CA1071189A - Chemical compounds, process for preparing said compounds and process for preparing 6-(p-hydroxyphenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compounds - Google Patents
Chemical compounds, process for preparing said compounds and process for preparing 6-(p-hydroxyphenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compoundsInfo
- Publication number
- CA1071189A CA1071189A CA254,379A CA254379A CA1071189A CA 1071189 A CA1071189 A CA 1071189A CA 254379 A CA254379 A CA 254379A CA 1071189 A CA1071189 A CA 1071189A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxyphenylglycylamido
- preparing
- compounds
- mmoles
- cephem
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 title claims description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- -1 phos-phite amide Chemical class 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 9
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- RJFPBECTFIUTHB-INEUFUBQSA-N (6r,7r)-7-azaniumyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 RJFPBECTFIUTHB-INEUFUBQSA-N 0.000 claims abstract description 5
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical group [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 12
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims 3
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 claims 3
- RHEFYFUGIMENJN-GLGOKHISSA-N (2,5-dioxopyrrolidin-3-yl) (2R)-2-amino-2-(4-trimethylsilyloxyphenyl)acetate Chemical compound C[Si](OC1=CC=C([C@@H](N)C(=O)OC2C(=O)NC(C2)=O)C=C1)(C)C RHEFYFUGIMENJN-GLGOKHISSA-N 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- OLSFRDLMFAOSIA-UHFFFAOYSA-N 2-chloro-1,3,2-dioxaphospholane Chemical compound ClP1OCCO1 OLSFRDLMFAOSIA-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 4
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 4
- 238000001962 electrophoresis Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000013350 formula milk Nutrition 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000005051 trimethylchlorosilane Substances 0.000 description 3
- VFERFGLYBXDICV-MRXNPFEDSA-N (1,3-dioxoisoindol-4-yl) (2R)-2-amino-2-(4-trimethylsilyloxyphenyl)acetate Chemical compound C[Si](OC1=CC=C([C@@H](N)C(=O)OC2=C3C(C(=O)NC3=O)=CC=C2)C=C1)(C)C VFERFGLYBXDICV-MRXNPFEDSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- MLOZJRLUNNFSGD-IOJJLOCKSA-N (6r)-7-amino-8-oxo-3-(2h-triazol-4-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1C(C(N1C=1C(O)=O)=O)N)CC=1CSC=1C=NNN=1 MLOZJRLUNNFSGD-IOJJLOCKSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- DRTZAIDVOGUYSP-UHFFFAOYSA-N pyridin-1-ium;chloride;hydrochloride Chemical compound Cl.Cl.C1=CC=NC=C1 DRTZAIDVOGUYSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
Classifications
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure p-Trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide or -phthalimide, process of preparing p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide or -phthalimide by react-ing D-(-)-p-trimethylsilyloxyphenylglycin-N-carboxyanhydride with a N-hydroxyimide, and process for preparing 6-(p-hydroxyphenylglycylamido)-penam or 7-(p-hydroxyphenylglycyl-amido)-cephem compounds by reacting p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide or -phthalimide with a phos-phite amide of an ester of 6-aminopenicillanic acid or of an ester of a 7-amino-3-cephem-4-carboxylic acid in the presence of the hydrochloride of a weak amine.
Description
107~89 This invention relates to novel chemical compounds which are useful as intermediates in the synthesis of 6-(p-hydroxyphenylglycylamido)-penam or 7-~p-hydroxyphenylglycylamido)-cephem compounds.
The novel chemical compounds of the invention have the general formula:
H o h ( 3 )3 ~ N~ 3 Cl~ l I
wherein Y is I or ~
These novel compounds are prepared by reacting D-~-)-p-trimethyl-silyloxyphenylglycin-N-carboxyanhydride with a N-hydroxyimide of the general formula:
O
C
HON / ~ Y II
O
~herein Y has the meaning defined above, in the presence of a hydrochloride of a weak amine and in an inert solvent.
The reaction is preferably carried out in the presence of pyridine hydrochloride and in methylene chloride.
