GB2078725A - N-chlorocarbonyl Lactams - Google Patents
N-chlorocarbonyl Lactams Download PDFInfo
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- GB2078725A GB2078725A GB8114762A GB8114762A GB2078725A GB 2078725 A GB2078725 A GB 2078725A GB 8114762 A GB8114762 A GB 8114762A GB 8114762 A GB8114762 A GB 8114762A GB 2078725 A GB2078725 A GB 2078725A
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- GB
- United Kingdom
- Prior art keywords
- group
- chlorocarbonyl
- reaction
- toluene
- triethylamine
- 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.)
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- 150000003951 lactams Chemical class 0.000 title claims abstract description 15
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 8
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract 1
- -1 heterocyclic lactam Chemical class 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 11
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 5
- 239000005051 trimethylchlorosilane Substances 0.000 description 5
- JDBQKESLZWCKHY-UHFFFAOYSA-N 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo[3.2.1]octan-2-one Chemical compound C(C)(=O)N1C2C(NCC1SC2(C)C)=O JDBQKESLZWCKHY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical compound O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UMLPONXXJIKBMA-UHFFFAOYSA-N 2-oxopyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1=O UMLPONXXJIKBMA-UHFFFAOYSA-N 0.000 description 1
- IBBKJIHHXITFOF-UHFFFAOYSA-N 8-acetyl-7,7-dimethyl-2-oxo-6-thia-3,8-diazabicyclo[3.2.1]octane-3-carbonyl chloride Chemical compound ClC(=O)N1C(C2C(SC(C1)N2C(C)=O)(C)C)=O IBBKJIHHXITFOF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 101100219264 Petunia hybrida C4H2 gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- SXFPXZSENHPCSH-UHFFFAOYSA-N bicyclo[3.2.1]octan-4-one Chemical compound O=C1CCC2CCC1C2 SXFPXZSENHPCSH-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- XHLLMVSEBKZODD-UHFFFAOYSA-N n-acetyl-n-methylcarbamoyl chloride Chemical compound CC(=O)N(C)C(Cl)=O XHLLMVSEBKZODD-UHFFFAOYSA-N 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—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
- 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
- C07D513/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
N-chlorocarbonyl lactams are made by reacting the corresponding heterocyclic lactam, or a trimethylsilyl derivative or a sodium salt, with carbonyl dichloride. Products can thus be made of the formula: <IMAGE> wherein X is C1-6 alkylene, C1-5 aliphatic with N, O or S as a heteroatom, cycloalkyl up to C6, aryl or aralkyl with up to C5 in the alkyl moiety or <IMAGE> where Y is a C1-5 group or a C0-4 group with N, O or S as a heteroatom and n is 0-3.
Description
SPECIFICATION
N-chlorocarbonyl Lactams
This invention relates to the manufacture of N-chlorocarbonyl lactams of the general formula:
wherein X is a C16 alkyiene group, a C15 aliphatic group comprising a heteroatom selected from N, O and S, a cycloalkyl group having up to 6 carbon atoms, an aryl or aralkyl group having up to 5 carbon atoms in the alkyl moiety or a group of the formula
wherein Y represents a C15 group or a C,, group comprising a heteroatom selected from N, 0 and S and n represents an integer from 0 to 3.
Some less complex N-chlorocarbonyl lactams of formula I are known compounds and are used in the preparation of ureidopenicillins (DE-OS 2025414).
We have now found that compounds of formula I may be generally used in the preparation of mixed anhydrides, which are important intermediates in the synthesis of semi-synthetic penicillins. Of special interest is the hitherto unknown N3-chlorocarbonyl-N8-acetyl-7 ,7-dimethyl-6-thia-3 8-diaza bicyclo[3,2,1]octan-2-one, owing to the possibility of regeneration of N6-acetyl-7,7-dimethyl-6-thia- 3,8-diazabicyclo[3,2,1 ]octan-2-one and its reconversion to the corresponding N3-chlorocarbonyl derivative.
