DE2658961A1 - 1-Hydroxy-3-amino-propane-1,1-di:phosphonic acid prodn. - from beta alanine or deriv., phosphorous acid and phosphorus oxychloride - Google Patents
1-Hydroxy-3-amino-propane-1,1-di:phosphonic acid prodn. - from beta alanine or deriv., phosphorous acid and phosphorus oxychlorideInfo
- Publication number
- DE2658961A1 DE2658961A1 DE19762658961 DE2658961A DE2658961A1 DE 2658961 A1 DE2658961 A1 DE 2658961A1 DE 19762658961 DE19762658961 DE 19762658961 DE 2658961 A DE2658961 A DE 2658961A DE 2658961 A1 DE2658961 A1 DE 2658961A1
- Authority
- DE
- Germany
- Prior art keywords
- alanine
- phosphorus oxychloride
- phosphorous acid
- hydroxy
- acid
- 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
Links
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229940000635 beta-alanine Drugs 0.000 title claims abstract description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 title claims abstract description 24
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 title claims description 12
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- -1 phosphorus halide Chemical class 0.000 claims description 2
- 229910019213 POCl3 Inorganic materials 0.000 abstract description 2
- IVFGIXMLURJXBZ-UHFFFAOYSA-N 1-phosphonopropylphosphonic acid Chemical class CCC(P(O)(O)=O)P(O)(O)=O IVFGIXMLURJXBZ-UHFFFAOYSA-N 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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)
Abstract
Description
Verfahren zur Herstellung von 1-Hydroxy-3-amino-propan-Process for the preparation of 1-hydroxy-3-aminopropane
1 , 1 -diphosphonsäuren Gegenstand der Anmeldung ist ein Verfahren zur Herstellung von 1 -Hydroxy-3-amino-propan-1 , 1 -diphosphonsäure bzw. deren am Stickstoff alkylierten Derivaten sowie Salzen davon der allgemeinen Formel: wobei R1 und R2 ein Wasserstoffatom oder einen Alkylrest mit 1 - 4 Kohlenstoffatomen bedeuten, durch Umsetzung von ß-Alanin oder Poly-ß-alanin oder am Stickstoff alkyliertem ß-Alanin mit phosphoriger Säure und einem Phosphorhalogenid.1, 1 -diphosphonic acids The application relates to a process for the preparation of 1-hydroxy-3-aminopropane-1, 1 -diphosphonic acid or its derivatives alkylated on the nitrogen and salts thereof of the general formula: where R1 and R2 denote a hydrogen atom or an alkyl radical with 1 - 4 carbon atoms, by reaction of ß-alanine or poly-ß-alanine or ß-alanine alkylated on nitrogen with phosphorous acid and a phosphorus halide.
Es ist aus der deutschen Patentschrift 2 130 794 bekannt 1 -Hydroxy-3-amino-propan-1 , 1 -diphosphonsäure durch Umsetzung von ß-Alanin oder Poly-ß-alanin mit einem Gemisch aus phosphoriger Säure und Phosphortrichlorid in Gegenwart oder Abwesenheit eines organischen Verdünnungsmittels herzustellen. ß-Alanin, phosphorige Säure und das Verdünnungsmittel werden im siedenden Wasserbad erhitzt und dazu Phosphortrichlorid getropft. Der Nachteil dieser Methode besteht darin, daß sich beim Zutropfen des Phosphortrichlorids ein klebriges Reaktionsprodukt bildet, das sich nur schwer durchrühren läßt. Außerdem treten gelbe Nebenprodukte auf, die auf teilweises Zersetzen des Phosphortrichlorids bei Siedetemperatur zurückzuführen sind. Auch ist das Arbeiten mit einem organischen Verdünnungsmittel bei technischen Ansätzen schon aus preislichen Gründen nachteilig und das Abtrennen des Verdünnungsmittels erfordert einen zusätzlichen Arbeitsgang.It is known from German Patent 2,130,794 1-hydroxy-3-aminopropane-1 , 1-diphosphonic acid by reacting ß-alanine or poly-ß-alanine with a mixture of phosphorous acid and phosphorus trichloride in the presence or absence of one organic diluent. ß-alanine, phosphorous acid and that Diluents are heated in a boiling water bath, along with phosphorus trichloride dripped. The disadvantage of this method is that when the dropwise Phosphorus trichloride forms a sticky reaction product that is difficult to stir leaves. In addition, yellow by-products occur, which are due to the partial decomposition of the Phosphorus trichloride are due at boiling point. Also is working with an organic diluent for technical approaches already from the price point Reasons disadvantageous and the separation of the diluent requires an additional one Operation.