The novel compounds thus prepared may be isolated or may be utilized in situ in a process for the production of 6-(p-hydroxyphenylglycylamido)-penam or 7-~p-hydroxyphenylglycylamido)-cephem compounds as active esters.
Several activated esters of protonated amino acids have been described in the 20 literature (Tetrahedron Letters 1965, 95, J. Chem. Soc. C 1968, 1219), but such compounds have only been utilized as amino components in peptide syn-thesis.
In general, the utilization of proton protection of amino groups in peptide synthesis has up till now met with at least one major obstacle:
-1- ~
1071~89 Proton migration is unavoidable, thus hampering the formation of the peptide bond with the unprotonated amino component.
The invention also relates to a process for preparing 6-~p-hydroxy-phenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compounds, said process comprising the steps of reacting a compound of the general for-mula:
(~3C)35i - O- ~ ~H3 Cl~ ~ I
~hrroin Y is ¦ 2 or ~
with a phosphite amide of an ester of 6-aminopenicillanic acid or of an - 10 ester of 7-amino-3-cephem-4-carboxylic acid in the presence of the hydro-chloride of a weak amine.
Phosphite amides of esters of 6-aminopenicillanic acid or of esters of 7-aminocephalosporanic acid are described in Belgian Patent Specification No. 809,110.
Since the acylation of said phosphite amides with the above de-fined activated esters is proton catalyzed, a high proton activity has to be maintained in the reaction medium throughout the acylation. Such a high proton activity is preferably provided by using as said hydrochloride pyridine hydrochloride.
The yields obtained by the process of the invention are high and racemisation of the sterically labile D-(-)-p-hydroxyphenylglycyl is not observed.
The invention will now be described in further detail with reference to the following examples.
p-Trimethylsilyloxy-D-(-)-phenylglycyloxysucc _ imide, hydrochloride.
0.575 g (5 mmoles) of N-hydroxysuccinimide are added to a solution .
107~8~
of 0.58 g (5 mmoles) of pyridine hydrochloride and 1.33 g ~5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride in 17 ml of dry methylene chloride at 0C. Carbon dioxide is evolved, and after 1 hour only traces of N-carboxyanhydride can be detected by a thin layer chromatography (silica gel, benzene/acetone 1:1, sprayed with nin-hydrin). The white, crystalline precipitate formed is isolated by filtration to yield 1.02 g (55%) of p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide, hydrochloride.
Analysis:
Calculated for C15H21N25SiCl C: 48.33%, H: 5.68%, N: 7.51%, Cl: 9.51%
Found: C: 48.25%, H: 5.37%, N: 7.54%, Cl: 9.74%
The IR spectrum (KBr) shows characteristic absorption at 1815 cm 1, 1780 cm 1 (ester), 1730 cm 1, 1710 cm 1 (cyclic imide),and 840 cm 1 (tri-methylsilyl).
The NMR spectrum (D-DMF, Ext.) shows characteristic signals at:
~ ppm Correlation Integral 0.05 (s) Trimethylsilyl 9 H
The novel chemical compounds of the invention have the general formula:
H o h ( 3 )3 ~ N~ 3 Cl~ l I
wherein Y is I or ~
These novel compounds are prepared by reacting D-~-)-p-trimethyl-silyloxyphenylglycin-N-carboxyanhydride with a N-hydroxyimide of the general formula:
O
C
HON / ~ Y II
O
~herein Y has the meaning defined above, in the presence of a hydrochloride of a weak amine and in an inert solvent.
The reaction is preferably carried out in the presence of pyridine hydrochloride and in methylene chloride.
The novel compounds thus prepared may be isolated or may be utilized in situ in a process for the production of 6-(p-hydroxyphenylglycylamido)-penam or 7-~p-hydroxyphenylglycylamido)-cephem compounds as active esters.
Several activated esters of protonated amino acids have been described in the 20 literature (Tetrahedron Letters 1965, 95, J. Chem. Soc. C 1968, 1219), but such compounds have only been utilized as amino components in peptide syn-thesis.
