GB2047689A - A process for preparing pivaloyloxymethyl esters of 6- beta - amidinopenicillanic acids - Google Patents
A process for preparing pivaloyloxymethyl esters of 6- beta - amidinopenicillanic acids Download PDFInfo
- Publication number
- GB2047689A GB2047689A GB8009291A GB8009291A GB2047689A GB 2047689 A GB2047689 A GB 2047689A GB 8009291 A GB8009291 A GB 8009291A GB 8009291 A GB8009291 A GB 8009291A GB 2047689 A GB2047689 A GB 2047689A
- Authority
- GB
- United Kingdom
- Prior art keywords
- preparing
- beta
- compound
- amidinopenicillanic
- carbon atoms
- 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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- -1 pivaloyloxymethyl esters Chemical class 0.000 title claims abstract description 20
- 239000002253 acid Substances 0.000 title claims abstract description 13
- 150000007513 acids Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 13
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 claims abstract description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- NPGNOVNWUSPMDP-UTEPHESZSA-N chembl1650818 Chemical compound N(/[C@H]1[C@@H]2N(C1=O)[C@H](C(S2)(C)C)C(=O)OCOC(=O)C(C)(C)C)=C\N1CCCCCC1 NPGNOVNWUSPMDP-UTEPHESZSA-N 0.000 abstract description 3
- 229960004212 pivmecillinam Drugs 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 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 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000003948 formamides Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin 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=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 150000003952 β-lactams Chemical class 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing the pivaloyloxymethyl esters of 6- beta - amidinopenicillanic acids, in which a derivative of 6- beta -amidinopenicillanic acid is reacted with chloromethylpivalate in an aprotic dipolar solvent in the presence of an alkaline metal carbonate at a temperature of from +20 DEG to +40 DEG C. The process is carried out in high yield and is particularly useful for preparing the medicine pivmecillinam which has a pronounced antibiotic activity.
Description
SPECIFICATION
A process for preparing pivalòyloxymethyl esters of 6 ss-amidinópeniciltariie acids
This invention relates to a process for preparing pivaloyloxymethyl esters of 6-ss-amidinopencillanic acids, particularly the pivaloyloxymethyl ester of 6-[(hexahydro-1 H-azepin-1yl)methyleneimino]penicillanic acid, commonly referred to as pivmecillinam.
The pivaloyloxymethyl esters of 6-P-amidinopenicillanic acids are already known and are described; for example, in British Patent No. 1,293,590. Such compounds are characterized by having a high antibiotic effect, particularly on gram-negative bacteria.
According to British Patent No.1,293,590, such pivaioyloxymethyl esters can be obtained by a reaction between pivaloyloxymethyl ester of 6-aminopenicillanic acid and reactive derivatives of disubstituted formamides and disubstituted thioformamides, or by reaction between reactive derivatives of esters (particularly the pivaloyloxymethyl ester) of 6:formamidopenicillanic acid and secondary amines.
Another method for-obtaining the pivaloyloxymethyl esters is described in British Patent No. 1,482,388, according to which the pivaloyloxymethyl ester of 6-aminopenicillanic acids reacted with secondary amines together with orthoformic ororthothioform ic'esters.
British Patent No. 1,315,566 extends the teaching of British Patent No, 1)293590 by using the-disubstituted amides and disubstituted thioamides as reactants instead of the corresponding formamides and thioformamides of British Patent No. 1,293,590.
Ail of the above cited patents of the prior art use as a reactant the pivaloyloxymethyl esther of 6-aminopenicillanic acid, which is a highly unstable compound and has to be sallfied and then converted again in situ to the free base.
The present invention provides a method of preparing pivaloyloxymethyl esters of 6-amidinopenicillanic acids by using stable reactants. The reection-proceeds with good yieldsand short reaction times as compared with the above prior art.
The invention comprises preparing pivaloyloxymethyl esters of 6-ss-amidinopenicillanic acids having the formula I
wherein R and R2-each represents an alkyl group having from 1 to 4 carbon atoms or atycloalkyl group having 5 or 6 carbon atoms, or R1 and R2, together with the nitrogen atom to which they are bonded, form a cyclic group;R3 represents the group -CH2-O-CO-C(CH3)3; and R4 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; wherein a compound of the general formula (I) in which R1, R2 and R4 are as above indicated, but R3 is a hydrogen atom, is reacted with chloromethylpivalate in an aprotic dipolar solvent in the presence of an alkaline carbonate at a temperature of from +20 C to +40 C.
The chloromethylpivalate is a per se well known compound'and is described, for example, in J.Amer.Chem.Soc. 89,5442, (1967). The compound of formula (I) in vhich-R1, R2 and R4are as aboveshown but R3 is -H, is well known per se and is described in British Patent No. 1,293,590; and a method of preparing it with high yields is disclosed in our copending Italian Patent Application No. 21809 A/79 In the prior art methods referred to above, one reactant is always the pivaloyloxymethyl ester of 6-aminopenicillanic acid, which is separately prepared and then reacted td produce the desired-final -product, whereas according to the present invention, the final compound is directly obtained by esterification of 6-B-amidinopenicillanic acid (which is a stable compound}.
The use of an alkaline carbonate, as an acceptor of the hydrochloric acid liberated in the esterification step in the method of the invention, enables high yields to be obtained. It has been found that yields are considerably lower and the reaction times considerably longer when using conventional acceptors of hydrochloric acid, such as triethylamine (J.Med. Chem. 13, 607 (1970)).
It is surprising that the process of the invention can be carried out and with high yields using, as a starting compound, a compound of formula (I), wherein R3 is -H, whereas when using analogous starting materials which have in their molecules a free carboxyl group and an amine group (such as ampicillin and cephalexin), in which the pivaloylmethyl esters are obtained from the pivaloyloxymethyl ester of 6-APA and 7-ADCA, as described in German Patent Applications DOS 2,012,022 and DOS 1,951, 012, the reaction would not occur at all or would occur with extremely low yields.
The following Examples illustrate the invention
EXAMPLE 1
Pivaloyloxymethyl ester of 6--[(hexah ydro- ill-azepin- l-yl) methyleneimino]penicillanic acid.
(PIVMECILLINAM)
3.25g 6-ss-[(hexahydro-1 H-azepin-1 -yl) methyleneiminol pencillanicacid, 9 potassium carbonate, 2.25 g chloromethylpivalate and 0.2 g sodium iodide were added, in that order, to 50 ml dimethylformamide, and the suspension thus obtained was stirred for 3 hours at 30"C. The reaction mixture was diluted with 100 ml
ethyl acetate and washed three times with 100-ml water. The organic solution dried on sodium sulphate was vacuum evaporated to dryness and the residue was crystallized from a mixture of acetone and water (1:1).
3.5 g of a compound of formula I was obtained in which R1 and R2 together form a hexamethylene chain, R4 is hydrogen and R3 is -CH2OCOC(CH3)3 Melting point: 1190C [a) DO =+231 + (C= 1.96 in ethyl alcohol) I.R.: 1780 (C=O, ss -lactam), 1765 (C =0 ester), 1745 (C=Og ester), 1630 (C = N)..
This compound was converted to its hydrochloride according to known methods.
EXAMPLE 2 Pivmecllllnam 3.25 g 6-ss- [(hexahydro-1 H-azepin-1 -yl) methyleneimino]-penicillanic acid, 1.1 g sodium carbonate, 3.25 g chloromethylpivalate and 0.2 g sodium iodide were added, in that order, to 50 ml dimethyl sulphoxide and the suspension was stirred for 5 hours at 30"C. The reaction mixture was diluted with 150 mi ethyl acetate
and washed several times with water. The organic phase was dried on sodium sulphate and then vacuum
evaporated to dryness. The residue was crystallized from a mixture of acetone-water (1 :1).
Thus, 3,3 g of a product identical to that described in Example 1 were obtained.
EXAMPLE 3
Pivaloyloxymethyl ester of 6-P-1(morpholln- i-yl)methyleneimino]peniclllanic acid
3.13 g 6-ss- [{morpholin-l-yi)methyleneiminol penicillanic acid, 1.4g potassium carbonate, 2.25 g
chloromethylpivalate and 0.2 g sodium iodide were added in that order to 50 ml dimethyl formamide and the suspension thus obtained was stirred for 3 hours at 30"C.
The reaction mixture was diluted with 100 ml methylene chloride and washed 3 times with 100 ml water.
The organic solution was dried on magnesium sulphate and vacuum evaporated to dryness.
The residue was crystallized from a mixture of acetone and water (1:2). 3.3 g of a compound of formula I were obtained, in which R1 and R2, together with the nitrogen atom to which they are bonded, form a 6 atom ring, comprising four carbon atoms, one oxygen atom and the nitrogen atom, R4 is hydrogen and R3 is -CH20COC(CH3)3.
Melting point: 78 - 80"C.
I.R.: 1775 (C= 0, p-lactam), 1765 (C = 0, ester), 1745 (C = q, ester), 1630 (C = N).
Claims (5)
1. A method of preparing pivaloyloxymethyl esters of 6-ss-amidinopenicillanic acids having the formula I, wherein R' and R2 each represents an alkyl group having from 1 to 4 carbon atoms or a cycloalkyl group
having 5 or6 carbon atoms, or R1 and R2, together with the nitrogen atom to which they are bonded, form a cyclic group; R3 represents the group -CH2-O-CO-C(CH3)3; and R4 is a hydrogen atom or an alkyl radical
having from 1 to 4 carbon atoms; wherein a compound of the general formula I in which R', R2 and R4 are as above indicated, but R3 is a hydrogen atom, is reacted with chloromethylpivalate in an aprotic dipolar solvent in the presence of an alkaline carbonate at a temperature of from +20"C to +40on.
2. A method according to claim 1, wherein the alkaline carbonate is sodium carbonate or potassium carbonate.
3. A method according to either of claims 1 and 2, wherein the aprotic solvent is dimethyl sulphoxide or dimethyl formamide.
4. A method according to any preceding claim, wherein the compound thus obtained is converted to its
hydrochloride.
5. A method according to any preceding claim, substantially as illustrated in the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21862/79A IT1119739B (en) | 1979-04-13 | 1979-04-13 | METHOD FOR THE PRODUCTION OF ESTERS OF 6-B-AMIDINE-PENICILLANIC ACID DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2047689A true GB2047689A (en) | 1980-12-03 |
Family
ID=11187898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8009291A Withdrawn GB2047689A (en) | 1979-04-13 | 1980-03-19 | A process for preparing pivaloyloxymethyl esters of 6- beta - amidinopenicillanic acids |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS55147288A (en) |
| BE (1) | BE882556A (en) |
| DE (1) | DE3012666A1 (en) |
| DK (1) | DK154980A (en) |
| ES (1) | ES8102573A1 (en) |
| FR (1) | FR2453863A1 (en) |
| GB (1) | GB2047689A (en) |
| IT (1) | IT1119739B (en) |
| NL (1) | NL8002107A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573603A (en) * | 2022-03-07 | 2022-06-03 | 南京美智德合成材料有限公司 | Process for synthesizing pimecrcillin in one pot |
-
1979
- 1979-04-13 IT IT21862/79A patent/IT1119739B/en active
-
1980
- 1980-03-19 GB GB8009291A patent/GB2047689A/en not_active Withdrawn
- 1980-03-28 FR FR8006992A patent/FR2453863A1/en not_active Withdrawn
- 1980-03-31 BE BE0/200056A patent/BE882556A/en unknown
- 1980-04-01 JP JP4125580A patent/JPS55147288A/en active Pending
- 1980-04-01 DE DE19803012666 patent/DE3012666A1/en not_active Withdrawn
- 1980-04-10 DK DK154980A patent/DK154980A/en not_active IP Right Cessation
- 1980-04-10 NL NL8002107A patent/NL8002107A/en not_active Application Discontinuation
- 1980-04-12 ES ES490521A patent/ES8102573A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES490521A0 (en) | 1981-02-16 |
| ES8102573A1 (en) | 1981-02-16 |
| DE3012666A1 (en) | 1980-11-27 |
| NL8002107A (en) | 1980-10-15 |
| JPS55147288A (en) | 1980-11-17 |
| IT7921862A0 (en) | 1979-04-13 |
| IT1119739B (en) | 1986-03-10 |
| FR2453863A1 (en) | 1980-11-07 |
| BE882556A (en) | 1980-07-16 |
| DK154980A (en) | 1980-10-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |