IL41986A - Total synthesis of cephalosporins - Google Patents
Total synthesis of cephalosporinsInfo
- Publication number
- IL41986A IL41986A IL41986A IL4198673A IL41986A IL 41986 A IL41986 A IL 41986A IL 41986 A IL41986 A IL 41986A IL 4198673 A IL4198673 A IL 4198673A IL 41986 A IL41986 A IL 41986A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- compound
- hydrogen
- methyl
- methoxy
- Prior art date
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims 19
- 229940124587 cephalosporin Drugs 0.000 title claims 19
- 150000001780 cephalosporins Chemical class 0.000 title claims 6
- 238000006257 total synthesis reaction Methods 0.000 title 1
- -1 azido, amino Chemical group 0.000 claims 49
- 150000001875 compounds Chemical class 0.000 claims 40
- 229910052739 hydrogen Inorganic materials 0.000 claims 38
- 239000001257 hydrogen Substances 0.000 claims 38
- 238000000034 method Methods 0.000 claims 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 26
- 150000003839 salts Chemical class 0.000 claims 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 19
- 150000002148 esters Chemical class 0.000 claims 14
- 239000000047 product Substances 0.000 claims 14
- 230000000903 blocking effect Effects 0.000 claims 12
- 150000002431 hydrogen Chemical group 0.000 claims 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 11
- 238000006243 chemical reaction Methods 0.000 claims 10
- 239000002253 acid Substances 0.000 claims 8
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 7
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 6
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims 6
- 125000003545 alkoxy group Chemical group 0.000 claims 6
- 239000002585 base Substances 0.000 claims 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 5
- 239000000203 mixture Substances 0.000 claims 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims 5
- 239000007858 starting material Substances 0.000 claims 5
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 150000001412 amines Chemical class 0.000 claims 4
- 229910052736 halogen Inorganic materials 0.000 claims 4
- 150000002367 halogens Chemical group 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- 230000010933 acylation Effects 0.000 claims 3
- 238000005917 acylation reaction Methods 0.000 claims 3
- 125000005843 halogen group Chemical group 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000003287 optical effect Effects 0.000 claims 3
- QLAJNZSPVITUCQ-UHFFFAOYSA-N 1,3,2-dioxathietane 2,2-dioxide Chemical compound O=S1(=O)OCO1 QLAJNZSPVITUCQ-UHFFFAOYSA-N 0.000 claims 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 2
- 239000003377 acid catalyst Substances 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 2
- 125000004442 acylamino group Chemical group 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000002153 concerted effect Effects 0.000 claims 2
- 125000004185 ester group Chemical group 0.000 claims 2
- 125000001188 haloalkyl group Chemical group 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 claims 1
- CVRHUOVQGJXGAV-UHFFFAOYSA-N 1-hydroxysulfanyl-2-methylbenzene Chemical compound CC1=CC=CC=C1SO CVRHUOVQGJXGAV-UHFFFAOYSA-N 0.000 claims 1
- NZYLEVMJODSINC-UHFFFAOYSA-N 1-methoxypyridin-1-ium Chemical compound CO[N+]1=CC=CC=C1 NZYLEVMJODSINC-UHFFFAOYSA-N 0.000 claims 1
- YUMSFEDUCCHSIV-UHFFFAOYSA-N 2-methyl-2-methylperoxypropane Chemical compound COOC(C)(C)C YUMSFEDUCCHSIV-UHFFFAOYSA-N 0.000 claims 1
- 229930184397 7-Methoxycephalosporin Natural products 0.000 claims 1
- 229910000761 Aluminium amalgam Inorganic materials 0.000 claims 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims 1
- 229930182555 Penicillin Natural products 0.000 claims 1
- SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 1
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001260 acyclic compounds Chemical class 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000003934 aromatic aldehydes Chemical class 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- DHDCEZNLFYNPOD-SSDOTTSWSA-N carbamoyloxymethyl (6R)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(N)(=O)OCOC(=O)C1=CCS[C@H]2N1C(C2)=O DHDCEZNLFYNPOD-SSDOTTSWSA-N 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- SRXOCFMDUSFFAK-UHFFFAOYSA-N dimethyl peroxide Chemical compound COOC SRXOCFMDUSFFAK-UHFFFAOYSA-N 0.000 claims 1