In general, the utilization of proton protection of amino groups in peptide synthesis has up till now met with at least one major obstacle:
-1- ~
1071~89 Proton migration is unavoidable, thus hampering the formation of the peptide bond with the unprotonated amino component.
The invention also relates to a process for preparing 6-~p-hydroxy-phenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compounds, said process comprising the steps of reacting a compound of the general for-mula:
(~3C)35i - O- ~ ~H3 Cl~ ~ I
~hrroin Y is ¦ 2 or ~
with a phosphite amide of an ester of 6-aminopenicillanic acid or of an - 10 ester of 7-amino-3-cephem-4-carboxylic acid in the presence of the hydro-chloride of a weak amine.
Phosphite amides of esters of 6-aminopenicillanic acid or of esters of 7-aminocephalosporanic acid are described in Belgian Patent Specification No. 809,110.
Since the acylation of said phosphite amides with the above de-fined activated esters is proton catalyzed, a high proton activity has to be maintained in the reaction medium throughout the acylation. Such a high proton activity is preferably provided by using as said hydrochloride pyridine hydrochloride.
The yields obtained by the process of the invention are high and racemisation of the sterically labile D-(-)-p-hydroxyphenylglycyl is not observed.
The invention will now be described in further detail with reference to the following examples.
p-Trimethylsilyloxy-D-(-)-phenylglycyloxysucc _ imide, hydrochloride.
0.575 g (5 mmoles) of N-hydroxysuccinimide are added to a solution .
107~8~
of 0.58 g (5 mmoles) of pyridine hydrochloride and 1.33 g ~5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride in 17 ml of dry methylene chloride at 0C. Carbon dioxide is evolved, and after 1 hour only traces of N-carboxyanhydride can be detected by a thin layer chromatography (silica gel, benzene/acetone 1:1, sprayed with nin-hydrin). The white, crystalline precipitate formed is isolated by filtration to yield 1.02 g (55%) of p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide, hydrochloride.
Analysis:
Calculated for C15H21N25SiCl C: 48.33%, H: 5.68%, N: 7.51%, Cl: 9.51%
Found: C: 48.25%, H: 5.37%, N: 7.54%, Cl: 9.74%
The IR spectrum (KBr) shows characteristic absorption at 1815 cm 1, 1780 cm 1 (ester), 1730 cm 1, 1710 cm 1 (cyclic imide),and 840 cm 1 (tri-methylsilyl).
The NMR spectrum (D-DMF, Ext.) shows characteristic signals at:
~ ppm Correlation Integral 0.05 (s) Trimethylsilyl 9 H
2.9 (s) 0=C-CH2-CH2-C=0 4 H
5.9 (s) Benzyl-H 1 H
7.05 (d) J=9 Aromatic-H 2 H
7.6 ~d) J=9 Aromatic-H 2 H
8-10 ~broad) NH 3 H
p-Trimethylsilyloxy-D-(-)-phenylglycyloxyphthalimide, hydrochloride.
2.65 g (10 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride and 1.16 g (10 mmoles) of pyridine hydrochloride are suspend-ed in 200 ml of dry toluene at room temperature. Finely powdered N-hydroxy-phthalimide (1.67 g, 10 mmoles) is added, and the mixture is stirred for 24 hours. The precipitate is isolated by filtration and washed thoroughly with methylene chloride to yield 3.66 g (85%) of p-trimethylsilyloxy-D-(-)-phenylglycyloxyphthalimide, hydrochloride.
~C~71~89 Analysis:
Calculated for ClgH21N205SiCl:
C: 54.33% H: 5.03%
Found: C: 54.37% H: 4.92%.
The IR spectrum (KBr) shows characteristic absorption at 1820 cm 1 and 1790 cm 1 (ester), 1750 cm 1 ~cyclic imide), and 840 cm 1 (trimethylsilyl).
p-Hydroxyampicillin Method A:
4.2 ml (30 mmoles) of triethylamine are added to a suspension of
5.9 (s) Benzyl-H 1 H
7.05 (d) J=9 Aromatic-H 2 H
7.6 ~d) J=9 Aromatic-H 2 H
8-10 ~broad) NH 3 H
p-Trimethylsilyloxy-D-(-)-phenylglycyloxyphthalimide, hydrochloride.