Es wurde @un gefunden, daß die geschilderten Schwierigkeiten nicht auftreten, wenn man ß-Alanin oder Poly-ß-alanin oder am Stickstoff alkyliertes ß-Alanin mit phosphoriger Säure und Phosphoroxychlorid umsetzt.It was found @un that the difficulties described do not occur when using ß-alanine or poly-ß-alanine or ß-alanine alkylated on the nitrogen Reacts with phosphorous acid and phosphorus oxychloride.
Vorteilhaft arbeitet man so, daß man ß-Alanin, phosphorige Säure It!d Phosphoroxychlorid bei Zimmertemperatur unter Rühren zusammengibt und die Mischung anschließend bis zu einer Innentemperatur von 100°C erhitzt oder es werde: ß-Alanin und phosphorige Säure bei 90 - 100°C als klare Schmelze vorgelegt, dazu das Phosphoroxychlorid getropft und noch kurz bei 1000C Innentemperatur nachgerührt. iJach Verdünnen mit Wasser fällt die Phosphonsäure in kristalliner Form aus.It is advantageous to work in such a way that ß-alanine, phosphorous acid It! D Phosphorus oxychloride combines at room temperature with stirring and the mixture then heated to an internal temperature of 100 ° C or it becomes: ß-alanine and phosphorous acid at 90-100 ° C presented as a clear melt, plus the phosphorus oxychloride added dropwise and stirred briefly at an internal temperature of 1000C. iJach thinning with The phosphonic acid precipitates in crystalline form in water.
Man kann auch ß-Alanin und Wasser bei Zimmertemperatur vorlegen und die zur Bildung der phosphorigen Säure entsprechende Menge Phosphortrichlorid zutropficrl. Anschließend gibt man Phosphoroxychlorid zu, -erhitzt auf eine Innentemperatur von 100°C und verdünnt mit Wasser. Bei dieser Arbeitsmethode muß die wässrige Endlösung zweckmäßig noch kurz aufgekocht werden, da sonst die phosphonsäure nur schwer kristallisiert.You can also submit ß-alanine and water at room temperature and the amount of phosphorus trichloride corresponding to the formation of the phosphorous acid is added. Phosphorus oxychloride is then added, heated to an internal temperature of 100 ° C and diluted with water. In this working method, the final aqueous solution must It is advisable to boil briefly, otherwise the phosphonic acid will only crystallize with difficulty.
Im Gegensatz zu dem bisherigen Verfahren mit Phosphortrichlorid anstelle des Phosphoroxychlorids wird st-ets ein gut rührbarer Sirup erhalten, der- sich gut in W-asser löst. Gelbe Nebenprodukte treten nicht auf.In contrast to the previous method with phosphorus trichloride instead of the phosphorus oxychloride, a well-stirrable syrup is always obtained, which is dissolves well in water. Yellow by-products do not occur.
Beispiel 1: 89,1 g (1,0 Mol) ß-Alanin und 164,0 g (2 Mol) phosphorige Säure werden bei 90 - 10000 unter Rühren als klare Schmelze vorgelegt.Example 1: 89.1 g (1.0 mol) of β-alanine and 164.0 g (2 mol) of phosphorous Acid are presented as a clear melt at 90-10,000 with stirring.
Dazu tropft man in 30 - 40 Minuten 153,3 g (l Mol) Phosphoroxychlorid. Durch exotherme Reaktion steigt die Innentemperatur auf etwa 115°C an und fällt dann unter schwachem POCl3-Rückfluß auf ca. 850, Es wird 20 - 30 Minuten bis zum Rückflußende und bis zum Erreichen von etwa 1000C innen nachgerührt. Dann wird mit 198 g (11 Mol) Wasser verdünnt. Beim Verdünnen steigt die Innentemperatur kurzfristig bis 16500 an und fällt dann schnell unter Wasser-Rückfluß wieder ab.153.3 g (1 mol) of phosphorus oxychloride are added dropwise to this in 30-40 minutes. As a result of the exothermic reaction, the internal temperature rises to about 115 ° C. and falls then under weak POCl3 reflux to approx. 850, It's 20-30 Minutes until the end of the reflux and until about 1000C was reached inside. It is then diluted with 198 g (11 mol) of water. When thinning, the internal temperature rises briefly up to 16500 and then quickly falls again under water reflux.