- NALBLJLOBICXRH-UHFFFAOYSA-N dinitrogen monohydride Chemical group N=[N] NALBLJLOBICXRH-UHFFFAOYSA-N 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 238000006140 methanolysis reaction Methods 0.000 claims 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 229910000510 noble metal Inorganic materials 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 150000002900 organolithium compounds Chemical class 0.000 claims 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 150000002960 penicillins Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 229910003446 platinum oxide Inorganic materials 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 125000005537 sulfoxonium group Chemical group 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- LWRYDHOHXNQTSK-UHFFFAOYSA-N thiophene oxide Chemical compound O=S1C=CC=C1 LWRYDHOHXNQTSK-UHFFFAOYSA-N 0.000 claims 1
- 229910052727 yttrium Inorganic materials 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C265/00—Derivatives of isocyanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (9)
1. CLAIMS 1β Process for the preparation of <¾ ..7a- and 7β-azido-(amino-or acylamino- ) cephalosporins and of their optical enantiomers, having the general formula wherein A stands for an azido, amino or acylamino group AcEH- where Ac represents a carboxylic acyl group selected from those contained in natural and semisynthetic penicillins or cephalosporins, B is hydrogen, methyl or methoxy, provided that when B is hydrogen the azido group A is in the cc-positio and when B is methyl or methoxy the azido group A is in the β-position·· R is hydrogen, halogen, hydroxy, alkoxy, phenoxy, benzyloxy, aliphatic acyloxy, an alkyl-substituted thiadiazolylthio or tetrazolylthio group, or a carbamoyloxy group optionally N-mono or Ν,ΐϊ-disubstituted with alkyl, haloalkyl, alkoxy, benzyl or p-methoxybenzyl, is hydrogen or a carboxyl-blocking group, and of salts and esters of those compounds in which is hydrogen, which process comprises reacting, an ester of a-amino phosphonoacetate of the formula in which R is the same or different and is alkyl or aryl and 41986/2 reacting this latter in the presence of a base, with a substituted acetone of the formula R'CH2C0 CH2 X in which R1 is as defined above and X is halogen or a sulfonate ester group, either to form a corresponding S-substituted thioformimi date of the formula which is- then converted by ring closure to the corresponding thiazine of the formula or to produce the thiazine IV directly by reaction of the compound II with the substituted acetone in the presence of an excess of base, and then reacting either the acyclic compound of formula III or the cyclic thiazine of formula IV, or a mixture thereof, with an azidoacetyl reactant of the formula GH/- CO Y B in which B is hydrogen, methyl or methoxy and Y is halogen, 41986/2 the formula in which the azido group is in the a-position when B is hydrogen and in the β-position when B is methyl or methoxy, reducing the azido compound of formula V to the corresponding amine of the formula XVIII if desired resolving a racemic dl 7-azido or dl 7-amino compound into the d and 1 enantiomers, if desired removing the carboxy blocking group R-^ in the 4-position to form the corresponding carboxylic acid or salt thereof, if desired converting a dl 7a-aminocephalosporin compound into a 7β-amino, "Ifi-methox or 7 -methyl compound, acylatihg a compound of formula XVIII' with an acylating agent to form a dl 7a- or 7β-acylamido cephalosporin compound of the formula if desired deblocking the compound of formula XIX above to form the desired cephalosporins or salts thereof of the formula B 41986/2 in which H. represents hydrogen, a metal cation or an amino group or alternatively deblocking the compound of formula XVIII to form a compound of formula and acylating the latter and, if desired, resolving a dl 7a- or 7P-acylamido cephalosporin compound XXI into its d and 1 enantiomers, -and, if desired, converting a free acid into a pharmaceutically acceptable ester or salt.
2. A process according to Claim 1 wherein the substituted acetone starting material is al-acyloxy-3 halo acetone, l-carbamoyloxy-3-halo acetone, 1-lower alkoxy alkoxy-3-ha!o acetone 1,3-dihalo acetone or 1-monohalo acetone.
3. A process according to Claim 2 wherein the acetone is l-acetoxy-3-halo acetone or 1-chloro-acetone .
4. A process according to Claim 1 wherein the acetone is l-chloro-3- (N ,N-di-p-methoxybenzyl) -carbamoyloxy-2-propanone .
5. A process according to any of Claims 1 to 4 wherein the blocking group is methyl, tertiary butyl, phenacyl, p-bromophenacyl , 2 , 2 , 2-trichloroethyl , p-methoxybenzyl , p-nitro-benzyl, benzhydryl, p-methoxy-phenoxymethyl or methoxymethyl .
6. A process according to Claim 1 wherein the compound of formula II is obtained by reacting the phosphono-acetate of formula I with an ester of thionoformic acid at a temperature of from 0° to 100°C, preferably in an inert solvent medium. - 138 - 41986/2 7.. A^process. according to Claim-1- wherein the -reaction - between the compound II arid the substituted acetone is effected in the presence of an organic or inorganic base. 8. A process according to Claim 7 wherein the inorganic base is potassium carbonate. 9. The process of Claim 8 wherein the reaction is carried out in the presence of at least two equivalents of potassium carbonate, to form the thiazine of formula IV. in Claim 1. 10. A process according to Claim 7 or 8 wherein the compound of formula II is reacted with the substituted acetone in the presence _of one equivalent of . a_ base to form_.the__intermediate in Claim 1 of formula Ill/and the latter is converted into the thiazine in Claim 1 compound of formula IV/by reaction with a base such as an alkali metal carbonate or hydride or an organo lithium compound. 11. A process according to Claim 1 for the preparation of dl 7a or 7β azido cephalosporins of formula V wherein the intermediate of formula III or the thiazine of formula IV or a mixture thereof is reacted with the azidoacetyl reagent of formula I B where B and Y are as defined in Claim 1 , at a temperature of about 0°C and in the presence of a base such as a tertiary amine. 12. A process according to claim 11 wherein the compound of formula III is reacted with the azido acetyl reagent to form an intermediate of the formula 41986/2 and this latter is cyclized under the reactionconditions to the 7-azido compound of formula V. 13. A process according to any of Claims 11 or 12 wherein if B in the azidoacetyl compound is hydrogen the 7-a azidocephalosporin of formula V is formed and if B is methyl or methoxy the 7-3 azidocephalosporin of formula V is formed. 14. A process according to Claim 1 wherein the 7- -azidocephalo sporin compound of formula V in which B is hydrogen is reduced with hydrogen in the presence of a noble, metal catalyst such as platinum oxide or with aluminium amalgam, zinc- and acetic acid or copper and thiophenone, to form the corresponding 7-a-aminocephalosporin compounds. 15. A process according to Claim 14 wherein a mixture of dl 7-a azidocephalosporin enantiomers of formula V is used as starting material which is resolved into the optically active isomers prior to reduction. 16. A process ascording to Claim 14 wherein a mixture of dl enantiomers of the 7-a azidocephalosporin of formula V is reduced to form a mixture of dl 7-amino cephalosporins and the latter is resolved into the d and 1 isomers after the reduction. 1
7. A process according to Claim 1 for the preparation of 7-methoxy or 7-methylcephalosporin compoundsfrom the correspondi 7-a-azido compoundswhich comprises reducing a 7-a azido compound of the formula to the corresponding 7-a amino compound of the formula 41986/2 - VI condensing the ' compound of formula VI with an aromatic aldehyde of the formula G VII in which J, G and K are the same or different and are each hydrogen, a nitro, cyano, halo, sulfonyl, carboxylic amide or ester group, but at least one of them is other than hydrogen, to form an imino compound of the formula VIII recovering the imino compound from the reaction mixture, activating it with a base until change of colour is observed and substituting the hydrogen atom at the carbon atom adjacent to the imino nitrogen atom by a methoxy or methyl group B to 4J986/2 and replacing in this latter the imino moiety by an amino group, by reaction with an amine in the presence of an acid catalyst, to form a compound of formula 1
8. A process according to Claim 17 for the preparation of compounds of formula X wherein B is methoxy, wherein the activated compound of formula VIII is reacted with dimethyl peroxide, methyl t-butyl peroxide, methylphenylsulfenate , o-methyldimethyl sulfoxonium methosulfate, or N-methoxy pyridinium methosulfate , or the compound of formula VIII is halogenated and then subjected to methanolysis , to form the compound of formula IX and the latter is converted into the compound X by reaction with an amine in the presence of an acid catalyst. 1
9. A process according to Claim 17 for the preparation of compou of formula X wherein B is methyl wherein the activated compound of formula VIII is reacted with methyl sulphate or with a methyl halide to form the corresponding compound of formula IX and the latter is converted into the compound X by reaction with an amine 41986/2 20. A process according to Claim 1 for the preparation of 7-methoxy cephalosporins of the formula XIV wherein a 7 -amino cephalosporin of formula VI in Claim 17 is concerted by reaction with nitrite into the corresponding 7-diazocephalosporin ester of the formula this latter compound is concerted by reaction with a halo azide into the corresponding 7-halo-7-azidocephalosporanic acid ester of the formula which by reaction with a suitable nudeophile agent is conMepted to the 7-OCH_,-7-azidocephalosporanic acid ester of the formula 41986/2 XIII the 7-azido-7-methoxy compound of formula XIII is reduced to the corresponding 7-amino-7-methoxy compound of the formula XIV in Claim 20 by catalytic hydrogenation with a noble metal catalyst such as platinum/palladium or oxides thereof and, if desired, the ester of formula XIV is converted into the free acid of formula XV 21. A process for the preparation of 7 acylamino-7-methoxy cephalosporin compounds according to Claim 1 which comprises preparing a corresponding 7-azido-7-methoxy-cephalosporanic acid ester of formula XIII in Claim 20, subjecting the latter to simultaneous reduction and acylation to form a corresponding 7-OCH3-7-acylamino cephalosporanic ester of the formula 41986/2 and, if desired, converting the compound of formula XVI the corresponding free acid of the formula XVII or a salt thereof. 22. A process for the preparation of 7 acylamino-7-methoxy cephalosporin compoundsaccording to Claim 1 which comprises cleaving the ester group R^ from a compound of formula XIV in Claim 17 to form the free acid of formula XVin Claim 20 and subjecting this latter to acylation. 23. A process according to Claim 1 for the production of dl cephalosporin compounds of the formula wherein Ac is an acyl group, B is H, OCH^ or CH^ , R' is as defined in Claim 1 and R2 is hydrogen or a blocking group, and salts thereof when R2 is hydrogen and pharmaceutically acceptable esters thereof which comprises acylation of the dl amino cephalosporin of the formula XVIII in Claim 1. 24. A process according to Claim 23 wherein R2 is methyl, tertiary butyl, phenacyl, p_-bromophenacyl , 2 , 2 , 2-trichloroethyl , p-methoxybenzyl , benzyhydryl, p-nitrobenzyl , p-methoxyphenoxymeth or methoxymethyl . " • 41986/3 ' 25. A process according to Claim 23 for the production dl 7a-acylamido compounds of formula XIX wherein dl 7ct-amino cephalosporins of formula XVIII are used as starting materials ,26. A process according to Claim 23 for the production of dl 7 -acylamido compounds of formula XIX wherein dl 7£-amino cephalosporins of formula XVIII are used as starting materials 27. A process according to any of claims 23 to 26 wherein the dl 7-acylamido cephalosporins are resolved into the respec d- and 1- isomers. 