cal aralcoyle inférieur et Y représente un groupe imido ou un groupe acylamino où le terme acyl figure le reste d'un acide organique carboxylique infé rieur, obtient un y-lactame de l'acide 2-(a-R-oxy carbonyl a-Y- méthyl)
5-aminométhyl 2,3-dihydro 1,3-thiazine 4-carboxylique, de formule VIII:
EMI0001.0048
qui se présente sous forme d'un mélange d'isomères thréo et érythro, ottsous forme de l'un des deux, scinde le groupe imido ou le groupe acylamino, Y, par un échange de fonction à l'aide de l'hydrazine, par une hydrolyse acide ou par une hydrogénolyse,
obtient le y-lactame correspondant de formule VIII':
EMI0001.0060
pouvant exister sous forme d'isomères thréo et érythro, dont on libère le groupe carboxyle par l'action d'un agent acide, obtient un y-lactame de l'acide 2-(a-carboxy a-aminométhyl) 5-aminomé- thyl 2,3-dihydro 1,3-thiazine 4-carboxylique, de formule IX:
EMI0001.0073
pouvant exister sous forme d'isomères thréo et érythro qu'on traite par un agent de tritylation, obtient un y-lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3-thiazine 4-carboxylique de formule IX':
EMI0002.0010
EMI0002.0011
dans laquelle Rl a la signification précitée, et fait agir sur ces composés un agent acide pour obtenir respectivement les iso mères D et L du y-lactame de l'acide 6H, 7H cis 7-amino 3-ami- nométhyl céph-3-ème 4-carboxylique correspondants cherchés.
Le procédé, objet de la présente invention, possède sur celui du brevet suisse N 515276 l'avantage d'opérer le dédoublement à un stade moins avancé de la synthèse, ce qui est économiquement plus avantageux.
Les indications données ci-après ont trait, pour des raisons de simplifications, plus spécialement au cas où Ri = H.
Le réactif à l'aide duquel on effectue le dédoublement du dl y- lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5-aminomé- thyl 2,3-dihydro 1,3-thiazine 4-carboxylique est, de préférence,
la 1-spartéine. On opère de .manière avantageuse au sein d'un mélan ge d'eau et de méthanol et insolubilise le sel de spartéine du D y- lactame de l'acide 2-(a-carboxy oc-tritylaminométhyl) 5-aminomé- thyl 2,3-dihydro 1,3-thiazine 4-carboxylique. De ce sel, par acidifi- cation,
on libère le D y-lactame de l'acide 2-(a-carboxy oc-trityla- minométhyl) 5-aminométhyl 2,3-dihydro 1,3-thiazine 4-carboxyli- que.
Pour purifier ce dernier, on peut en former à nouveau le sel de 1-spartéine que l'on cristallise dans un solvant convenable, no- tamment dans un mélange d'eau et de méthanol, puis libère à nouveau le composé désiré par action d'un agent acide sur le sel de spartéine purifié.
Le sel de spartéine de l'isomère L du y-lactame de l'acide 2-(oc- carboxy oc-tritylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3- thiazine 4-carboxylique se trouve dans les liqueurs mères de cris tallisation du sel de spartéine de l'isomère D.
Par acidification de ces liqueurs mères, on insolubilise le L y- lactame de l'acide 2-(at-carboxy oc-tritylaminométhyl) 5-aminomé- thyl 2,3-dihydro 1,3-thiazine 4-carboxylique.
Ce composé peut être purifié par transformation en sel d'éphé- drine, cristallisation de ce sel d'éphédrine dans un-solvant ou un mélange de solvants convenables tel qu'un mélange de méthanol et de chlorure de méthylène, puis mise en liberté du composé dési ré par acidification du sel d'éphédrine purifié.
La 1-spartéine utilisée pour le dédoublement est récupérée dans les liqueurs mères d'obtention du D y-lactame de for- mule IX' et du L y-lactame de formule IX' par alcalinisation et élimination du solvant par distillation sous pression réduite.
Par action d'un agent de cyclisation, tel que le dicyclohexyl- carbodiimide, les y-lactames D et L de l'acide 2-(a-carboxy oc-tri- tylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3-thiazine 4-car- boxylique, de formule IX', sont transformés respectivement en y- lactame de l'acide D ou L 6H,
7H cis 7-tritylamino 3-aminomé- thyl céph-3-ème 4-carboxylique, en opérant par exemple dans un mélange de solvants constitué par le nitrométhane, la pyridine et le chlorure de méthylène.
La détritylation de ces y-lactames D et L est effectuée de pré férence à l'aide de l'acide chlorhydrique gazeux, en opérant dans le nitrométhane et l'on obtient respectivement les y-lactames D et L de l'acide 6H, 7H cis 7-amino 3-aminométhyl céph-3-ème 4-car- boxylique de formule I.
L'exemple suivant illustre l'invention. Pour les premières étapes du procédé, on se reportera au brevet principal mentionné précédemment. Exemple: y-lactame <I>de l'acide L (ou D) 6H, 7H</I> cis 7-amino 3-ami- nométhyl céph-3-ème 4-carboxylique.
Stade <I>A: Dédoublement du dl</I> y-lactame <I>de l'acide</I> 2-(a-carboxy <I>a-</I> <I>tritylaminométhyl)</I> 5-aminométhy12,3-dihydro 1,3-thiazine 4-car- boxylique <I>(isomère</I> thréo).
<I>a) Obtention de l'isomère D</I> A une solution de 3,75 g de 1-spartéine dans 25 cm3 de métha nol, on ajoute, sous agitation, 5 g de DL y-lactame de l'acide 2-(a- carboxy a-tritylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3- thiazine 4-carboxylique (isomère thréo), ajoute 25 cm3 d'eau, ar rête l'agitation,
ajoute quelques amorces cristallines de sel de spartéine du D y-lactame de l'acide 2-(a-carboxy a-tritylaminomé- thyl) 5-aminométhyl 2,3-dihydro 1,3-thiazine 4-carboxylique (iso mère thréo), laisse au repos une heure à 20 C, isole le précipité de sel de spartéine, par essorage, le lave, le sèche. On conserve les li queurs mères de cristallisation (liqueurs mères A).
Les 3,67 g de précipité obtenus sont dissous dans 20 volumes de méthanol, on acidifie par l'acide acétique, laisse cristalliser, essore, lave au mé thanol puis à l'éther, sèche et obtient 2,15 g de D y-lactame de l'acide 2-(oc-carboxy oa-tritylaminométhyl) 5-aminométhyl 2,3-di- hydro 1,3-thiazine 4-carboxylique (isomère thréo) brut, conserve les liqueurs mères de cristallisation (liqueurs mères B).
EMI0002.0168
(c=0,6%, méthanol à 1% de triéthylamine). On <I>Purification:</I> On opère sur 15 g d'isomère D brut provenant de plusieurs es sais de dédoublement que l'on introduit dans une solution de 11,25 g de I-spartéine dans 100 cm3 de méthanol, chauffe à 40 C pour obtenir la dissolution, refroidit à 20 C, ajoute 100 cm3 d'eau distillée, laisse cristalliser, isole le précipité par essorage, le lave par un mélange méthanol-eau (1,1) puis à l'éther, le reprend par 250 cm3 de méthanol, filtre, acidifie par l'acide acétique, laisse cristalliser, isole par essorage le précipité formé, le lave au métha nol, à l'éther, le sèche et obtient 12,
1 g de D y-lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3-thiazine 4-carboxylique (isomère thréo)
EMI0002.0182
(c=0,5%, méthanol à 1 % de triéthylamine).
Pour autant que l'on sache, ce composé n'est pas décrit dans la littérature.
Il en est de même du sel de 1-spartéine du D y-lactame de l'acide 2-(oc-carboxy a-tritylaminométhyl) 5-aminométhyl 2,3-di- hydro 1,3-thiazine 4-carboxylique.
