GB2081263A - Manufacture of N-actyl Amides - Google Patents
Manufacture of N-actyl Amides Download PDFInfo
- Publication number
- GB2081263A GB2081263A GB8122653A GB8122653A GB2081263A GB 2081263 A GB2081263 A GB 2081263A GB 8122653 A GB8122653 A GB 8122653A GB 8122653 A GB8122653 A GB 8122653A GB 2081263 A GB2081263 A GB 2081263A
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- GB
- United Kingdom
- Prior art keywords
- group
- formula
- amides
- methylene chloride
- mmole
- 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.)
- Granted
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- 150000001408 amides Chemical class 0.000 title description 6
- 238000004519 manufacturing process Methods 0.000 title description 4
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 11
- 150000001199 N-acyl amides Chemical class 0.000 claims abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 230000008707 rearrangement Effects 0.000 claims abstract description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims abstract description 3
- 125000000524 functional group Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 5
- 150000003951 lactams Chemical class 0.000 abstract description 5
- -1 penicillin amides Chemical class 0.000 abstract description 4
- 229930182555 Penicillin Natural products 0.000 abstract description 3
- 229940049954 penicillin Drugs 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 238000006243 chemical reaction Methods 0.000 description 8
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 8
- 229940056360 penicillin g Drugs 0.000 description 7
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- QUHMHRSLQIMTIH-UHFFFAOYSA-N 2-oxoazocane-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCCCC1=O QUHMHRSLQIMTIH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 3
- 102220139156 rs774350715 Human genes 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- UMLPONXXJIKBMA-UHFFFAOYSA-N 2-oxopyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1=O UMLPONXXJIKBMA-UHFFFAOYSA-N 0.000 description 1
- FUTGEIKCIPBZGS-UHFFFAOYSA-N 4-thia-1-azabicyclo[3.2.0]heptane Chemical compound C1CSC2CCN21 FUTGEIKCIPBZGS-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- BUIPKAJYDWUZHQ-UHFFFAOYSA-N N-benzoyl-N-propylcarbamoyl chloride Chemical compound ClC(=O)N(C(C1=CC=CC=C1)=O)CCC BUIPKAJYDWUZHQ-UHFFFAOYSA-N 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical class ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- OMISGTJSZGSFEN-UHFFFAOYSA-N n-acetyl-n-phenylcarbamoyl chloride Chemical compound CC(=O)N(C(Cl)=O)C1=CC=CC=C1 OMISGTJSZGSFEN-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005924 transacylation reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
N-acyl amides, including the penicillin amides, are made by reacting a carboxylic acid with an N- chlorocarbonyl-sec.-amide or lactam to form a mixed anhydride of the formula: <IMAGE> wherein R is an organic acid radical, especially a heterocyclic group, substituted with other functional groups, and X is a bis[mono-C1-C6- alkyl] group a bis-[monoaryl]group or a mono-C1-C6-alkyl group or a monoaryl group, a divalent C1-C6- alkyl group or a C1-C5-alkyl group comprising a heteroatom selected from N, O and S, and subjecting the mixed anhydride to rearrangement. The N-acyl amide products have the formula: <IMAGE> wherein R and X have the above- defined meanings.
Description
SPECIFICATION
Manufacture of N-Acyl Am ides
This invention relates to the manufacture of N-acyl amides of the general formula:
wherein R represents an organic acid radical, especially a heterocyclic group, e.g. 4-thia-1 - azabicyclo[3,2,0]-heptane, substituted with other functional groups, and X represents a bis[mono-C1- Ce-alkyl] group, a bis[mono-aryl] group or a mono-C,C-alkyl group or a monoaryl group, a diva lent C1-C6-alkyl group or a C1-C5-alkyl group comprising a heteroatom selected from N, 0 and S.
The compounds of formula I are known and several of them are widely used in the pharmaceutical industry, because they include inter alia penicillin amides, which are important intermediates in the synthesis of antibiotics.
It is known that simple N-acyl amides may be obtained by acylating amides, e.g. by heating them with an anhydride or a chloride of the corresponding acid, provided an inorganic acid is added as a catalyst, because the absence of a catalyst results predominantly in the formation of the nitrile of the acid [D. Davidson and H. Skovronek, J. Amer. Chem. Soc. 80 (1958) 376.] In order to prepare N-acyl lactams, an analogous method has been used, namely where the corresponding lactams are heated with anhydrides or chlorides of simple acids, such as acetic anhydride, e.g. in the manufacture of Nacetyl derivatives of butyrolactam [W. Reppe et al., Ann. 596(1955) 201], valerolactam [C. Schotten,
Ber. (1888) 2242] or caprolactam [R. E. Benson and T. L. Cairns, J. Amer. Chem.Soc. 70 (1948) 211 5], or with benzoyl chloride, e.g. in the preparation of N-benzoyl derivatives of butyrolactam (W.
Reppe, ibid.), valerolactam [T. B. Graves, J. Amer. Chem. Soc. 46 (1924) 1469] or caprolactam [L.
Ruzicka, Hel. Chim. Acta 4 (1921) 478].
Also, N-acetyl derivatives of amides are obtainable by reacting amides with isopropenyl acetate [W. Hentschel, Ber. 23 (1890) 2395, A. W. Hoffmann, Ber. 14 (1881) 2731, U.S. Patent 2,656,360] and also by the use of ketenes [R. E. Dunbar and W. M. Svebson, J. Org. Chem. 23 (1958) 1793].
Mumm's reaction between imino chlorides and carboxylic acid salts is known, yielding N-acyl amides as final products [0. Mumm, H. Hesse and H. Volquartz, Ber. 48 (1915) 388]. This reaction is used for instance in the preparation of semi-synthetic penicillins, for the trans-acylation of benzylpenicillin with corresponding carboxylic acids [German Patent 1,943,667, J. Cieslak et al., Rocz.
Chem. 45 (1971) 111]. The preparation of certain N-penicillinyl amides by a modification of this method has also been disclosed (A. B. A. Jansen and T. J. Russell, J. Chem. Soc. 1965, 2127).
Recently it has been disclosed that mixed anhydrides of carboxylic acids with secondary amides may be successfully manufactured by the reaction of carboxylic acids with N-chlorocarbonyl-sec.amides (our co-pending Patent Application 8114761).
It has now been found, in accordance with the present invention, that N-acyl amides of formula I may be obtained by reacting a carboxylic acid of the formula:
with an N-chlorocarbonyl-sec.-amide or lactam of the formula:
wherein R and X have the above-defined meanings, and subjecting to rearrangement the resultant
mixed anhydride of the formula:
Preparation of the mixed anhydride is preferably carried out in an inert organic solvent immiscible with water, most suitably methylene chloride or toluene, and in the presence of an organic tertiary base, preferably pyridine or triethylamine. The reaction is advantageously carried out at a temperature in the range from 200 to +1 00C or +200C, most suitably at OOC.
The carboxylic acid may be used in the form of an alkali metal salt, most suitably as its sodium or potassium salt. The reaction time for preparation of the mixed anhydride IV typically ranges from 5 to 30 minutes, with stirring.
Rearrangement of the mixed anhydride IV is preferably achieved by stirring the reaction mixture i resulting from the reaction of the carboxylic acid with the N-chloro-carbonyl amide or lactam for 10 to 120 minutes at a temperature in the range from 0 to 400C.
In both reaction steps, the reactants are employed in equimolar ratios as a rule, although an excess of up to 10 mol% of the organic base or the N-chlorocarbonyl-sec.-amide or lactam with respect to the carboxylic acid may be used.
The advantages of the present invention in comparison with the prior art are considerable, since it provides a general method for acylating N-amides, whereas the known processes do not go beyond the preparation of simple N-acyl derivatives, e.g. acetyl or benzoyi derivatives. The method of the invention is particularly suitable in acylation by means of sensitive carboxylic acids, e.g. amino acids and penicillanic acid and cephalosporanic acid derivatives.
The resulting product of formula I is isolated from the reaction mixture and purified in a conventional manner, e.g. by adding cold water, stirring, separating the organic layer, washing with water, drying (e.g. over Na2SO4 or MgSO4) and evaporating the solvent. The residue may be digested with a suitable organic solvent, such as n-hexane, if desired, or it may be recrystallized from toluenepetroleum ether. Alternatively, the reaction mixture may be slightly acidified, e.g. with 0.1 N HCI, whereupon the organic layer is separated, washed with water and then with a NaHCO3 solution. The subsequent purification steps are performed in the above-indicated manner.
The invention is illustrated but in no way limited by the following Examples.
Example 1
N-6-Phenylacetamidopenicillinyl-enantholactam
(a) A suspension of benzylpenicillin potassium (7.4 g, 20 mmole) and pyridine (1.6 g, 20.2 mmole) in methylene chloride (100 ml) was added dropwise at a temperature of OOC to a solution of
N-chlorocarbonyl enantholactam (3.8 g, 20 mmole) in methylene chloride (50 ml), whereupon the reaction mixture was stirred for 40 minutes. Under stirring, water was added over a period of 5 minutes and the organic layer was separated, washed with water and dried (Na2SO4). Evaporation of the solvent yielded a frothy residue, Rf0.5 (methylene chloride-ether=4:1).
Yield: 6.75 g (76%)
Prior to the analysis, the product was crystallized from an ethyl acetate-ether mixture; a crysta!line product of m.p.=1 58c1 61 OC was obtained; Rf 0.5 (methylene chloride-ether=4:1 );[a]=+1 85.30 (0.5; CH2Cl2) Analysis: Q3HN3O4S (443.5)
Calc.: C 62.27; H 6.59; N 9.47; S 7.22%
Found: C 62.07; H 6.62; N 9.76; S 6.04%
IR (KBr): 3390 (s), 1777 (s), 1678 (s), 1510 (m), 1375 (s), 1295 (m), 1250 (m), 1205 (s), 1130
(m) and 700 (m) cm~'.
1H NMR (CDCl3) b: 1.43 [s, C(CH3)2]; 1.0--2.2 [m,-(CH2)4-]; 2.35-2.85 [m. CO--CH,]; 3.60
[s, PhCH2]; 3.60--4.30 [m, -NH2-j; 5.30-5.70 [m, C3-H, C5-H, C6-H]; 6.23 [d,
J=9 Hz, NHi and 7.34 [s, Cf,H51 ppm.
(b) 10 drops of triethylamine were introduced under stirring at OOC into a suspension of benzylpenicillin potassium (7.4 g, 20 mmole) in methylene chloride (100 ml), whereupon a solution of
N-chlorocarbonyl enantholactam (3.8 g, 20 mmole) in methylene chloride (50 ml) was added dropwise over a period of 20 minutes. The reaction mixture was stirred for 90 minutes at a temperature of OOC and finally worked up as indicated in (a).
Yield: 5.17 9 (58.3%) Example 2
N-6-Phenylacetamidopenicillinyl-butyrolactam
A solution of N-chlorocarbonyl-pyrrolidin-2-one (2.95 g, 20 mmole) in methylene chloride (50 ml) was added dropwise, with stirring at OOC over a period of 10 minutes, to a suspension of benzylpenicillin potassium (7.4 g, 20 mmole) and pyridine (1.6 B, 20 mmole) in methylene chloride (100 mi). The reaction mixture was then warmed to 400C and then stirred for 30 minutes, without further warming. The mixture was cooled to +50C, cold water (+50C, 50 ml) was introduced with stirring over a period of 5 minutes, the organic layer was separated, again washed with water, dried (MgSO4) and filtered and the solvent was evaporated.A frothy residue was obtained, Rf 0.35 (methylene chloride-ether=4:1).
Yield: 5.36 g (66.8%).
Prior to the analysis, the product was crystallized from a mixture of ethylacetate-ether-n-hexane; a crystalline product of m.p.=152 -1 56 OC was obtained; Rf 0.35 (methylene chloride-ether=4:1; [α]D23=+90.0 (0.5; CH2CI2).