28. A process according to Claim 1 wherein the starting material of formula I is prepared by reacting a compound of th formula wherein R is lower alkyl or phenyl w th a strong b treating the resulting reaction product with a hal formate ester to obtain a compound of the formula wherein R is the same as above and R^ is a blocking group, and reacting this compound with p-toluenesulfonic acid to produce a compound of the formula wherein R and ¾ are the same as defined above, 41986/2 29. A process for the preparation of compounds of formula D in Claim 1 substantially as described herein with reference to •the Examples. 0 30. dl 7a- and 7β- azido- (amin^- or acylamino-). cephalosporins and their optical enantiomers, of the general formula wherein A' stands for an azido, amino or acylamino group selected from a-aminophenylacetamido , 2-thienylacetamido , 1-(1H) tetra-zolylacetamido and 2-furylacetamido, B is hydrogen ,methyl or methoxy, provided that when B is hydrogen the azido group A is in the α-position and when B is methyl or methoxy the azido group A is in the β-position. R1 is hydrogen, halogen, hydroxy, alkoxy, phenoxy, benzyloxy, aliphatic acyloxy, an alkyl-substituted thiadiazolylthio or tetrazolylthio group, or a carbamoyloxy group optionally N-mono or Ν,Ν-disubstituted with alkyl , haloalkyl , alkoxy, benzyl or p-methoxybenzyl , is hydrogen or a carboxyl-blocking group, and salts and esters of those compounds in which I¾2 is hydrogen. 31. dl-7a-azido compounds according to Claim 30 and having the formula: 41986/2 32. dl-73-azido compounds according to Claim.. 30 of the-* formula: wherein is a blocking group, R1 has the same meaning as in Claim 30 and B is -CH^ or -OCH^. 33. dl-azido compounds according to Claim 30 of the formula where R2 is hydrogen or a blocking group, R' has the same meaning as in Claim 30, B is OCH^ or CH^ and salts thereof when R2 is hydrogen. 34. The compounds of Claim 31, 32 or 33 wherein R^ is methyl, tertiary butyl , phenacyl , p_-bromophenacyl , 2,2, 2-trichloro-ethyl , p_-methoxybenzyl¾ p-nitrobenzyl , benzhydryl , p-methoxy-phenoxymethyl or methoxymethyl . 35. The compoundsof Claim 31, 32 or 33 wherein R' is hydrogen 36. The compoundsof Claim 3}., 32 or 33 wherein R' is lower alkoxy. 37. The compoundsof Claim 36 wherein R' is methoxy. 38. The compoundsof Claim 31, 32 or 33 wherein R' is aliphatic acyloxy. 39; The compoundsof Claim 31, 32 or 33 wherein R1 is 41986/2 40. The compounds of Claim 31, 32 or 33 wherein R' is (N ,N-di-p-methoxybenzyl) carbamoyloxy . 41. The compoundsof Claim 38 wherein R' is acetoxy. 42. The compoundsof Claim 31, 32 or 33 wherein R' is halo. 43. The compoundsof Claim 31, 32 or 33 wherein R' is .methoxymethox . 44. g-Methoxybenzyl dl-7f3-azido-7-methoxy-3-ace'toxymethyl- 3-cephem-4-carboxylate according to Claim 32. 45. p-Methoxybenzyl dl-73-azido-7-meth xy-3-methyl-3-cephem- 4-carboxylate according to Claim 32. 46. Methyl dl-7g-azido-7-methoxy-3-methyl-3-cephem-4-carboxylate according to Claim 32. 47. p-Methoxybenzyl dl-7$-azido-7-methoxy-3-carbamoyloxymethy 3-cephem-4-carboxylate according to Claim 32. 48. p-Methoxybenzyl dl-7f3-azido-7-methoxy-3- (N,N-di-p-methoxybenzyl) -carbamoyloxymethyl-3-cephem-4-carboxylate according to Claim 32. 49. dl-7a-Amino compounds according to Claim 30 of the formul wherein R2 represents hydrogen or a blocking group and R' has the same meaning as in Claim 30, and salts thereof when R2 is hydrogen. 50. dl-amino compounds according to Claim 30 of the formula 41986/2 where R2 is hydrogen or a blocking group and R' has the same meaning as in Claim 30, g is methyl or methoxy, and salts thereof when R2 is hydrogen. 