<I>b)</I> Obtention <I>de l'isomère L</I> Les liqueurs mères de cristallisation du sel de 1-spartéine de l'isomère D (liqueurs mères A) sont acidifiées par l'acide acétique, on isole par essorage le précipité formé, le lave au méthanol, à l'éther, le sèche et obtient 1,6 g de L y-lactame de l'acide 2-(at-car- boxy a-tritylaminométhyl) 5-aminométhyl 2,3-dihydro 1,3-thia- zine 4-carboxylique (isomère thréo)
brut
EMI0002.0206
(c=0,5%, méthanol à I % de triêthylamine). On conserve les liqueurs mères de cristallisation (liqueurs mères C).
<I>Purification:</I> On opère sur 13,2 g d'isomère L brut provenant de divers es sais de dédoublement, que l'on introduit dans une solution de 6,6 g de 1-éphédrine dans 82 CM3 de méthanol. Dans la solution obtenue, on introduit lentement 164 cm3 d'éther éthylique, laisse cristalliser, isole par essorage le précipité formé; lave à l'éther, sè che.
Les 12,5 g de sel d'éphédrine brut obtenus sont dissous dans 400 CM3 d'un mélange de méthanol et de chlorure de méthylène (1-1), on filtre, acidifie par l'acide acétique, laisse cristalliser, isole par essorage le précipité formé, le lave au méthanol, à l'éther, le sèche et obtient 8,43 g de L y-laetame de l'acide 2-(ix-carboxy a tritylaminométhyl)
5-aminométhyl 2,3-dihydro 1,3-thiazine 4-car- boxylique (isomère thréo@
EMI0003.0034
(c=0,57%, méthanol à 1 % de triéthylamine): Pour autant que l'on sache, ce composé n'est pas décrit dans la littérature.
I l en est de même du sel de 1-éphédrine du L y-lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5-aminornéthyl 2,3-di- hydro 1,3-thiazine 4-carboxylique. Récupération <I>de la</I> l-spartéine On réunit les liqueurs mères B et C, les alcalinise par la soude 2N, extrait à l'éther,
lave la solution éthérée à l'eau, sèche, élimine le solvant par distillation sous pression réduite, et récu- père la I-spartéine avec un rendement pratiquement quantitatif.
Stade <I>B:</I> y-lacrame <I>de</I> l'acide <I>L 6H, 7H</I> cis 7-tritylamino 3-amino- méthyl céph-3-ème 4-carboxylique Dans 20 em3 de pyridine, on introduit 2 g de L y-lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5-aminométhyl 2,
3-di- hydro 1,3-thiazine 4-carboxylique (isomère thréo), ajoute 1,5 g de dicyclohexylcarbodiimide, 40 CM3 de chlorure de méthylène, 40 CM3 de nitrométhane, laisse au repos à 20 C, sous atmosphère d'azote, à l'obscurité, pendant dix-huit heures;
élimine par filtra tion la dicyclohexyhrrée, concentre le filtrat à sec par distillation sous pression réduite, ajouté' de l'éther, isole par essorage le préci pité formé, le reprend su chlorure de méthylène, ajoute du char bon actif à la solution obtenue, agite,
élimine le charbon actif par filtration, concentre le filtrat à sec par distillation sous pression réduite, purifie le résidu par chromatographie sur gel de silice en éluant par un mélange de chloroforme, d'acétate d'éthyle et d'éthanol (75-15-10), obtient 2'g d'un produit homogène,
le dis sout dans le chlorure de méthylène, ajoute de l'éther éthylique, isole par essorage le précipité formé et obtient 1,22 g de y-lactame de l'acide L 6H, 7H cis 7-trityiamino 3-aminornéthyl céph-3-ème 4-carboxylique,
EMI0003.0143
(c-0,5%, chloroforme).
Pour autant que l'on sache, ce composé n'est pas décrit dans la littérature.
De manière analogue à celle utilisée dans. l'exemple, au départ du D y-lactame de l'acide 2-(a-carboxy a-tritylaminométhyl) 5- aminométhyi 2,3-dihydro 1,3-thiazine 4-carboxylique, on obtient le y-lactame de l'acide D 6H,<B>7H</B> cis 7-tritylamino 3-aminométhyl oéph-3-ème4-caiboxylique,
EMI0003.0168
(c=0,5%,chloroforme).
Pour autant que l'on sache, ce composé n'est pas décrit dans la littérature.
Stade <I>C:</I> y-lacrame <I>de</I> l'acide <I>L</I> 6H, <I>7H</I> cis 7-amino 3-aminométhyl céph-3-ème 4-carboxylique Dans 8 cm3 de nitrornéthane, on dissout 1 g de y-lactame de l'acide L<B>6H,
</B> 7H cis 7-tritylamiuo 3-aminométhyl céph-3-ème 4- carboxylique, refroidit la solution obtenue à + 10 C, y fait barbo ter de l'acide chlorhydrique gazeux pendant vingt minutes,
éli- mine 1 cm3 <B>de</B> nitrométhane par distillation sous pression réduite, ajoute 30 CM3 d'éther, isole par essorage le précipité formé, le lave à l'éther, le reprend par de l'éthanol, ajoute un léger excès de trié- thylamine, laisse cristalliser,
isole par essorage le précipité formé, le lave à l'éthanol, à l'éther, le sèche et obtient 400 mg de y-lac- tame de l'acide L 6H, 7H cis 7-amino 3-aminométhyl céph-3-ème 4-carboxylique,
EMI0003.0225
(c=0,5%, eau).
Un échantillon de ce produit est purifié par dissolution dans une solution aqueuse normale d'acide chlorhydrique, passage au charbon actif et addition de triéthylamine (rendement de purifica tion: 80%i
EMI0003.0230
(c=0,5%, eau).
De la même façon, au départ du y-lactame de l'acide D 6H, 7H cis 7-tritylamino 3-aminométhyl céph-3-ème 4-carboxylique, on obtient le y-lactame de l'acide D 6H, 7H cis RTI ID="0003.0239" WI="11" HE="4" LX="1683" LY="609"> 7-amino 3-amino- méthyl céph-3-ème 4-carboxylique.
Les isomères D et L du y-lactame obtenus sont identiques à ceux décrits dans le brevet suisse N 515276.
Swiss Patent No. 515276 has described a process for the preparation of cephalosporin derivatives, racemic or optically active, of general formula:
EMI0001.0010
EMI0001.0011
EMI0001.0012
EMI0001.0013
in which <B> R '</B> and <B> R "</B> represent alkyl or aralkyl radicals or together form the residue of a heterocycle, in this compound replaces the substituted amine group
EMI0001.0027
by a thioacyl group,
EMI0001.0029
EMI0001.0030
condenses the latter with an enamine of formula VII
EMI0001.0033
in which R represents a lower alkyl radical or a radi cal aralkyl lower and Y represents an imido group or an acylamino group where the term acyl is the residue of a lower organic carboxylic acid, obtains a y-lactam of acid 2 - (aR-oxy carbonyl aY- methyl)
4-carboxylic 5-aminomethyl 2,3-dihydro 1,3-thiazine, of formula VIII:
EMI0001.0048
which is in the form of a mixture of threo and erythro isomers, otts in the form of one of the two, cleaves the imido group or the acylamino group, Y, by an exchange of functions using hydrazine, by acid hydrolysis or by hydrogenolysis,
obtains the corresponding γ-lactam of formula VIII ':
EMI0001.0060
which may exist as threo and erythro isomers, the carboxyl group of which is released by the action of an acidic agent, obtains a γ-lactam of 2- (a-carboxy a-aminomethyl) 5-aminomé acid thyl 2,3-dihydro 1,3-thiazine 4-carboxylic, of formula IX:
EMI0001.0073
which may exist in the form of threo and erythro isomers which are treated with a tritylating agent, obtains a y-lactam of 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3 -4-carboxylic thiazine of formula IX ':
EMI0002.0010
EMI0002.0011
in which Rl has the aforementioned meaning, and causes an acidic agent to act on these compounds to obtain respectively the isomers D and L of the γ-lactam of 6H, 7H cis 7-amino 3-aminomethyl ceph-3- acid th 4-carboxylic correspondents sought.