It is known that certain less complex N-chlorocarbonyl lactams may be prepared by the hydrolysis of 1 -aza-2-methoxy-cycloalk-2-ene-1-carbonyl chlorides (DE-OS 1939236), which in turn are obtainable by the reaction of l-aza-2-methoxy- 1 -aza-2-methoxy-cycloalk-2-enes with carbonyl di chloride in the presence of triethylamine [G. Falkenstein and H. Doerfel, Makromol. Chem. 1969 (127) 34]. The preparation of N-chlorocarbonyl caprolactam by the action of CH3Li and then carbonyl chloride on caprolactam has also been described (DE-OS 2025414).
The preparation of simple N-chlorocarbonyl derivatives of sec.amides has also been described, by means of the reaction of the corresponding N-trimethylsilyl derivatives of sec.amides with carbonyl dichloride; in this way, N-chlorocarbonyl N-methyl-acetamide and N-methyl-benzamide were obtained [V. F. Mironov, V. D. Seludiakov, V. P. Koziukov, Zur. Obscei Him. 39 (1 969) 220].
It has now been found that complex or non-compiex N-chlorocarbonyl lactams of formula I can be obtained, if a lactam of the general formula:
wherein X has the above-defined meaning, or a trimethylsilyl derivative or a sodium salt thereof, is reacted with carbonyl dichloride.
The reaction is preferably carried out in an appropriate inert organic solvent, preferably methylene chloride or toluene, and most suitably at a temperature of about OOC. Optionally, the reaction may be conducted in the presence of a tertiary organic base, e.g. triethylamine, as an acid-binding agent. The reaction time may typically range from 30 to 1 20 minutes, under stirring.
The trimethylsilyl derivative of the lactam II is obtained in a conventional manner by silylation with trimethylsilyl chloride in an inert organic solvent, preferably methylene chloride ortoluene, at a temperature within the range from about 200C to the boiling point of the reaction mixture. The reaction is suitably carried out in the presence of a tertiary organic base, e.g. triethylamine, as an acidbinding agent.
Conversion of the lactam Il to its sodium salt is effected in a conventional manner as well, preferably by the action of metallic sodium on the lactam.
The reactants are convenientiy employed in stoichiometric quantities or a slight excess of the silylation agent, the tertiary base or carbonyl dichloride with respect to the lactam may be used.
The resulting product I is isolated from the reaction mixture and purified in conventional manner, e.g. by the addition of water to the reaction mixture, followed by an immediate separation of the layers, drying of the organic layer and evaporation of the solvent. Alternatively, the precipitated triethylamine hydrochloride is filtered off, the solvent is evaporated from the reaction solution and the residue is purified by distillation or, provided the product is a solid, by washing the solid residue with a suitable solvent.
The invention is illustrated but in no way limited by the following Examples.
Example 1
N-Chlorocarbonyl-pyrrolidin-2-one
a) Pyrrolidin-2-one (8.5 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) were added to toluene (100 ml) and, while stirring and under a continuous stream of nitrogen at 250C, trimethyl-chlorosilane (10.86 g, 0.1 mole) was added. The reaction mixture was stirred at 400C for 30 minutes, whereupon it was cooled to 0 C. The triethylamine hydrochloride which precipitated was aspirated and the mother liquor was mixed at OOC with stirring, for 30 minutes, with a 20% w/w solution of carbonyl chloride in toluene (52 ml). The reaction mixture was then stirred for 1 hour, whereupon the solvent was evaporated, leaving an oily residue. The residue was distilled at a b.p. of 11 2a1 1 60C and 0.13 Pa.
Yield: 10.5 g (71.2%) of a colourless oil.
Analysis: QH6NO2Cl (147.56) Cain.: C 40.69 H 4.10 N 9.49 Cl 24.03
Found: C 40.55 H 4.43 N 9.71 Cl 25.20
IR spectrum (film): 1810 (vs), 1764 (m), 1720 (s), 1350 (m), 1265 (s), 1227 (m), 1170 (s), 1095 (m), 885 (w) cm-11H NMR (CDCI3)a: 1.78-2.90 (m, CH,--CH,,-CO), 3.654.35 (m, CH2N).
b) Trimethyl-chlorosilane (10.86 g, 0.1 mole) was added at a temperature of 25"C, with stirring, to a solution of pyrrolidin-2-one (8.5 g, 0.1 mole) triethylamine (10.1 g, 0.1 mole) and methylene chloride (100 ml). The reaction mixture was stirred for 1 hour at a temperature of 400C, whereupon it was cooled to OOC and carbonyl dichloride (lOg, 0.11 mole) was added over 30 to 40 minutes. The reaction mixture was stirred for 1 hour and subsequently mixed with water (60 ml), while the temperature was kept at 0 to +50C for 5 minutes, with stirring. The organic layer was separated, dried and worked up as indicated under a).
Yield: 1 3 g (88.2%) of an oily product showing the same characteristics as the product described
in a).
c) A solution of pyrrolidin-2-one (8.5 g, 0.1 mole) in toluene (20 ml) was added over 30 minutes to molten sodium (2.3 g, 0.1 mole) in toluene (120 ml), kept at 1 100C. The reaction mixture was stirred for 1 hour, whereupon it was cooled to OOC and, over 30 minutes, a 20% w/w solution of carbon dichloride in toluene (52 ml) was added dropwise. The reaction mixture was stirred for another 1 hour at OOC, the sodium chloride which precipitated was filtered off and the mother liquor was evaporated to yield an oily residue, which was worked up as in a).
Yield: 9.7 g (66%) of an oily product, showing the same characteristics as the product described
in a).
d) A solution of pyrrolidin-2-one (8.5 g, 0.1 mole) triethylamine (10.1 g, 0.1 mole) and toluene (80 ml) was cooled to OOC, whereupon a 20% w/w solution of carbonyl chloride in toluene (52 ml) was added at a temperature of OOC over a period of 30 minutes, with stirring. The reaction mixture was stirred for 1 hour and subsequently the precipitated triethylamine hydrochloride was aspirated and the mother liquor was evaporated, yielding an oily residue.
Yield: 11.8 g (80%) of an oily residue, showing the same characteristics as in a).
e) A solution of pyrrolidin-2-one (8.5 g, 0.1 mole), triethylamine (10.1 g, 0.1 mole) and methylene chloride (100 ml) was cooled to OOC, whereupon carbonyl chloride (lOg, 0.11 mole) was added over 1 5 to 20 minutes. The reaction mixture was stirred for 2 hours at OOC, whereupon water (50 ml) was added. The organic layer was separated, dried and evaporated, yielding an oily residue, which was purified as in a).
Yield: 12.3 g (83%) of an oily product, showing the same characteristics as the product described
in a).
Example 2
NChlorocarbonyl Enantholactam
Trimethyl-chlorosilane (3.2 ml, 25 mmole) was added with stirring at 250C to a solution of enantholactam (3.17 g, 25 mmole), triethylamine (2.53 g, 25 mmole) and toluene (30 ml), whereupon the reaction mixture was stirred for a further 2 hours at a temperature of 500 C. The solution was cooled to OOC and subsequently a 20% w/w solution of carbonyl chloride in toluene (13 ml) was added over 30 minutes. The reaction mixture was stirred for 1 hour at OOC and the precipitated triethylamine hydrochloride was then aspirated. The mother liquor was evaporated, yielding an oily residue.
Yield: 4.14 9 (87.4%); b.p. 103 105 C/O. 13 Pa (dec.)
IR spectrum (CH2CI2): 1787 (s), 1715 (vs) cam~' Example 3 3-Chlorocarbonyl-8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo[3,2,1]octan-2-one a)Triethylamine (1.01 g, 10 mmole) and trimethyl-chlorosilane (1.086 g, 10 mmole) were added to a suspension of 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo[3,2, 1 ]octan-2-one (2.14 g, 10 mmole) in dry toluene (30 ml).The reaction mixture was stirred for 3 hours at 500 C, subsequently cooled to OOC and a 20% w/w solution of carbonyl chloride in toluene (5.2 ml) was added dropwise over 1 5 minutes and the stirring continued for 3 hours. The precipitated crystalline triethylamine hydrochloride was aspirated, whereas the mother liquor was evaporated to dryness. The residue is suspended in cold ether (5 ml) and filtered.
Yield: 2.35 g (85%) of a product with a m.p. of 1050-1070C.
IR spectrum (CH2Cl2): 1800 (s), 1730(s), 1660 (vs), 1400(s), 1290(s), 1200 (vs), 1160(s),
1110 (m) cm~'.
1H NMR (CDCI3)a: 1.46; 1.68 and 1.53; 1.68 [4 S, 2 C(CH3)2], 2.22; 2.30 (2 S, COCH3); 3.70- 4.30 (m, C4H2), 4.43; 5.08 (2 S, C,H), 5.70; 6.20 (2m, C5H).
b) Triethylamine (1.01 g, 10 mmole) and trimethylchlorosilane (1.08 g, 10 mmole) were added to a suspension of 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo-[3,2,1]octan-2-one (2.14 g, 10 mmole) in dry methylene chloride (20 ml). The reaction mixture was stirred for 1 hour at the boiling point of the solution, whereupon it was cooled to OOC and, over a period of 15 minutes, a 20% w/w solution of carbonyl dichloride in toluene (5.2 ml) was added dropwise. Cold water (20 ml) was added to the reaction mixture, the resultant layers were separated and the organic layer was washed with water (2x20 ml). After drying, the solvent was evaporated, yielding a dry residue, to which ether (5 ml) was added and the resultant crystalline precipitate was aspirated.
Yield: 2.12 g (76.8%) of product, showing the same characteristics as in a).
c) Triethylamine (1.01 g, 10 mmole) was added to a suspension of 8-acetyl-7,7-dimethyl-6-thia 3,8-diazabicyclo[3,2,1]octan-2-one (2.14 g, 10 mmole) in dry toluene (30 ml), the mixture was cooled to OOC. A 20% w/w solution of carbonyl dichloride in toluene (5.5 ml) was added to the reaction mixture and it was stirred for 3 hours at the aforesaid temperature. After the addition of cold water, the organic layer was separated, washed with water and worked up as in a).
Yield: 2.30 g (83%) of the product, showing the same characteristics as in a).
d) Triethylamine (1.01 g, 10 mmole) was added to a suspension of 8-acetyl-7,7-dimethyl-6-thia3,8-diazabicyclo[3,2,1]octan-2-one (2.14 g, 10 mmole) in dry methylene chloride (20 ml) and the mixture was cooled to OOC. A 20% w/w solution of carbonyl dichloride in toluene (5.5 ml) was added to the reaction mixture dropwise over 30 minutes and the mixture was stirred for 3 hours. After the addition of water and working up as in a), a product was obtained having the same characteristics as in a).
Yield: 2.9 g (79%).
Claims (8)
1. A process of manufacture of an N-chlorocarbonyl lactam of the general formula:
wherein X is a C18 alkylene group, a C, < aliphatic group comprising a heteroatom selected from N, O and S, a cycloalkyl group having up to 6 carbon atoms, an aryl or aralkyl group having up to 5 carbon atoms in the alkyl moiety or a group of the formula
wherein Y represents a C15 group or a C,, group comprising a heteroatom selected from N, 0 and S and n represents an integer from 0 to 3, which comprises reacting a lactam of the general formula:
wherein X has the above-defined meaning, or a trimethylsilyl derivative or a sodium salt thereof, with carbonyl dichloride.