Beim Abkühlen auf Raumtemperatur scheidet sich die Phosphonsäure als rein-weißes Kristallisat ab. Die Ausbeute beträgt 112,0 g (51,14 % der Theorie).On cooling to room temperature, the phosphonic acid separates out as pure white crystals. The yield is 112.0 g (51.14% of theory).
Durch Einengen der Mutterlauge und Zugabe von Methanol fällt noch weitere Phosphonsäure aus.Concentration of the mother liquor and addition of methanol still precipitate further phosphonic acid from.
Beispiel 2: 89,1 g (1,0 Mol) ß-Alanin und 72 g (4,0 Mol) Wasser werden bei Raumtemperatur als Suspension unter Rühren vorgelegt.Example 2: 89.1 g (1.0 mol) of β-alanine and 72 g (4.0 mol) of water are obtained presented as a suspension with stirring at room temperature.
In 20 - 30 Minuten werden dann 274,7 g (2,0 Mol) Phosphortrichlorid zugetropft. Die Temperatur wird dabei durch Kühlen unter 3500 gehalten.274.7 g (2.0 mol) of phosphorus trichloride are then obtained in 20-30 minutes added dropwise. The temperature is kept below 3500 by cooling.
Nach der Zugabe des Phosphortrichlorid wird die Innentemperatur auf 90 - 10000 gesteigert. Dann tropft man 122,7 g (0,8 Mol) Phosphoroxychlorid in 20 - 30 Minuten zu und rührt anschließend noch 10 - 15 Minuten bei 90 - 1000C Innentemperatur nach.After the addition of the phosphorus trichloride, the internal temperature increases 90 - 10,000 increased. 122.7 g (0.8 mol) of phosphorus oxychloride are then added dropwise to 20 - Add 30 minutes and then stir for a further 10-15 minutes at 90-1000C internal temperature after.
Zur Kristallisation der Phosphonsäure gibt man 180 ml (10,0 Mol) Wasser dazu und kocht 5 Minuten unter Rückfluß auf.180 ml (10.0 mol) of water are added to crystallize the phosphonic acid to this and refluxed for 5 minutes.
Nach Abkühlen und Absaugen-erhält man 99,0 g (45,2 % der Theorie) Phosphonsäure.After cooling and suction-one receives 99.0 g (45.2% of theory) Phosphonic acid.
Beispiel 3: Zu einem Gemisch aus 89>1 g (1 Mol) ß-Alanin und 221,4 g (2,7 Mol) phosphorige Säure gießt man 222,3 g (1,45 Mol) Phosphoroxychlorid. Es bildet sich ftlr wenige Sekunden unter HCl-Entwioklung ein dünner, weißer Schaum und die Innentemperatur steigt durch die exotherme Realtion auf 45 - 500C an.Example 3: To a mixture of 89> 1 g (1 mol) ß-alanine and 221.4 222.3 g (1.45 mol) of phosphorus oxychloride are poured into g (2.7 mol) of phosphorous acid. It A thin, white foam forms for a few seconds with evolution of HCl and the internal temperature rises to 45 - 500C due to the exothermic reaction.
Danach wird unter Rühren aufgeheizt. Sind innen 95 - 100°C erreicht, BO rUhrt man noch 30 Minuten bei dieser Temperatur nach. Dann tropft man in 2 - 3 Minuten 180 g (10 Mol) Wasser zu, wobei die Innentemperatur kurz auf ca. 1600C ansteigt.Then the mixture is heated while stirring. If 95 - 100 ° C are reached inside, BO is stirred for a further 30 minutes at this temperature. Then one drips into 2 - 3 minutes 180 g (10 mol) of water, the internal temperature briefly to about 1600C increases.
Nach Abkühlen saugt man das rein-weiße Kristallisat ab.After cooling, the pure white crystals are filtered off with suction.
Ausbeute: 93,7 g (42,8 % der Theorie).Yield: 93.7 g (42.8% of theory).