The process, which is the subject of the present invention, has the advantage over that of Swiss Patent No. 515276 of performing the resolution at a less advanced stage of the synthesis, which is economically more advantageous.
The indications given below relate, for reasons of simplification, more especially to the case where Ri = H.
The reagent with the aid of which the resolution of the dl y-lactam from 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid is carried out is, preferably,
1-sparteine. The procedure is advantageously carried out in a mixture of water and methanol and the sparteine salt of D y-lactam of 2- (a-carboxy oc-tritylaminomethyl) 5-aminomethyl acid is insolubilized. , 3-dihydro 1,3-thiazine 4-carboxylic. Of this salt, by acidification,
the D y-lactam is freed from 2- (a-carboxy oc-tritylomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid.
To purify the latter, it is possible to form again the salt of 1-sparteine which is crystallized in a suitable solvent, in particular in a mixture of water and methanol, then liberates again the desired compound by the action of an acidic agent on the purified spartein salt.
The sparteine salt of the L-isomer of 2- (oc-carboxy oc-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid isomer is found in mother liquors of crystallization of the spartein salt of the D isomer.
By acidification of these mother liquors, the L y-lactam of 2- (at-carboxy α-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid is insolubilized.
This compound can be purified by transformation into the ephedrine salt, crystallization of this ephedrine salt in a solvent or a mixture of suitable solvents such as a mixture of methanol and methylene chloride, and then setting free of the solvent. compound desired by acidifying the purified ephedrine salt.
The 1-sparteine used for the resolution is recovered in the mother liquors for obtaining D y-lactam of formula IX 'and L y-lactam of formula IX' by basification and removal of the solvent by distillation under reduced pressure.
By the action of a cyclizing agent, such as dicyclohexylcarbodiimide, γ-lactams D and L of 2- (α-carboxy α-tri-tylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3 -thiazine 4-carboxylic, of formula IX ', are transformed respectively into y-lactam of acid D or L 6H,
7H cis 7-tritylamino 3-aminomethyl ceph-3-rd 4-carboxylic, for example by operating in a mixture of solvents consisting of nitromethane, pyridine and methylene chloride.
The detritylation of these γ-lactams D and L is preferably carried out using gaseous hydrochloric acid, operating in nitromethane, and the γ-lactams D and L of the 6H acid are respectively obtained, 7H cis 7-amino 3-aminomethyl ceph-3-rd 4-carboxylic of formula I.
The following example illustrates the invention. For the first steps of the process, reference is made to the main patent mentioned above. Example: L (or D) 6H, 7H </I> cis 7-amino 3-aminomethyl ceph-3-rd 4-carboxylic acid γ-lactam.
Stage <I> A: Depletion of dl </I> y-lactam <I> from acid </I> 2- (a-carboxy <I> a- </I> <I> tritylaminomethyl) </ I > 5-aminomethy12,3-dihydro 1,3-thiazine 4-carboxylic <I> (isomer </I> threo).
<I> a) Obtaining the D isomer </I> To a solution of 3.75 g of 1-sparteine in 25 cm3 of methanol, is added, with stirring, 5 g of DL y-lactam of the 2- (α-carboxy α-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid (threo isomer), add 25 cm3 of water, stop stirring,
add some crystalline primers of 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid (a-carboxy a-tritylaminomethyl) sparteine salt (thiazine isomer) 4-carboxylic (threo isomer) , left to stand for one hour at 20 C, isolate the precipitate of sparteine salt, by wringing, washing it and drying it. The mother liquors of crystallization (mother liquors A) are kept.
The 3.67 g of precipitate obtained are dissolved in 20 volumes of methanol, acidified with acetic acid, allowed to crystallize, filtered off, washed with methanol and then with ether, dried and 2.15 g of D y- 2- (oc-carboxy oa-tritylaminomethyl) 5-aminomethyl 2,3-di-hydro 1,3-thiazine 4-carboxylic acid lactam (threo isomer) crude, preserves mother liquors of crystallization (mother liquors B) .
EMI0002.0168
(c = 0.6%, methanol 1% triethylamine). It is <I> Purification: </I> The operation is carried out on 15 g of crude D isomer originating from several resolution tests which is introduced into a solution of 11.25 g of I-sparteine in 100 cm3 of methanol, heat to 40 ° C. to obtain the dissolution, cool to 20 ° C., add 100 cm3 of distilled water, allow to crystallize, isolate the precipitate by draining, wash it with a methanol-water mixture (1.1) then with ether, It is taken up in 250 cm3 of methanol, filtered, acidified with acetic acid, left to crystallize, isolate the precipitate formed by draining, wash it with methanol and ether, dry it and obtain 12,
1 g of 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic acid D y-lactam (threo isomer)
EMI0002.0182
(c = 0.5%, methanol at 1% triethylamine).
As far as we know, this compound is not described in the literature.
The same is true of the 1-sparteine salt of D y-lactam of 2- (α-carboxy α-tritylaminomethyl) 5-aminomethyl 2,3-di-hydro 1,3-thiazine 4-carboxylic acid.
<I> b) </I> Obtaining <I> of the L isomer </I> The mother liquors of crystallization of the 1-sparteine salt of the D isomer (mother liquors A) are acidified with acetic acid , the precipitate formed is isolated by suction, washed with methanol, with ether, dried and 1.6 g of L y-lactam of 2- (at-carboxyl a-tritylaminomethyl) 5- acid are obtained. aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic (threo isomer)
gross
EMI0002.0206
(c = 0.5%, methanol at 1% triethylamine). The mother liquors of crystallization (mother liquors C) are kept.
<I> Purification: </I> The operation is carried out on 13.2 g of crude L isomer originating from various resolution tests, which is introduced into a solution of 6.6 g of 1-ephedrine in 82 cm3 of methanol. 164 cm3 of ethyl ether are slowly introduced into the solution obtained, allowed to crystallize and the precipitate formed is isolated by suction; washed with ether, dry.
The 12.5 g of raw ephedrine salt obtained are dissolved in 400 cm3 of a mixture of methanol and methylene chloride (1-1), filtered, acidified with acetic acid, left to crystallize, isolated by draining the precipitate formed, washed with methanol and with ether, dried and obtained 8.43 g of L y-laetam of 2- (ix-carboxy a tritylaminomethyl) acid
5-aminomethyl 2,3-dihydro 1,3-thiazine 4-carboxylic (threo isomer @
EMI0003.0034
(c = 0.57%, methanol at 1% triethylamine): As far as we know, this compound is not described in the literature.
The same is true of the 1-ephedrine salt of 2- (α-carboxy α-tritylaminomethyl) 5-aminornethyl 2,3-di-hydro 1,3-thiazine 4-carboxylic acid L y-lactam. Recovery <I> of </I> l-sparteine The mother liquors B and C are combined, basified with 2N soda, extracted with ether,
washing the ethereal solution with water, drying, removing the solvent by distillation under reduced pressure, and recovering the I-spartein in practically quantitative yield.