51. dl-7£-Amino compounds according to Claim 30 of the formula: wherein R2 represents hydrogen or a blocking group, R1 has the same meaning as in Claim 30, and salts thereof when R2 is hydrogen. 52. The product of Claim 49, 50 or 51 wherein R2 is methyl, tertiary butyl, phenacyl, p_-bromophenacyl , 2 , 2 , 2-trichloroethyl p-methoxybenzyl , benzhydryl, p-nitrobenzyl , p-methoxyphenoxy- methyl or methoxymethyl . 53. The product of Claim 49, 50 or 51 wherein R2 is hydrogen. 54. The salts of the compounds of Claim 53. 55. 2 , 2 , 2-Trichloroethyl dl-7a-amino-3-methyl-3-cephem- 4-carboxylate according to daim 49. 56. Methyl dl-7a-amino-3-methyl-3-cephem-4-carboxylate according to Claim 49. 57. p_-Methoxybenzyl dl-7a-amino-3-acetoxymethyl-3-cephem- 4-carboxylate according to Claim 49 58. £-Methoxybenzyl dl-7a-aminc—3- (N,N-di-p-methoxybenzyl)- carbamoyloxymethyl) -3-cephem-4-carboxylate according to Claim 49. 59. The product of Claim 50 or 51 wherein R' is hydrogen 60. The product of Claim 50 or 51 wherein R' is acyloxy. 61. The product of Claim 50 or 51 wherein R' is acetoxy. 41986/2 63. 2 , 2 , 2-Trichloroethyl dl-73-amino-3-methyl-3-cephem-4-carboxylate according to Claim 51. 64. Methyl dl-73i2amino-3-methyl-3-cephem-4-carboxylate according to Claim 51. 65. p_-Methoxybenzyl dl-73_amino-3-acetoxymethyl-3-cephem-4-carboxylate according to Claim 51. 66. p_-Methoxybenzyl dl-73-amino-3- (N,N-di-p-methoxybenzyl) carbamoyloxymethyl-3-cephem-4-carboxylate according to Claim 51. 67. dl Cephalosporin compounds according to Claim 30 of the formula wherein Ac and R* have the same meaning as in Claim 30 and R2 is hydrogen or a blocking group, and sals thereof when R is hydrogen and pharmaceutically acceptable esters thereof 68. The product of Claim 67 wherein the AcN- group is in the -position. H 69. The product ofeClainr 67 wherein the AcN- group is in the 3-position. 70. The product of Claim 68 or 69 wherein R2 is methyl, tertiary butyl, phenacyl, p_-bromophenacyl , 2 , 2 , 2-trichloro-ethyl, p_-methoxybenzyl, benzhydryl, p-nitrobenzyl , p_-methoxy phenoxymethyl or methoxymethyl . 71. The product of Claim 68 or 69 wherein R2 is hydrogen. 72. The salts of the product of Claim 71. 41986/2 73. dl-3-Acetoxymethyl-73- (2-thienylacetamido) -3-cepherif-4-carboxylic acid and salts thereof according to Claim 67. 74. dl-3-Methyl-7£- (D-phenylglycylamido) -3-cephem-4-carboxyl acid and salts thereof according to Claim 67. 75. dl-N- [7- (21 -thienylacetamidoceph-3-ylmethyl) ] -pyridium-2-carboxylate and salts thereof according to Claim 67. 76. dl-3- (5-Methyl-l,3,4-thiadiazol-2-yl) -7 -tetrazolyl-methyl) -3-cephem-4-carboxylic acid and salts thereof accordin to Claim 67. 77. dl Cephalosporin compounds according to Claim 30 of the formula: wherein Ac and R' have the same meanings as in Claim 30, B CH^ or OCH^, -*-s hydrogen or a blocking group, and salts thereof when R2 is hydrogen and pharmaceutically acceptable esters thereof. H 78. The product of Claim 73 wherein the AcN- group is in the β- position. 79. The product of Claim 77 or 78 wherein R2 is methyl, tertiary butyl, phenacyl, p_-bromophenacyl , 2 , 2 , 2-trichloro-ethyl, p_-methoxybenzyl , benzhydryl, p-ritrobenzyl , p_-methoxy phenoxymethyl or methoxymethyl. 80. The product of Claim 77 or 78 wherein R2 is hydrogen. 81. The salts of the product of Claim 80. 82. dl-3-Acetoxymethyl-7-methyl-7£-(2-thienylacetamido) -3-cephem-4-carboxylic acid and salts thereof according to a 41986/2 83. A d , 1 compound according to Claim 77 of the formula wherein is a blocking group and Ac is an acyl group as defined in Claim 30. 84. dl-3-Acetoxymethyl-7-methoxy-73- (2-thienylacetamido) -3-cephem-4-carboxylic acid and salts thereof according to Claim 83. 85. dl-3-Carbamoyloxymethyl-7-methoxy-73- (2-thienylacetamido) -3-cephem-4-carboxylic acid and salts thereof according to Claim ,83. 86. p- ethoxybenzyl- dl-3-carbamoyloxymethyl-7-methoxy-7P- (2-thienylacetamido) -3-cephem-4-carboxylate according to Claim 83. 87. Methoxymethyl dl-3-carbamoyloxymethyl-7-methoxy-73- (2-thienylacetamido) -3-cephem-4-carboxylate according to Claim 8a 88. Compounds according to any of Claims 30 to 87, substantially as described herein with reference to the Example 89. Compounds according to Claim 88 when prepared by a process according to any of Claims 1 to 29. 90. Pharmaceutical compositions comprising as active ingredient a compound of formula D in Claim 1 in which A is an an Ac NH group where Ac is as defined in Claim 1, or /optical isomer of such compounds or a pharmaceutically acceptable salt or ester? of those compounds in which R, is hydrogen.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24427172A | 1972-04-14 | 1972-04-14 | |
| US26784572A | 1972-06-30 | 1972-06-30 | |
| US26784672A | 1972-06-30 | 1972-06-30 | |
| US29635672A | 1972-10-10 | 1972-10-10 | |
| US05/336,561 US3962224A (en) | 1972-10-10 | 1973-03-05 | Cephalosporin compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL41986A0 IL41986A0 (en) | 1973-06-29 |
| IL41986A true IL41986A (en) | 1976-12-31 |
Family
ID=27540192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL41986A IL41986A (en) | 1972-04-14 | 1973-04-09 | Total synthesis of cephalosporins |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5538957B2 (en) |
| CH (1) | CH599220A5 (en) |
| DD (3) | DD112272A5 (en) |
| DE (3) | DE2365582C2 (en) |
| FR (1) | FR2182953B1 (en) |
| GB (2) | GB1424373A (en) |
| IE (1) | IE37510B1 (en) |
| IL (1) | IL41986A (en) |
| NL (1) | NL7304755A (en) |
| SE (2) | SE7513006L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3947413A (en) * | 1972-11-13 | 1976-03-30 | Merck & Co., Inc. | 3-α-Substituted cephalosporins |
| GB2300856A (en) * | 1995-05-16 | 1996-11-20 | Pfizer Ltd | Beta-lactam preparation |
-
1973
- 1973-04-05 NL NL7304755A patent/NL7304755A/xx not_active Application Discontinuation
- 1973-04-09 IL IL41986A patent/IL41986A/en unknown
- 1973-04-10 IE IE562/73A patent/IE37510B1/en unknown
- 1973-04-10 GB GB1705073A patent/GB1424373A/en not_active Expired
- 1973-04-10 GB GB596475A patent/GB1424375A/en not_active Expired
- 1973-04-11 FR FR7313062A patent/FR2182953B1/fr not_active Expired
- 1973-04-11 CH CH525173A patent/CH599220A5/xx not_active IP Right Cessation
- 1973-04-13 DD DD179575*A patent/DD112272A5/xx unknown
- 1973-04-13 DE DE2365582A patent/DE2365582C2/en not_active Expired
- 1973-04-13 DD DD179995*A patent/DD112455A5/xx unknown
- 1973-04-13 DE DE2365406*A patent/DE2365406A1/en not_active Ceased
- 1973-04-13 DD DD170170A patent/DD107053A5/xx unknown
- 1973-04-13 DE DE2365456*A patent/DE2365456A1/en not_active Ceased
- 1973-04-14 JP JP4184973A patent/JPS5538957B2/ja not_active Expired
-
1975
- 1975-11-19 SE SE7513006A patent/SE7513006L/en unknown
- 1975-11-19 SE SE7513005A patent/SE7513005L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2365582A1 (en) | 1975-06-26 |
| DE2318829A1 (en) | 1973-10-31 |
| GB1424375A (en) | 1976-02-11 |
| SE7513005L (en) | 1975-11-19 |
| DD112455A5 (en) | 1975-04-12 |
| DE2365456A1 (en) | 1975-02-20 |
| GB1424373A (en) | 1976-02-11 |
| JPS4914488A (en) | 1974-02-07 |
| FR2182953A1 (en) | 1973-12-14 |
| SE7513006L (en) | 1975-11-19 |
| IE37510B1 (en) | 1977-08-03 |
| JPS5538957B2 (en) | 1980-10-07 |
| DD112272A5 (en) | 1975-04-05 |
| IE37510L (en) | 1973-10-14 |
| NL7304755A (en) | 1973-10-16 |
| CH599220A5 (en) | 1978-05-12 |
| DD107053A5 (en) | 1974-07-12 |
| FR2182953B1 (en) | 1976-07-02 |
| DE2365406A1 (en) | 1975-01-23 |
| DE2318829B2 (en) | 1976-01-02 |
| DE2365582C2 (en) | 1982-03-25 |
| IL41986A0 (en) | 1973-06-29 |
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