Analysis: C20H23N304S (401.4)
Calc: C 59.83; H 5.77; N 10.47%
Found: C 59.58; H 6.27; N 10.21%
IR (KBr): 3340 (m), 1774 (ns), 1737 (s), 1680 (vs), 1515(s), 1365 (s), 1310(s), 1255 (s), 720
(m) and 705 (m) cm-1.
1H NMR (CDCl3) : 1.37 and 1.40 [2s, C(CH3)2]; 1.75-2.32 [m, -CH2-]; 2.35-2.85 [m,
-CO-CH2-]; 3.63 [s, Ph-CH2]; 3.50-4.00 [m, N-CH2]; 5.35-5.75 [m, C5-H and C6-H]; 5.87 [s, C3-H]; 6.34 [d, J=9 Hz, NH] and 7.34 [s, C6H5] ppm.
Example 3
N-6-Phenylaceta midopenicillinyl-caprolacta m
A solution of N-chlorocarbonyl caprolactam (3.7 g, 21 mmole) in methylene chloride (20 ml) was added at OOC, with stirring over a period of 10 minutes, to a sususpension of benzylpenicillin potassium (7.4 g, 20 mmole) and pyridine (1.6 g, 20.2 mmole) in methylene chloride (100 ml).The reaction mixture was stirred for 90 minutes at OOC, cold water (+50C, 50 ml) was then introduced and the mixture was worked up as in Example 1(a). A frothy product was obtained, which was crystallized from a mixture of ethyl acetate-ether (1:1); m.p.=157 -163 C; Rf 0.60 (CH2Cl2-ether=4:1); [α]D23=+180.6 (0.5;CH2Cl2) Yield: 6.6 g (77.2%)
IR (KBr): 3345 (m), 1775 (vs), 1678 (vs) cm-1
'H NMR (CDCl3) b: 1.41 and 1.42 [2s, C(CH3)2]; 1.40--2.0 [m, -(CH3)2]; 2.5--2.8 [m, -C0CH2-J; 3.67 [s, Ph-CH2]; 3.70-4.0 [m, N-CH2J; 5.35-5.67 [m, C5-H and C6- H; 5.7 [s, C3-H]; 6.23 [d, J=8 Hz, NH]; 7.38 [s, C6H ppm.
Example 4
N-(1 -Oxido-6-phenoxymethyl-amido-penicillinyl)-enantholactam A solution of N-chlorocarbonyl enantholactam (3.8 g, 20 mmole) in methylene chloride (50 ml) was added, with stirring at 20 C, to a solution of phenoxymethyl-penicillin-1-oxide (6.6 g, 18 mmole) and pyridine (1.6 g, 20.2 mmole) in methylene chloride (100 ml). The reaction solution was stirred at 0 C for 120 minutes, whereupon cold water (+20C, 50 ml) was introduced and the reaction solution was worked up as indicated in Example 1 (a). A frothy residue was obtained, Rf 0.45 (CH2CI2 ether=4:1); [α]D23=+75.3 (0.5; CH2CI2).
Yield: 6.94 g (81%)
IR (CH2CI2): 3370 (s), 1795 (vs), 1685 (vs) cm-'.
gH NMR (CDCls) #: 1.34 and 1.80 [2s,-C(CH3)2]; 0.9-2.15 [m, -(CH2)4-]; 2.20-2.60 [m, -CO-CH2-J; 3.0-3.5 [m,-N-CH2-]; 4.5 [s, PhCH2]; 4.9 [s, C3H]; 5.07 [d, J=4 Hz, C5-H]; 6.03 [2d,J=4.10 Hz, C6-H]; 6.4-7.5 [m, C6H; 8.34 [d, J=10 Hz, NH] ppm.
Example 5
N-6-Phenoxymethylamidopenicillinyl-N-phenyl-acetamide
Pyridine (4.0 g, 50 mmole) was introduced into a solution of N-chlorocarbonylacetanilide (9.85 g, 50 mmole) in toluene (100 ml), cooled to 0 C, followed by the addition of phenoxymethylpenicillin (1 7.5 g, 50 mmole). The mixture was stirred at a temperature of 0 C over a period of 30 minutes, whereupon 0.1 N HCI (50 ml) was added and the organic layer was separated, washed with water and a saturated NaHCO3 solution and again with water. Drying and elimination of the solvent by distillation yielded a frothy residue, which was digested in n-hexane. A crystalline product of m.p.=65 -67 C was obtained.
Yield: 17.45 g (74%)
Prior to the analysis, the sample was subjected to chromatography on a silica gel column; elution with a mixture of methylene chloride-ether (10:1) yielded a product of m.p.=78 -80 C; Rf 0.58 (CH2CI2-ether=4:1 ); [ai23-+1 54.3 (0.5; CH2CI2).
Analysis: C24H25N305S (467.5)
Calc.: C 61.66; H 5.40; N 8.99%
Found: C 61.42; H 5.13; N 9.17%
IR (CH2CI2): 1780 (s), 1700 (vs), 1600 (m), 1510 (s), 1490 (s), 1560 (m), and 1230 (vs) cm-'.
1H NMR (CDCl3) : 1.66 [s, -C(CH3)2]; 2.00 [s, CH3CO]; 4.50 [s, -OCH2]; 5.4-5.65 [m, C5-H and C6-H] 5.75 [s, C3-H]; 6.7-7.6 [m, C6H5 and CONH] ppm.
Example 6
N-6-Phenylacetamidopenicillinyl-N-phenyl-acetamide
A solution of N-chlorncarbonyl acetanilide (9.85 g, 50 mmole) in methylene chloride (50 ml) was
added to a suspension of benzylpenicillin potassium (18.62 g, 50 mmole) and pyridine (4.0 g, 50
mmole) in methylene chloride (100 ml), cooled to OOC, and the mixture was stirred for 2 hours at this 1 temperature.
The reaction mixture was worked up and the product was isolated as a frothy residue, as
indicated in Example 5.
The product obtained was dissolved in methylene chloride and chromatographed on a silica gel
column. Elution with a methylene chloride-ether mixture (10:1) yielded a crystalline product of m.p.=82 -85 C; R, 0.50 (CH2CI2-ether=4:1 ); [cr]D3=+185.1 0 (0.5; CH2CI2).
Yield: 15.8 g (70%)
Analysis: C24H25N304S (451.5)
Calc.: C 63.38; H 5.59; N 9.30% Found: C 63.52; H 5.82; N 9.57%
IR (CH2CI2): 1780 (vs), 1710 (vs), 1690 (vs), 1490 (s), 1370 (m), 1230 (vs) cm-1.
'H NMR (CDCl3) #: 1.46 and 1.55 [s, -C(CH3)2]; 2.0 [s, COCH3]; 3.67 [s, CH2j; 5.3-5.65 [m, C-H and C6-H]; 5.75 [s, C3-H]; 6.23 [d, J=10 Hz, CONH]; 6.95-7.5 [m, C6HJ; 7.33 [s, N-C6H5] ppm.
Example 7
N-6-Phenylacetamidopenicillinyl-N-propylbenzamide
A solution of N-chlorocarbonyl-N-propylbenzamide (11.25 g, 50 mmole) in toluene (50 ml) was added to a suspension of benzylpenicillin potassium (18.62 g, 50 mmole) and pyridine (10 drops) in toluene (200 ml), cooled to OOC, and the mixture was stirred for 1 hour at OOC. Water (+50C, 100 ml) was introduced into the reaction mixture, the organic layer was separated, washed again with water and dried (Na2SO4) and subsequently the solvent was evaporated. The solid residue obtained was crystallized from a toluene-petroleum ether (1 :1 ) mixture. A crystalline product of m.p.=122 - 1 250C. was obtained.
Yield: 16.5 g (69%)
Prior to the analysis, the sample was recrystallized from the same solvent, yielding a product of m.p.=1 2801 290C; Rf 0.61 (CH2Cl2-ether=4:1); [a]23=+l 55.10(0.2; CH2CI2).
Analysis: C26H29N304S (479.5)
Calc.: C 65.12; H 6.10; N 8.76%
Found: C 64.97; H 6.35; N 8.92%
IR (KBr): 3340 (m), 2960 (m), 1770(s), 1670 (vs), 1520 (m), 1565 (s), 1500 (vs), 1210 (vs), 1120(s) cm1.
1H NMR (CDCl3) b: 0.78 [t, J=8 Hz, C-CH3]; 1.15-1.75 [m, C-CH2-C]; 1.43 and 1.60 [s, C2-(CH3)2]; 3.20-4.20 [m, N-CH2]; 3.65 [s, CH2CO]; 5.13 [s, C3-H]; 5.40-5.70 [m, C5-H and C8-Hj; 6.13 [d, J=9 Hz, CONH]; 7.32 and 7.58 [s, C6H ppm.
Claims (9)
1. A method of manufacutre of an N-acyl amide of the formula:
wherein R represents an organic acid radical and X represents a bis[mono-C1-C6-alkyl] group, a bis[monoaryl] group or a mono-C1-C8-alkyl group or X represents a monoaryl group, a divalent C1- C6-alkyl group or a C1-C5-alkyl group comprising a heteroatom selected from N, 0 and S, which comprises reacting a carboxylic acid of the formula:
with an N-chlorocarbonyl-sec.-amide or lactarn of the formula:
wherein R and X have the above-defined meanings, and subjecting to rearrangement the resultant mixed anhydride of the formula:
2.A method according to claim 1, wherein the mixed anhydride IV is prepared in an inert organic solvent immiscible with water.
3. A method according to claim 2, wherein the solvent is methylene chloride or toluene.
4. A method according to any preceding claim, wherein the preparation is carried out in the presence of an organic tertiary base at a temperature in the range from 200 to +200C.
5. A method according to claim 4, wherein the base is pyridine or triethylamine.
6. A method according to any preceding claim, wherein the arrangement is performed at a temperature in the range from 0 to 400C.
7. A method according to any preceding claim, wherein R represents a heterocyclic group substituted with one or more other functional groups.
8. A method according to claim 1, substantially as described with reference to the foregoing
Examples.
9. An N-acyl amide of formula I as defined in claim 1, when made by a method according to any preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU190680A YU42533B (en) | 1980-07-28 | 1980-07-28 | Process for preparing penicilin n-acyl amides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2081263A true GB2081263A (en) | 1982-02-17 |
| GB2081263B GB2081263B (en) | 1984-04-11 |
Family
ID=25556062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8122653A Expired GB2081263B (en) | 1980-07-28 | 1981-07-22 | Manufacture of n-acyl amides |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT374202B (en) |
| CH (1) | CH649529A5 (en) |
| DE (1) | DE3129137A1 (en) |
| GB (1) | GB2081263B (en) |
| YU (1) | YU42533B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL32964A (en) * | 1968-09-16 | 1974-05-16 | American Home Prod | Penicillin and cephalosporin derivatives,their preparation and pharmaceutical compositions containing them |
| US3692774A (en) * | 1970-08-31 | 1972-09-19 | John H Sellstedt | 2-carboxamido penicillin derivatives |
| YU140880A (en) * | 1980-05-24 | 1983-02-28 | Pliva Pharm & Chem Works | Process for preparing amides by means of aminolysis of mixed anhydrides |
-
1980
- 1980-07-28 YU YU190680A patent/YU42533B/en unknown
-
1981
- 1981-07-22 GB GB8122653A patent/GB2081263B/en not_active Expired
- 1981-07-23 DE DE19813129137 patent/DE3129137A1/en not_active Ceased
- 1981-07-27 AT AT329881A patent/AT374202B/en not_active IP Right Cessation
- 1981-07-28 CH CH489281A patent/CH649529A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| GB2081263B (en) | 1984-04-11 |
| AT374202B (en) | 1984-03-26 |
| YU42533B (en) | 1988-10-31 |
| ATA329881A (en) | 1983-08-15 |
| CH649529A5 (en) | 1985-05-31 |
| YU190680A (en) | 1983-01-21 |
| DE3129137A1 (en) | 1982-03-18 |
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| PCNP | Patent ceased through non-payment of renewal fee |