Stage <I> B: </I> y-lacrame <I> of </I> acid <I> L 6H, 7H </I> cis 7-tritylamino 3-amino-methyl ceph-3-rd 4 -carboxylic In 20 em3 of pyridine, 2 g of L y-lactam of 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyl 2 are introduced,
3-dihydro 1,3-thiazine 4-carboxylic (threo isomer), add 1.5 g of dicyclohexylcarbodiimide, 40 CM3 of methylene chloride, 40 CM3 of nitromethane, leave to stand at 20 C, under a nitrogen atmosphere , in the dark, for eighteen hours;
the dicyclohexyhrrea is filtered off, the filtrate is concentrated to dryness by distillation under reduced pressure, ether is added, the precipitate formed is isolated by filtering, it is taken up in methylene chloride, and activated charcoal is added to the solution obtained, shake,
eliminates the activated carbon by filtration, concentrates the filtrate to dryness by distillation under reduced pressure, purifies the residue by chromatography on silica gel, eluting with a mixture of chloroform, ethyl acetate and ethanol (75-15- 10), obtains 2'g of a homogeneous product,
dissolve it in methylene chloride, add ethyl ether, filter off the precipitate formed and obtain 1.22 g of y-lactam from L 6H, 7H cis 7-trityiamino 3-aminornethyl ceph-3 acid -th 4-carboxylic,
EMI0003.0143
(c-0.5%, chloroform).
As far as we know, this compound is not described in the literature.
Analogously to that used in. Example, starting from D y-lactam of 2- (a-carboxy a-tritylaminomethyl) 5-aminomethyi 2,3-dihydro 1,3-thiazine 4-carboxylic acid, we obtain the y-lactam of l 'D 6H, <B> 7H </B> cis 7-tritylamino 3-aminomethyl oeph-3-rd4-caiboxylic acid,
EMI0003.0168
(c = 0.5%, chloroform).
As far as we know, this compound is not described in the literature.
Stage <I> C: </I> y-lacrame <I> of </I> acid <I> L </I> 6H, <I> 7H </I> cis 7-amino 3-aminomethyl ceph -3-rd 4-carboxylic In 8 cm3 of nitrornethane, 1 g of γ-lactam of L <B> 6H acid is dissolved,
</B> 7H cis 7-tritylamiuo 3-aminomethyl ceph-3-rd 4- carboxylic, cools the solution obtained to + 10 C, bubbling gaseous hydrochloric acid therein for twenty minutes,
eliminates 1 cm3 <B> of </B> nitromethane by distillation under reduced pressure, adds 30 cm3 of ether, isolates the precipitate formed by draining, washing it with ether, taking it up in ethanol, adding a slight excess of triethylamine, allows to crystallize,
isolates the precipitate formed by filtering, washing it with ethanol and ether, drying it and obtaining 400 mg of y-lactam from L 6H, 7H cis 7-amino 3-aminomethyl ceph-3- acid. th 4-carboxylic,
EMI0003.0225
(c = 0.5%, water).
A sample of this product is purified by dissolving in normal aqueous hydrochloric acid solution, passing through activated carbon and adding triethylamine (purification yield: 80% i
EMI0003.0230
(c = 0.5%, water).
In the same way, starting from the y-lactam of D 6H, 7H cis 7-tritylamino 3-aminomethyl ceph-3-rd 4-carboxylic acid, the y-lactam of D 6H, 7H cis acid is obtained RTI ID = "0003.0239" WI = "11" HE = "4" LX = "1683" LY = "609"> 7-amino 3-amino-methyl ceph-3-rd 4-carboxylic.
The D and L isomers of the y-lactam obtained are identical to those described in Swiss Patent No. 515276.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR156898 | 1968-06-27 | ||
| FR7033898A FR2120214A6 (en) | 1970-09-18 | 1970-09-18 | D-and l-isomers of 6h, 7h, cis-7-amino-3-aminomethyl cef -3 - em-4-car acid-gamma- lactams |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH544775A true CH544775A (en) | 1973-11-30 |
Family
ID=26182082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1334071A CH544775A (en) | 1968-06-27 | 1971-09-10 | D-and l-isomers of 6h, 7h, cis-7-amino-3-aminomethyl cef -3 |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH544775A (en) |
-
1971
- 1971-09-10 CH CH1334071A patent/CH544775A/en not_active IP Right Cessation
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