2.65 g (10 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride and 1.16 g (10 mmoles) of pyridine hydrochloride are suspend-ed in 200 ml of dry toluene at room temperature. Finely powdered N-hydroxy-phthalimide (1.67 g, 10 mmoles) is added, and the mixture is stirred for 24 hours. The precipitate is isolated by filtration and washed thoroughly with methylene chloride to yield 3.66 g (85%) of p-trimethylsilyloxy-D-(-)-phenylglycyloxyphthalimide, hydrochloride.
~C~71~89 Analysis:
Calculated for ClgH21N205SiCl:
C: 54.33% H: 5.03%
Found: C: 54.37% H: 4.92%.
The IR spectrum (KBr) shows characteristic absorption at 1820 cm 1 and 1790 cm 1 (ester), 1750 cm 1 ~cyclic imide), and 840 cm 1 (trimethylsilyl).
p-Hydroxyampicillin Method A:
4.2 ml (30 mmoles) of triethylamine are added to a suspension of
3.24 g (15 mmoles) of 6-aminopenicillanic acid and the mixture is stirred at room temperature until a clear solution is formed. 1.89 ml ~15 mmoles) of trimethylchlorosilane are added dropwise and the mixture stirred for 1 hour, then cooled to 0C, whereafter 1.35 ml (15 mmoles) of ethylene chlorophosphite is added during 1/2 hour to produce trimethylsilyl 6-ethylenephosphiteamido-penicillinate. At this point, 2.9 g (25 mmoles) of pyridine hydrochloride, 2.66 g (10 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxy-anhydride, and 1.15 g (10 mmoles) of N-hydroxysuccinimide are added all at once and in the order mentioned. The mixture is stirred at 0C overnight, whereafter enzymatic titration indicates a 96% yield of penicillin.
A solution of 6.7 g of sodium dioctyl sulfosuccinate (Manoxol OT, BDH) in 50 ml of ethyl acetate are added, and the methylene chloride evaporat-ed in vacuo. The mixture is poured into ice-water, the pH adjust~d to 2 with phosphoric acid, and the phases separated. The aqueous phase is extracted twice with 1.67 g of sodium dioctyl sulfosuccinate in 10 ml of ethyl acetate.
The combined organic extracts are added to 10 ml water, and the pH adjusted to 4.9 with dicocomethylamine (KEMAMINE T-6501), and stirred 1 hour at 0C
to complete precipitation of the crystalline p-hydroxyampicillin trihydrate.
3.4 g of the product (80%) are isolated by filtration. Enzymatic titration indicates a purity of 80%, and one reprecipitation from water at iso-electric pH produces the pure compound, showing IR and NMR spectra identical with Trade Mark ~ 4 ~
1~:97~39 those of the authentic material.
Method s:
2.4 ml ~30 mmoles) of pyridine followed by 1.9 ml ~15 mmoles) of trimethylchlorosilane and 1.35 ml ~15 mmoles) of ethylene chlorophosphite are added to a suspension of 3.24 g ~15 mmoles) of 6-aminopenicillanic acid in 23 ml of dry methylene chloride. An exothermic reaction starts, bringing the mixture to a mild reflux. After 2 hours stirring at room temperature a small sample is evaporated, dissolved in deuteriochloroform, and the NMR spectrum recorded: ~External standard: TMS). The 6-hydrogen is represented by a multiplet of four signals, centered at ~ = 5 ppm, from which by first order analysis the following coupling constants may be deduced:
JPNCH JHccH: 4 5 Hz Addition Gf excess of triethylamine to the NMR tube converts this spectrum to the known pattern of the free base.
The reaction mixture is cooled to 0C, 2.66 g ~10 mmoles) of p-tri-methylsilyloxy-D-~ phenylglycine-N-carboxyanhydride, and 1.15 g ~10 mmoles) of N-hydroxysuccinimide are added, and the mixture stirred at 0C overnight.