Durch Einengen der Mutterlauge und Zugabe von Methanol fällt noch weitere Phosphonsäure aus.Concentration of the mother liquor and addition of methanol still precipitate further phosphonic acid from.
In analoger Weise lassen sich N-alkylierte ß-Alanine umsetzen.N-alkylated β-alanines can be converted in an analogous manner.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762658961 DE2658961C3 (en) | 1976-12-24 | 1976-12-24 | Process for the preparation of 1-hydroxy-3-aminopropane-1,1-diphosphonic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762658961 DE2658961C3 (en) | 1976-12-24 | 1976-12-24 | Process for the preparation of 1-hydroxy-3-aminopropane-1,1-diphosphonic acids |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2658961A1 true DE2658961A1 (en) | 1978-06-29 |
| DE2658961B2 DE2658961B2 (en) | 1980-09-25 |
| DE2658961C3 DE2658961C3 (en) | 1981-09-24 |
Family
ID=5996718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19762658961 Expired DE2658961C3 (en) | 1976-12-24 | 1976-12-24 | Process for the preparation of 1-hydroxy-3-aminopropane-1,1-diphosphonic acids |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2658961C3 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0027982A1 (en) * | 1979-10-27 | 1981-05-06 | Henkel Kommanditgesellschaft auf Aktien | Process for preparing 3-amino-1-hydroxypropane-1,1-diphosphonic acid |
| US4608368A (en) * | 1984-07-13 | 1986-08-26 | Henkel Kommanditgesellschaft Auf Aktien | 1-hydroxy-1,1-diphosphonic acids and cytostatic use thereof |
| US4847017A (en) * | 1986-07-05 | 1989-07-11 | Ciga-Geigy Corporation | Hydroxyphosphonocarboxylic acids |
| WO2001057052A1 (en) * | 2000-02-01 | 2001-08-09 | The Procter & Gamble Company | Process for making geminal bisphosphonates |
| WO2005063779A2 (en) * | 2003-12-23 | 2005-07-14 | Lyogen Limited | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3016289A1 (en) | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | METHOD FOR PRODUCING OMEGA-AMINO-1-HYDROXYALKYLIDEN-1,1-BIS-PHOSPHONIC ACIDS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2130794C3 (en) * | 1971-06-22 | 1974-07-11 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | Process for the preparation of l-hydroxy-S-aminopropane-ljl-diphosphonic acid |
-
1976
- 1976-12-24 DE DE19762658961 patent/DE2658961C3/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2130794C3 (en) * | 1971-06-22 | 1974-07-11 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | Process for the preparation of l-hydroxy-S-aminopropane-ljl-diphosphonic acid |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0027982A1 (en) * | 1979-10-27 | 1981-05-06 | Henkel Kommanditgesellschaft auf Aktien | Process for preparing 3-amino-1-hydroxypropane-1,1-diphosphonic acid |
| US4608368A (en) * | 1984-07-13 | 1986-08-26 | Henkel Kommanditgesellschaft Auf Aktien | 1-hydroxy-1,1-diphosphonic acids and cytostatic use thereof |
| US4847017A (en) * | 1986-07-05 | 1989-07-11 | Ciga-Geigy Corporation | Hydroxyphosphonocarboxylic acids |
| WO2001057052A1 (en) * | 2000-02-01 | 2001-08-09 | The Procter & Gamble Company | Process for making geminal bisphosphonates |
| US6562974B2 (en) | 2000-02-01 | 2003-05-13 | The Procter & Gamble Company | Process for making geminal bisphosphonates |
| JP2003522181A (en) * | 2000-02-01 | 2003-07-22 | ザ プロクター アンド ギャンブル カンパニー | Method for producing gem-like bisphosphonic acid |
| WO2005063779A2 (en) * | 2003-12-23 | 2005-07-14 | Lyogen Limited | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
| WO2005063779A3 (en) * | 2003-12-23 | 2005-09-29 | Lyogen Ltd | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
| US7723542B2 (en) | 2003-12-23 | 2010-05-25 | Trifarma S.P.A. | Process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
| EP2206717A1 (en) * | 2003-12-23 | 2010-07-14 | Alchymars S.p.A. | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2658961C3 (en) | 1981-09-24 |
| DE2658961B2 (en) | 1980-09-25 |
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| C3 | Grant after two publication steps (3rd publication) | ||
| 8339 | Ceased/non-payment of the annual fee |