2. A process as claimed in claim 1, wherein the reaction is carried out at about 0 C.
3. A process as claimed in claim 1 or 2, wherein the reaction is carried out in an inert organic solvent.
4. A process as claimed in claim 3, wherein the solvent is methylene chloride or toluene.
5. A process as claimed in any preceding claim, wherein the reaction is carried out in the presence of a tertiary organic base.
6. A process as claimed in claim 5, wherein the base is triethylamine.
7. A process as claimed in claim 1, substantially as described in any of the foregoing Examples.
8. An N-chlorocarbonyl lactam of formula I, when manufactured by a process as claimed in any preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU141080A YU141080A (en) | 1980-05-24 | 1980-05-24 | Process for preparing n-chlorocarbonl-lactams |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2078725A true GB2078725A (en) | 1982-01-13 |
| GB2078725B GB2078725B (en) | 1984-04-18 |
Family
ID=25554062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8114762A Expired GB2078725B (en) | 1980-05-24 | 1981-05-14 | N-chlorocarbonyl lactams |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT374788B (en) |
| CH (1) | CH649992A5 (en) |
| DE (1) | DE3120451A1 (en) |
| GB (1) | GB2078725B (en) |
| YU (1) | YU141080A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4755535A (en) * | 1986-04-23 | 1988-07-05 | Nelson Research & Development Co. | Compositions comprising 1-substituted azacycloalkenes |
| US4801586A (en) * | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US4879275A (en) * | 1987-09-30 | 1989-11-07 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agent |
| US4886783A (en) * | 1986-01-31 | 1989-12-12 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US4920101A (en) * | 1987-09-30 | 1990-04-24 | Nelson Research & Development Co. | Compositions comprising 1-oxo- or thiohydrocarbyl substituted azacycloaklkanes |
| US5034386A (en) * | 1986-01-31 | 1991-07-23 | Whitby Research, Inc. | Methods for administration using 1-substituted azacycloalkanes |
| US5204339A (en) * | 1986-01-31 | 1993-04-20 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USD605700S1 (en) * | 2008-04-22 | 2009-12-08 | Beifa Group Co., Ltd. | Pen |
-
1980
- 1980-05-24 YU YU141080A patent/YU141080A/en unknown
-
1981
- 1981-05-14 GB GB8114762A patent/GB2078725B/en not_active Expired
- 1981-05-22 CH CH336481A patent/CH649992A5/en not_active IP Right Cessation
- 1981-05-22 DE DE19813120451 patent/DE3120451A1/en not_active Withdrawn
- 1981-05-22 AT AT230881A patent/AT374788B/en not_active IP Right Cessation
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4886783A (en) * | 1986-01-31 | 1989-12-12 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US5034386A (en) * | 1986-01-31 | 1991-07-23 | Whitby Research, Inc. | Methods for administration using 1-substituted azacycloalkanes |
| US5204339A (en) * | 1986-01-31 | 1993-04-20 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
| US4755535A (en) * | 1986-04-23 | 1988-07-05 | Nelson Research & Development Co. | Compositions comprising 1-substituted azacycloalkenes |
| US4801586A (en) * | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US4879275A (en) * | 1987-09-30 | 1989-11-07 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agent |
| US4920101A (en) * | 1987-09-30 | 1990-04-24 | Nelson Research & Development Co. | Compositions comprising 1-oxo- or thiohydrocarbyl substituted azacycloaklkanes |
Also Published As
| Publication number | Publication date |
|---|---|
| AT374788B (en) | 1984-05-25 |
| DE3120451A1 (en) | 1982-02-04 |
| CH649992A5 (en) | 1985-06-28 |
| ATA230881A (en) | 1983-10-15 |
| GB2078725B (en) | 1984-04-18 |
| YU141080A (en) | 1983-04-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |