IE48590B1 - Salts of(-)cis-1,2-epoxypropylphosphonic acid - Google Patents
Salts of(-)cis-1,2-epoxypropylphosphonic acidInfo
- Publication number
- IE48590B1 IE48590B1 IE1272/79A IE127279A IE48590B1 IE 48590 B1 IE48590 B1 IE 48590B1 IE 1272/79 A IE1272/79 A IE 1272/79A IE 127279 A IE127279 A IE 127279A IE 48590 B1 IE48590 B1 IE 48590B1
- Authority
- IE
- Ireland
- Prior art keywords
- cis
- acid
- salt
- thiomicamine
- epoxypropylphosphonic
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- QWMFKVNJIYNWII-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine Chemical compound CC1=CC=C(C)N1C1=CC=C(Br)C=N1 QWMFKVNJIYNWII-UHFFFAOYSA-N 0.000 claims description 4
- 238000000354 decomposition reaction Methods 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- -1 alkali metal salt Chemical class 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- 229910001868 water Inorganic materials 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000021962 pH elevation Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- WUUPHKMXFXHDKJ-UHFFFAOYSA-L O.[Ca+2].P([O-])([O-])=O Chemical compound O.[Ca+2].P([O-])([O-])=O WUUPHKMXFXHDKJ-UHFFFAOYSA-L 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- QHFQAJHNDKBRBO-UHFFFAOYSA-L calcium chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ca+2] QHFQAJHNDKBRBO-UHFFFAOYSA-L 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940126572 wide-spectrum antibiotic Drugs 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65502—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a three-membered ring
- C07F9/65505—Phosphonic acids containing oxirane groups; esters thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
Salts of (-)-cis-1,2- epoxypropylphosphonic acid with non toxic bases, useful as antibiotics, are prepared from racemic cis-1,2- epoxypropylphosphonic acid using L(+)-threo-1-(p- methylmercaptophenyl)-2-amino-1,3- propanediol as resolving agent.
Description
The invention relates to a new method for the preparation of salts of (-)cis-l,2- epoxypropylphosphonic acid.
Racemic cis-l,2-epoxypropylphosphonic acid has the formula (1) ·
CH.;
CH
CH
OH
(I)
OH
Its preparation by oxidation of cis-l-propenyl-phosphonic acid, which has the formula 11,
OH
using hydrogen peroxide in the presence of sodium tungstate dihydrate and its resolution into its optically active isomers are known. The resolution is generally carried out using (+)alpha-phenethylamine as resolving agent. (-)cis-l,2-Epoxypropylphosphonic acid and pharmaceutically acceptable salts
- 3 thereof are widely used in both human and veterinary fields as wide spectrum antibiotics to inhibit the growth of both gram-positive and gram-negative pathogenic bacteria.
The invention provides a process for a preparation of pharmaceutically acceptable salts of (-)cis-1,2-epoxypropylphosphonic acid, the process comprising adding L(+)-threo-1(p-methylmercaptophenyl)-2-amino-l,3-propanediol (thiomicamine) to racemic cis-1,2-epoxypropylphosphonic acid, isolating the resultant thiomicamine salt of (-)cis-1,2-epoxypropylphosphonic acid and adding an alkali metal hydroxide to a suspension of the isolated salt to precipitate the thiomicamine and, when the desired salts is not an alkali metal salt, effecting a double decomposition reaction with another salt to give the desired pharmaceutically acceptable salt.
Preferably the racemic cis-1,2-epoxypropylphosphonic acid is in the form of a solution obtained by oxidising cis-l-propenylphosphonic acid with hydrogen peroxide in the presence of sodium tungstate dihydrate and decomposing any excess hydrogen peroxide, which would otherwise oxidise the thiomicamine. The decomposition of hydrogen peroxide may be effected by addition of hydrazine hydrate and a catalytic amount of reduced copper, desirably at from 45 to 50°C. Preferably the thiomicamine is added gradually in alternation with the addition of an acid to maintain the pH at from 5 to 6 throughout the addition.
The method according to the invention allows an almost complete recovery of the used thiomicamine (higher than 93%) by a combination of ordinary recovery techniques.
The following Examples illustrate the invention.
EXAMPLE 1
Preparation of the calcium salt of (-)cis-1,2-epoxypropylphosphonic acid monohydrate.
- 4 600 g (4.91 mol) of cis-l-propenylphosphonic acid were dissolved in 3,500 ml of water and the resultant solution was adjusted to pH 5.9 with 30% sodium hydroxide. A solution, containing 11.2 g sodium tungstate dihydrate, 4.8 g. edetate disodium and 53 ml water was added to the above prepared solution under stirring and working at room temperature.
The solution thus obtained was heated to from 45° to 50 °C and 620 g (7.3 mols) of 40% hydrogen peroxide were slowly added under stirring. After the addition had been completed, the solution was allowed to stand under these conditions for li hours.
3.2 g (0.064 mol) hydrazine hydrate and 0.32 g reduced copper were then poured into the solution to decompose the excess hydrogen peroxide.
The solution, thus freed of the oxidising agent, was cooled to 20°C, decoloured, filtered and treated with 1,045 g (4.91 mols) L(+)-threo-1-(p-methylmercaptophenyl)-2-amino-l,
3-propanediol (thiomicamine) and concentrated hydrochloric acid at room temperature and under stirring. The addition of the thiomicamine and hydrochloric acid was effected gradually and in alternation in order to keep the pH of the mixture between 5 and 6; at the end of the addition the pH was 5.8.
The whole is kept for one hour under stirring at room temperature, and was then cooled to 0°C. After two hours, the resultant precipitate was filtered off and washed with water. From the mother liquors 265 g thiomicamine were recovered by alkalinization. The precipitate, being the thiomicamine salt of (-)cis-1,2-epoxypropylphosphonic acid was crystallized from isopropanol and suspended in 2,700 ml water. The mixture was stirred at room temperature and made alkaline with 10% sodium hydroxide.
4-8590
- 5 After one hour under stirring, thiomicamine was filtered off. The dried thiomicamine weighed 570 g.
Treatment of the aqueous solution containing the sodium salt of (-)cis-1,2-epoxypropylphosphonic acid with 760 g (3.47 mols) of calcium chloride hexahydrate dissolved in 760 ml water caused precipitation of the calcium salt of (-)cis-l,2-epoxypropylphosphonic acid monohydrate. This was filtered off, washed with water and dried. 250 g of product were obtained.
[a] = “6° (0.3% H2O); [a]”5 = -18° (0.3% H2O)
By distilling off the isopropanol present in the isopropanol mother liquors obtained by crystallizing the thiomicamine salt of (-)cis-1,2-epoxypropylphosphonic acid there are recovered by alkalinization 141 g thiomicamine.
EXAMPLE 2
Preparation of disodium salt of (-)cis-1,2-epoxypropylphosphonic acid.
The procedure described in Example 1 was followed until the aqueous solution containing the sodium salt of (-)cis-1,
2-epoxypropylphosphonic acid was obtained.
The pH of the solution was adjusted to 8.8 by addition of acetic acid. Evaporation off of the solvent under reduced pressure gave a syrup from which, on treatment with ethyl alcohol, the disodium salt of (-)cis-1,2-epoxypropenylphosphonic acid separated. The product weighed 285 g.
[a] = 5°(5% H20);[a] = -17° (5% Hs0).
4-859 0
-6 EXAMPLE 3
Preparation of the calcium salt of the (+)cis-l,2,epoxypropylphosphonic acid monohydrate.
By working as described in Example 1, but substituting 5 D(-)-threol-1(p-methylmercaptophenyl)- 2-amino-l,3propanediol for thiomicamine, there were obtained 245 g of (+)cis-l,2-epoxypropyl calcium phosphonate monohydrate.
[a] p = +6°(0.3% H20) ; [a]
365 + 18° (0.3% H20)
Claims (5)
1. A process for the preparation of pharmaceutically acceptable salts of (-)cis-l,2-epoxypropylphosphonic acid, the process comprising adding L(+)-threo-l (p-methylmercaptophenyl)-2-amino-l,3-propanediol (thiomicamine) to racemic cis-1,2-epoxypropylphosphonic acid, isolating the resultant thiomicamine salt of (-)cis-1,2-epoxypropylphosphonic acid, and adding an alkali metal hydroxide to a suspension of the isolated salt to precipitate the thiomicamine and, when the desired salt is not an alkali metal salt, effecting a double decomposition reaction with another salt to give the desired pharmaceutically acceptable salt.
2. A process according to claim 1 in which the racemic cis-1,2-epoxypropylphosphonic acid is in the form of a solution obtained by oxidising cis-l-propenylphosphonic acid with hydrogen peroxide in the presence of sodium tungstate dihydrate and decomposing any excess hydrogen peroxide.
3. A process according to claim 2 in which the decomposition of hydrogen peroxide is effected by addition of hydrazine hydrate and a catalytic amount of reduced copper.
4. A process according to any preceding claim in which the thiomicamine is added gradually in alternation with the addition of an acid to maintain the pH at from 5 to 6 throughout the addition.
5. A process for the preparation of pharmaceutically acceptable salts of (-)cis-1,2-epoxypropylphosphonic acid, the process being substantially as described herein with reference to Example 1 or Example 2.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT25389/78A IT1097477B (en) | 1978-07-06 | 1978-07-06 | METHOD FOR THE PREPARATION OF SALTS OF (-) CIS-1,2-EPOXYPROPYLPHOSPHONIC ACID |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE791272L IE791272L (en) | 1980-01-06 |
| IE48590B1 true IE48590B1 (en) | 1985-03-20 |
Family
ID=11216556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1272/79A IE48590B1 (en) | 1978-07-06 | 1979-08-08 | Salts of(-)cis-1,2-epoxypropylphosphonic acid |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5511575A (en) |
| AT (1) | AT373264B (en) |
| CA (1) | CA1131648A (en) |
| CH (1) | CH640863A5 (en) |
| DE (1) | DE2925359C3 (en) |
| DK (1) | DK284679A (en) |
| ES (1) | ES482227A1 (en) |
| FR (1) | FR2430424A1 (en) |
| GB (1) | GB2024826B (en) |
| GR (1) | GR69597B (en) |
| IE (1) | IE48590B1 (en) |
| IT (1) | IT1097477B (en) |
| NL (1) | NL7905313A (en) |
| SE (1) | SE446739B (en) |
-
1978
- 1978-07-06 IT IT25389/78A patent/IT1097477B/en active
-
1979
- 1979-06-09 JP JP7185879A patent/JPS5511575A/en active Pending
- 1979-06-12 CH CH549079A patent/CH640863A5/en not_active IP Right Cessation
- 1979-06-22 DE DE2925359A patent/DE2925359C3/en not_active Expired
- 1979-06-22 FR FR7916110A patent/FR2430424A1/en active Granted
- 1979-06-27 GB GB7922413A patent/GB2024826B/en not_active Expired
- 1979-06-28 AT AT0455279A patent/AT373264B/en not_active IP Right Cessation
- 1979-07-03 GR GR59500A patent/GR69597B/el unknown
- 1979-07-05 SE SE7905874A patent/SE446739B/en not_active IP Right Cessation
- 1979-07-05 ES ES482227A patent/ES482227A1/en not_active Expired
- 1979-07-05 DK DK284679A patent/DK284679A/en not_active Application Discontinuation
- 1979-07-06 NL NL7905313A patent/NL7905313A/en not_active Application Discontinuation
- 1979-07-06 CA CA331,340A patent/CA1131648A/en not_active Expired
- 1979-08-08 IE IE1272/79A patent/IE48590B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE446739B (en) | 1986-10-06 |
| JPS5511575A (en) | 1980-01-26 |
| NL7905313A (en) | 1980-01-08 |
| CA1131648A (en) | 1982-09-14 |
| FR2430424B1 (en) | 1985-04-12 |
| DE2925359A1 (en) | 1980-01-24 |
| IT7825389A0 (en) | 1978-07-06 |
| GR69597B (en) | 1982-07-05 |
| GB2024826A (en) | 1980-01-16 |
| ATA455279A (en) | 1983-05-15 |
| DE2925359C3 (en) | 1981-08-06 |
| DK284679A (en) | 1980-01-07 |
| IE791272L (en) | 1980-01-06 |
| SE7905874L (en) | 1980-01-07 |
| CH640863A5 (en) | 1984-01-31 |
| AT373264B (en) | 1984-01-10 |
| GB2024826B (en) | 1982-12-01 |
| IT1097477B (en) | 1985-08-31 |
| FR2430424A1 (en) | 1980-02-01 |
| ES482227A1 (en) | 1980-04-01 |
| DE2925359B2 (en) | 1980-09-04 |
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