Enzymatic titration indicates a yield of 98%. The product is precipitated by addition of 1.6 ml of pyridine and 7 g of activated carbon ~NORIT SU 18, containing 7.5% of water). After being stirred for 1 hour at 0C and 1 hour at room temperature, the precipitate is isolated by filtration and resuspended in 50 ml of ice-water. The carbon is removed by filtration ~enzymatic titra-tion at this point indicates 75% yield), 4 g sodium perchlorate are added, pH is adjusted to 1.5 with perchloric acid, and the product extracted with n-butanol as the perchlorate salt. To the combined butanol extracts 50 ml water are added, pH is adjusted to 7 with triethylamine, and the product ex-tracted back into water. The combined aqueous phases are adjusted to pH 4.8, and dissolved butanol removed b~ azeotropic distillation in vacuo, whereby the p-hydroxyampicillin crystallizes as the trihydrate. The first crop of crystals amounts to 1.66 g ~39%) showing IR and NMR spectra identical with those of authentic material. A further crop of crystals may be obtained from the filtrate.
p-Hydroxyampicillin.
A suspension of 1.08 g (5 mmoles) of 6-aminopenicillanic acid in 12.5 ml of dry methylene chloride and 1.4 ml (10 mmoles) of triethylamine is stirred at room temperature until a clear solution is obtained. The mixture is then cooled to -40C, and 0.45 ml (5 mmoles) of ethylene chlorophosphite are added. The mixture is brought to room temperature and stirred for one hour. 0.3 ml (2.5 mmoles) of dimethyldichlorosilane is added and the mixture stirred overnight at 0C. 0.4 ml of pyridine and 1.86 g (5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide, prepared as described in Example 1, are added to said solution.
The reaction is followed by enzymatic titration of penicillin yield:
Time Yield 1 1/2 h 50%
2 1/2 h 63%
3 1/2 h 70%
20 h 70%
The penicillin produced behaved identically with authentic p-2Q hydroxyampicillin in high voltage electrophoresis at pH 7. The product may be isolated as described in Example 3.
7-(D-~-amino-~-(p-hydroxyphenyl)-acetamido)-3-(1,2,3-triazol-- 5-ylthiomethyl)-3-cephem-4-carboxylic acid.
1.56 g (5 mmoles) of 7-amino-3-(1,2,3-triazole-5-yl-thiomethyl)-3-cephem-4-carboxylic acid are suspended in 20 ml of dry acetonitrile, 2.1 ml (15 mmoles) of triethylamine are added, and the mixture is stirred for about 2-3 hours at ambient temperature until a clear solution is obtained. The solution is cooled to 0C, and 0.45 ml (5 mmoles) of ethylenechlorophosphite, 3Q dissolved in 2.5 ml of acetonitrile, is added. The mixture is stirred for 30 minutes, brought to room temperature, and 1.26 ml of trimethyl chlorosilane (10 mmoles) is added. After stirring for 2 hours, the precipitated triethyl-1~7~189 amine hydrochloride is removed by filtration (1.43 g). 2.32 g (20 mmoles) of pyridine hydrochloride, 2.0 g (7.5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride and 0.86 g (7.5 mmoles) of N-hydroxysuccin-imide are added to the solution of bis-trimethylsilyl-7-ethylenephosphite-amido-3-~1,2,3-triazol-5-yl-thiomethyl)-3-cephem-4-carboxylate, and the mix-ture is stirred at 0C overnight. High voltage paper electrophoresis indi-cates a nearly quantitative acylation.
For recovering of the reaction product, sodium dioctylsulfosuccinate (10 mmoles) are added, the solvent evaporated in vacuo and replaced by 30 ml of ethyl acetate followed by 15 ml of ice-water. The pH is adjusted to 1 and the mixture is stirred for 15 minutes and filtered,followed by separation of the phases. The aqueous phase is extracted tw~cewith 5 ml of ethyl acetate containing sodium dioctylsulfosuccinate ~2.5 mmoles).
The transfer of the product to the organic phase is confirmed by paper electrophoresis. The combined organic extracts are treated with 1 g of active carbon ~Norit SU 18) and filtered through filter aid. Methanol ~9.5 ml) and water ~0.5 ml) are added, and pH is adjusted to 4.5 with tri-caprylamine. A white precipitate is formed, and after stirring for 1.5 hour at 0 C the product is isolated by filtration, washed with ethyl acetate and methanol and dried in vacuo to yield 1.4 g of a white powder, showing a single spot on high voltage paper electrophoresis, moving as an anion at pH = 8, and as a cation at pH = 5. The MMR spectrum shows signals corresponding to the proposed structure.
A solution of 6.7 g of sodium dioctyl sulfosuccinate (Manoxol OT, BDH) in 50 ml of ethyl acetate are added, and the methylene chloride evaporat-ed in vacuo. The mixture is poured into ice-water, the pH adjust~d to 2 with phosphoric acid, and the phases separated. The aqueous phase is extracted twice with 1.67 g of sodium dioctyl sulfosuccinate in 10 ml of ethyl acetate.
The combined organic extracts are added to 10 ml water, and the pH adjusted to 4.9 with dicocomethylamine (KEMAMINE T-6501), and stirred 1 hour at 0C
to complete precipitation of the crystalline p-hydroxyampicillin trihydrate.
3.4 g of the product (80%) are isolated by filtration. Enzymatic titration indicates a purity of 80%, and one reprecipitation from water at iso-electric pH produces the pure compound, showing IR and NMR spectra identical with Trade Mark ~ 4 ~
1~:97~39 those of the authentic material.
Method s:
2.4 ml ~30 mmoles) of pyridine followed by 1.9 ml ~15 mmoles) of trimethylchlorosilane and 1.35 ml ~15 mmoles) of ethylene chlorophosphite are added to a suspension of 3.24 g ~15 mmoles) of 6-aminopenicillanic acid in 23 ml of dry methylene chloride. An exothermic reaction starts, bringing the mixture to a mild reflux. After 2 hours stirring at room temperature a small sample is evaporated, dissolved in deuteriochloroform, and the NMR spectrum recorded: ~External standard: TMS). The 6-hydrogen is represented by a multiplet of four signals, centered at ~ = 5 ppm, from which by first order analysis the following coupling constants may be deduced:
JPNCH JHccH: 4 5 Hz Addition Gf excess of triethylamine to the NMR tube converts this spectrum to the known pattern of the free base.
The reaction mixture is cooled to 0C, 2.66 g ~10 mmoles) of p-tri-methylsilyloxy-D-~ phenylglycine-N-carboxyanhydride, and 1.15 g ~10 mmoles) of N-hydroxysuccinimide are added, and the mixture stirred at 0C overnight.
Enzymatic titration indicates a yield of 98%. The product is precipitated by addition of 1.6 ml of pyridine and 7 g of activated carbon ~NORIT SU 18, containing 7.5% of water). After being stirred for 1 hour at 0C and 1 hour at room temperature, the precipitate is isolated by filtration and resuspended in 50 ml of ice-water. The carbon is removed by filtration ~enzymatic titra-tion at this point indicates 75% yield), 4 g sodium perchlorate are added, pH is adjusted to 1.5 with perchloric acid, and the product extracted with n-butanol as the perchlorate salt. To the combined butanol extracts 50 ml water are added, pH is adjusted to 7 with triethylamine, and the product ex-tracted back into water. The combined aqueous phases are adjusted to pH 4.8, and dissolved butanol removed b~ azeotropic distillation in vacuo, whereby the p-hydroxyampicillin crystallizes as the trihydrate. The first crop of crystals amounts to 1.66 g ~39%) showing IR and NMR spectra identical with those of authentic material. A further crop of crystals may be obtained from the filtrate.
p-Hydroxyampicillin.
A suspension of 1.08 g (5 mmoles) of 6-aminopenicillanic acid in 12.5 ml of dry methylene chloride and 1.4 ml (10 mmoles) of triethylamine is stirred at room temperature until a clear solution is obtained. The mixture is then cooled to -40C, and 0.45 ml (5 mmoles) of ethylene chlorophosphite are added. The mixture is brought to room temperature and stirred for one hour. 0.3 ml (2.5 mmoles) of dimethyldichlorosilane is added and the mixture stirred overnight at 0C. 0.4 ml of pyridine and 1.86 g (5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycyloxysuccinimide, prepared as described in Example 1, are added to said solution.
The reaction is followed by enzymatic titration of penicillin yield:
Time Yield 1 1/2 h 50%
2 1/2 h 63%
3 1/2 h 70%
20 h 70%
The penicillin produced behaved identically with authentic p-2Q hydroxyampicillin in high voltage electrophoresis at pH 7. The product may be isolated as described in Example 3.
7-(D-~-amino-~-(p-hydroxyphenyl)-acetamido)-3-(1,2,3-triazol-- 5-ylthiomethyl)-3-cephem-4-carboxylic acid.
1.56 g (5 mmoles) of 7-amino-3-(1,2,3-triazole-5-yl-thiomethyl)-3-cephem-4-carboxylic acid are suspended in 20 ml of dry acetonitrile, 2.1 ml (15 mmoles) of triethylamine are added, and the mixture is stirred for about 2-3 hours at ambient temperature until a clear solution is obtained. The solution is cooled to 0C, and 0.45 ml (5 mmoles) of ethylenechlorophosphite, 3Q dissolved in 2.5 ml of acetonitrile, is added. The mixture is stirred for 30 minutes, brought to room temperature, and 1.26 ml of trimethyl chlorosilane (10 mmoles) is added. After stirring for 2 hours, the precipitated triethyl-1~7~189 amine hydrochloride is removed by filtration (1.43 g). 2.32 g (20 mmoles) of pyridine hydrochloride, 2.0 g (7.5 mmoles) of p-trimethylsilyloxy-D-(-)-phenylglycine-N-carboxyanhydride and 0.86 g (7.5 mmoles) of N-hydroxysuccin-imide are added to the solution of bis-trimethylsilyl-7-ethylenephosphite-amido-3-~1,2,3-triazol-5-yl-thiomethyl)-3-cephem-4-carboxylate, and the mix-ture is stirred at 0C overnight. High voltage paper electrophoresis indi-cates a nearly quantitative acylation.
For recovering of the reaction product, sodium dioctylsulfosuccinate (10 mmoles) are added, the solvent evaporated in vacuo and replaced by 30 ml of ethyl acetate followed by 15 ml of ice-water. The pH is adjusted to 1 and the mixture is stirred for 15 minutes and filtered,followed by separation of the phases. The aqueous phase is extracted tw~cewith 5 ml of ethyl acetate containing sodium dioctylsulfosuccinate ~2.5 mmoles).
The transfer of the product to the organic phase is confirmed by paper electrophoresis. The combined organic extracts are treated with 1 g of active carbon ~Norit SU 18) and filtered through filter aid. Methanol ~9.5 ml) and water ~0.5 ml) are added, and pH is adjusted to 4.5 with tri-caprylamine. A white precipitate is formed, and after stirring for 1.5 hour at 0 C the product is isolated by filtration, washed with ethyl acetate and methanol and dried in vacuo to yield 1.4 g of a white powder, showing a single spot on high voltage paper electrophoresis, moving as an anion at pH = 8, and as a cation at pH = 5. The MMR spectrum shows signals corresponding to the proposed structure.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 6-(p-hydroxyphenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compound comprising the steps of reacting a compound of the general formula:
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of 6-aminopenicillanic acid or of an ester of a 7-amino-3-cephem-4-carboxylic acid in the presence of the hydrochloride of a weak amine.
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of 6-aminopenicillanic acid or of an ester of a 7-amino-3-cephem-4-carboxylic acid in the presence of the hydrochloride of a weak amine.
2. A process as claimed in claim 1 wherein the hydrochloride of a weak amine is pyridine hydrochloride.
3. A process as claimed in claim 1 wherein the compound having the formula (I) is reacted with a phosphite amide of a silylester of 6-aminopenicillanic acid or 7-amino-3-cephem-4-carboxylic acid.
4. A process for preparing 7-(p-hydroxyphenylglycylamido)-cephem compound comprising the steps of reacting a compound of the general formula:
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of a 7-amino-3-cephem-4-carboxylic acid in the presence of the hydrochloride of a weak amine.
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of a 7-amino-3-cephem-4-carboxylic acid in the presence of the hydrochloride of a weak amine.
5. A process for preparing a 6-(p-hydroxyphenylglycylamido)-penam compound comprising the steps of reacting a compound of the general formula:
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of 6-aminopenicillanic acid in the presence of the hydrochloride of a weak amine.
(I) wherein Y is dimethylene or o-phenylene, with a phosphite amide of an ester of 6-aminopenicillanic acid in the presence of the hydrochloride of a weak amine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB25447/75A GB1546077A (en) | 1975-06-13 | 1975-06-13 | Chemical compounds process for preparing said compounds and process for preparing 6-(p-hydroxyphenyl-glycylamido)-penam or 7-(p-hydroxyphenyl-glycylamido)-cephem compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071189A true CA1071189A (en) | 1980-02-05 |
Family
ID=10227825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA254,379A Expired CA1071189A (en) | 1975-06-13 | 1976-06-09 | Chemical compounds, process for preparing said compounds and process for preparing 6-(p-hydroxyphenylglycylamido)-penam or 7-(p-hydroxyphenylglycylamido)-cephem compounds |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS52260A (en) |
| BR (1) | BR7603793A (en) |
| CA (1) | CA1071189A (en) |
| DE (1) | DE2626280A1 (en) |
| DK (1) | DK263976A (en) |
| ES (2) | ES448787A1 (en) |
| FI (1) | FI761627A (en) |
| GB (1) | GB1546077A (en) |
| NL (1) | NL7606360A (en) |
| PT (1) | PT65212B (en) |
| SE (1) | SE7606567L (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9410480B2 (en) | 2008-12-23 | 2016-08-09 | Thyssenkrupp Uhde Gmbh | Method for use of the synthesis gas that comes from a gasifier |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0379892A (en) * | 1989-08-21 | 1991-04-04 | Yoshihisa Miura | Ferrule with chuck |
-
1975
- 1975-06-13 GB GB25447/75A patent/GB1546077A/en not_active Expired
-
1976
- 1976-06-08 FI FI761627A patent/FI761627A/fi not_active Application Discontinuation
- 1976-06-09 CA CA254,379A patent/CA1071189A/en not_active Expired
- 1976-06-10 SE SE7606567A patent/SE7606567L/en unknown
- 1976-06-11 NL NL7606360A patent/NL7606360A/en not_active Application Discontinuation
- 1976-06-11 DK DK263976A patent/DK263976A/en not_active Application Discontinuation
- 1976-06-11 DE DE19762626280 patent/DE2626280A1/en not_active Withdrawn
- 1976-06-11 ES ES448787A patent/ES448787A1/en not_active Expired
- 1976-06-11 BR BR7603793A patent/BR7603793A/en unknown
- 1976-06-11 PT PT65212A patent/PT65212B/en unknown
- 1976-06-14 JP JP51069639A patent/JPS52260A/en active Pending
-
1977
- 1977-08-01 ES ES461244A patent/ES461244A1/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9410480B2 (en) | 2008-12-23 | 2016-08-09 | Thyssenkrupp Uhde Gmbh | Method for use of the synthesis gas that comes from a gasifier |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52260A (en) | 1977-01-05 |
| DK263976A (en) | 1976-12-14 |
| ES461244A1 (en) | 1978-05-01 |
| GB1546077A (en) | 1979-05-16 |
| PT65212A (en) | 1976-07-01 |
| SE7606567L (en) | 1976-12-14 |
| ES448787A1 (en) | 1978-01-01 |
| NL7606360A (en) | 1976-12-15 |
| BR7603793A (en) | 1977-02-08 |
| FI761627A (en) | 1976-12-14 |
| DE2626280A1 (en) | 1976-12-30 |
| PT65212B (en) | 1977-11-23 |
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