CA1113475A - Process for producing carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane-aminoaryl- alkane diphosphonic acids - Google Patents
Process for producing carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane-aminoaryl- alkane diphosphonic acidsInfo
- Publication number
- CA1113475A CA1113475A CA337,563A CA337563A CA1113475A CA 1113475 A CA1113475 A CA 1113475A CA 337563 A CA337563 A CA 337563A CA 1113475 A CA1113475 A CA 1113475A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- alkane
- carboxy
- acyl
- phenyl
- 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.)
- Expired
Links
- 239000002253 acid Substances 0.000 title claims abstract description 21
- 150000007513 acids Chemical class 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000008569 process Effects 0.000 title claims abstract description 13
- 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 claims abstract description 15
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZJIPHXXDPROMEF-UHFFFAOYSA-N dihydroxyphosphanyl dihydrogen phosphite Chemical compound OP(O)OP(O)O ZJIPHXXDPROMEF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 12
- -1 phenyl-acetyl Chemical group 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 229940024606 amino acid Drugs 0.000 claims description 6
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 claims description 4
- TXPKUUXHNFRBPS-UHFFFAOYSA-N 3-(2-carboxyethylamino)propanoic acid Chemical compound OC(=O)CCNCCC(O)=O TXPKUUXHNFRBPS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 108010077895 Sarcosine Proteins 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 229960003646 lysine Drugs 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- 229960004452 methionine Drugs 0.000 claims description 3
- 229960003104 ornithine Drugs 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000008729 phenylalanine Nutrition 0.000 claims description 3
- 229960005190 phenylalanine Drugs 0.000 claims description 3
- 229960002429 proline Drugs 0.000 claims description 3
- 229940043230 sarcosine Drugs 0.000 claims description 3
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 claims 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims 2
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 17
- 229940116254 phosphonic acid Drugs 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
- 150000003009 phosphonic acids Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VIQIHJVEWLYSEJ-UHFFFAOYSA-N (2-amino-1-hydroxy-1-phosphonoethyl)phosphonic acid Chemical compound NCC(O)(P(O)(O)=O)P(O)(O)=O VIQIHJVEWLYSEJ-UHFFFAOYSA-N 0.000 description 1
- SVXPSKKRNACRPB-UHFFFAOYSA-N 2-[acetyl(methyl)amino]acetic acid Chemical compound CC(=O)N(C)CC(O)=O SVXPSKKRNACRPB-UHFFFAOYSA-N 0.000 description 1
- SRBATDDRZARFDZ-UHFFFAOYSA-N 2-formamidopropanoic acid Chemical compound OC(=O)C(C)NC=O SRBATDDRZARFDZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- NTRBNFOLBJWRAO-INIZCTEOSA-N N(2),N(5)-dibenzoyl-L-ornithine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)CCNC(=O)C1=CC=CC=C1 NTRBNFOLBJWRAO-INIZCTEOSA-N 0.000 description 1
- LJLLAWRMBZNPMO-UHFFFAOYSA-N N-acetyl-beta-alanine Chemical compound CC(=O)NCCC(O)=O LJLLAWRMBZNPMO-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 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
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical class OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- C07F9/3873—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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a process for producing carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane-aminoaryl-alkane diphosphonic acids having the general formula wherein R1 is H, CH3, C2H5, C6H5, C6H11 or HOOC CmH2m where m is 2 to 5, R2 is H, CH3, C2H5, C6H5, CH2COOH or C2H4COOH, R3 is H, CH3, C2H5, -CH2C6H5, -C2H4SCH3, -CH2COOH, -C2H4COOH, or R2+R3 is , or R1+R2 is CmH2mCO where m is 2-5, and n is 1-4, which comprises reacting an acyl-aminocarboxylic acid or an anhydride thereof having the general formula
The present invention provides a process for producing carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane-aminoaryl-alkane diphosphonic acids having the general formula wherein R1 is H, CH3, C2H5, C6H5, C6H11 or HOOC CmH2m where m is 2 to 5, R2 is H, CH3, C2H5, C6H5, CH2COOH or C2H4COOH, R3 is H, CH3, C2H5, -CH2C6H5, -C2H4SCH3, -CH2COOH, -C2H4COOH, or R2+R3 is , or R1+R2 is CmH2mCO where m is 2-5, and n is 1-4, which comprises reacting an acyl-aminocarboxylic acid or an anhydride thereof having the general formula
Description
1~347~
The present invention relates to a process for producing carboxy-alkane-amino-alkane diphosphonic acids and carboxy-alkane-aminoaryl-alkane diphosphonic acid having the general formula R - C - NR - CnR H2n lCH
wherein Rl is H, CH3, C2H5, C6Hll, C6~50rHOOCCmH2mwheremis2-5, R iS H~ CH3~ C2H5' C6H5~ CH2COOHorC2H4COOH, R isH, CH3, C2H5, - -CH~
-CH2C6H5, -C2H45CH3, -CH2COOH or -C2H4COOH, or R + R3 iS CH2 or Rl + R2 is CmH2mCO- where m is 2-5 and n is 1-4.
A ~J CC~a~r ~ -methane-aminoalkane phosphonic and carboxy-methane-aminoaryl-alkane phosphonic acids are disclosed in German Patent No, 2,318,416. The alkali metal salts of these phosphonic acids are obtained by reacting the aminoalkane phosphonic acids and aminoaryl-alkane phosphonic acids with formaldehyde and an alkali metal cyanide in an alkaline medium. A disadvantage of this process is that extensive safety precautions are required when operating with alkali metal cyanides. Moreover, this pro-cess is limited to the production of carboxy-methane derivatives while higher homologues cannot be obtained in this manner.
It has now been found that said carboxylated diphos-phonic acids can be produced in a simple manner when acyl-amino-carboxylic acids or their anhydrides having the general formula o R -C-NR -CnR H2n lCOOH
wherein Rl, R2, R3 and n have the same meaning as hereinbefore, are reacted with pyrosphorous acid or phosphorous acid and phos-phorus trichloride in the molar ratio of 5:1 to 1:2 at elevatedtemperature.
~nhydride derivatives of the carbo~y-alkane-amilloalkane l~i3475 phosphonic acids which form during the reaction can be hydrolyzed to the free carboxy-phosphonic acids in a simple manner.
Instead of pyrophorous acid, phosphorous acid and phos-phorus trichloride can also be used in a molar ratio similar to that required for the formation of pyrophosphorous acid.
This manner of carrying out the reaction is all the - more surprising since it is known that in the reaction with phos-phorous acid and phosphorus trichloride the carboxylic acids and - their anhydrides readily react to form l-hydroxy-alkane-l,l-diphosphonic acids as is evident from Z. anorg. allg. Chem. 381, 247 (1971). This also applies to ~-aminopropionic acid (see laid-open German Specification 2,130,794). However, under similar con-ditions for the reaction aminoacetic acid and imino diacetic acid undergo decomposition so that the corresponding phosphonic acids are formed only in small amounts. However, in the case of the acyl-aminocarboxylic acids the phosphonylation occurs on the amide group, but not, as expected, on the carboxylic acid group.
According to the invention either the anhydrides of the acyl-aminocarboxylic acid are reacted with pyrophosphorous acid or the acyl-aminocarboxylic acid itself is reacted with phosphorous acid and PC13 in the corresponding molar ratio with or without solvents at temperatures between 50 and 100~C. One mole of pyro-phosphorous acid is used per acyl-amino group.
Since pyrophosphorous acid is in any case obtained from phosphorous trichloride and phosphorous acid, the dehydrating effect of the PC13 can be utilized for the formation of the anhydrides of acyl-aminocarboxylic acids during the reaction.
Thus, it is not absolutely necessary to use the anhydrides of the acyl-aminocarboxylic acids as the starting material. In order to simplify the process, acyl-aminocarboxylic acids can also be reacted directly with a mixture of phosphorous acid and phosphol-us trichloride. Howeverl the proportion of phosphorus trichloride ~ 347~
which must be used is higher than that required for obtaining pyrophosphorous acid. It is advantageous to use 1.5 times to twice the amount.
Acyl-aminocarboxylic acids are compounds which can be easily obtained from aminocarboxylic acids by reaction with car-boxylic anhydrides. Acetyl-amino acids can also be obtained by addition of ketene to amino acids. For the production of the formyl derivatives the reaction of aminocarboxylic acids with formic acid in the presence of acetanhydride is used. Benzoyl derivatives, for example, hippuric acid or ornithuric acid, are obtained from aminocarboxylic acid and benzoyl chloride by means of the Schotten-Baumann reaction.
N-carboxy-acyl-aminocarboxylic acidswhich areparticularly suitable for the reactionwith phosphorousacid and phosphorus tri-chloride or pyrophosphorous acid are derived from the followinc3 amino acids: glycine, sarcosine, phenyl glycine, ~- and ~-alanine, phenyl alanine, ~- and ~-aminobutyric acid, lysine, ornithine, methionine, proline, imino-diacetic acid, imino-dipropionic acid, aspartic acid and glutamic acid.
Acyl-aminocarboxylic acids and their anhydrides, which are used for the reaction, preferably contain formyl, acetyl, chloro-acetyl, phenyl-acetyl, propionyl, succinyl, cyclohexanoyl and benzoyl radicals as the acyl group.
The carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane amino-aryl-alkane diphosphonic acids and their alkali salts which are obtained by neutralizing the free acid with alkali liquor are readily water-soluble. Their solubility is substantially higher than that o~ the aminophosphonic acids from which .hey are derived. They are distinguished as good com-plexing agents for metal cations such as calcium,magnesium, iron, copper and manganese.
Since they are resistant to hydrolysis cven ~t tClnpCra-_ 3 1~1347~
tures above 100C, they can also be used with advantage in cases in which polyphosphates cannot beused because of the hydrolysis.
The present invention will be further illustrated by way of the following Examples.
Example l 58.3 g of N-acetyl glycine are suspended in 250 ml of dimethyl diglycol and 62 g of phosphorous acid are added, where-upon 45 ml of phosphorus trichloride are added dropwise while stirring vigorously. After the addition of the phosphorous tri-chloride the mixture is heated to 70-80C and maintained at this temperature for three hours while stirring, whereupon 150 ml of H2O are added, followed by boiling for 15 minutes. The mixture is then evaporated to dryness in a water-jet vacuum, taken up with 50 ml of water and mixed with 200 ml of isopropanol while a white precipitate consisting substantially of N-carboxy-methane-aminoethane diphosphonic acid is deposited.
Yield: 119.5 g For the purification a portion of the precipitate is dissolved in water and treated with an intensely acid cation exchanger. The solution is then concentrated and the acid is precipitated with i-propanol.
Analysis o~tained: C 18.6% N 5.4~ P 23.9%
computed: C 18.25% N 5.32% P 23~55o Example 2 55 ml of phosphorus trichloride are added dropwise to a mixture of 70 g of N-acetyl glycine and 70 g of phosphorous acid while stirring slowly. The mixture is gradually heated to 75C
and maintained at this temperature for 3 to 4 hours, whereupon the mixture is cooled and 120 ml of water are added. The mixture is then boiled for a short time and concentrated by evaporation in the vacuum of a water-jet pump. 140 g of a residue having a 1~1347;~
slightly yellow colour are obtained. This residue contains pri-marily N-carboxy-methane-aminoethane-l,l-diphosphonic acid in addition to a small amount of 2-amino-1-hydroxy-ethane-1,1-di-phosphonic acid~
~nalysis obtained: C 18.4~ N 5.9% P 24.2%
computed: C 18. 25% N 5. 32r~ p 23 ~ 55rO
Example 3 /
-29~ 5 g of glutamic acid are gradually added to 60 ml of 1~ acetanhydride containing 0.4 g of p-toluene sulphonic acid while - stirring. The mixture is then held at a temperature of 100 to 110C for one hour. Acetic acid formed and excess acetanhydride are distilled off in the vacuum of a water-jet pump. The viscous oil obtained as the residue is dissolved in 50 ml of dimethyl di-glycol ether, whereupon 80 g of phosphorus trichloride are added.
Next, a solution of 20 g of phosphorous acid in 30 ml of dimethyl diglycol ether is added dropwise while stirring vigorously.
While stirring is continued the temperature is increased to 90-95C and this temperature is maintained for 3 to 4 hours. This is followed by heating with 50 ml of water for 30 minutes. The solvent is then distilled off in vacuo and the reaction product is precipitated by taking it up in alcohol.
Example 4 35 ml of phosphorus trichloride and 52 g OL N-acetyl-3-aminopropionic acid are added to 32 g of phosphorous acid while excluding the moisture. The components are mixed with the aid of a slowly rotating stirrer. The mixture is then heated for 4 hours to 80C, whereupon 100 ml of water are added. The mixture is then boiled with reflux for 1 to 2 hours and the N-carboxy-ethane-l-aminoethane-l,l-diphosphonic acid containing a small amount of ~-alanine as an inpurity is precipitated and dried.
Yield: r~ 7 6 g 15 ~347~
Example 5 40 g of hippuric acid are dissolved with 18 g of phos-phorous acid and 25 ml of PC13 in 150 ml of tetramethylene sul-phone and kept at a temperature of 80C for 3 to 4 hours, where-upon 50 ml of E~2O are added. The mixture is then heated for 1 hour to a temperature of 100 to 110C and freed from most of the water in vacuo while a portion of the N-carboxy-methane-phenyl-amino-methane diphosphonic acid precipitates. The precipitation is completed by adding isopropanol. The precipitate is filtered off and washed with isopropanol several times in order to free the crystallizate from adhering sulphone.
Yield: 56 g Analysis obtained: C 32.6% N 4 .1% P 18.8go computed: C 33.23% N 4.31% P 19.05%
~xample 6 39.5 g of acetyl sarcosine and 38 g of phosphorous acid are suspended in 150 ml of diglycol dimethyl ether. 38 ml of PC13 are added dropwise while stirring whereby the mixture is slightly heated. After increasing the temperature to 70C this temperature is maintained for four hours. The mixture is then hydrolized while adding 50 ml of water. After evaporating the solvent in vacuo the mixture is again taken up in 50 ml of water and mixed with 150 ml of ethanol. After drying the difficultly soluble residue its weight was 73.5 g.
Analysis obtained: C 22.0% N 5. 4o P 22 . 9~o computed: C 21.65% N 5.06% P 22. 36o On proceeding in the same manner 69 ~ 2 g of N-carboxy-ethane-amino-methane diphosphonic acid ~ere obtained from 35.5 y of N-formyl alanine.
~1347~
Example 7 A solution of 35 g of N-formyl-~-alanine anhydride in 100 ml of tetramethylene sulphone is added dropwise to a solution of 40 g of pyrophosphorous acid in 50 ml of tetramethylene sul-phone while stirring. The temperature of this mixture is main-tained at 90C for four hours. After adding 20 ml of water the mixture is heated once more for one hour to a temperature of 100 to 110C. The mixture is then cooled and mixed with 200 ml of acetone in order to precipitate the N-carboxy-ethane-aminomethane diphosphonic acid.
Analysis obtained: C 18.6% N 5.2% P 23.1%
computed: C 18.25% N 5.32% P 23.55%
The present invention relates to a process for producing carboxy-alkane-amino-alkane diphosphonic acids and carboxy-alkane-aminoaryl-alkane diphosphonic acid having the general formula R - C - NR - CnR H2n lCH
wherein Rl is H, CH3, C2H5, C6Hll, C6~50rHOOCCmH2mwheremis2-5, R iS H~ CH3~ C2H5' C6H5~ CH2COOHorC2H4COOH, R isH, CH3, C2H5, - -CH~
-CH2C6H5, -C2H45CH3, -CH2COOH or -C2H4COOH, or R + R3 iS CH2 or Rl + R2 is CmH2mCO- where m is 2-5 and n is 1-4.
A ~J CC~a~r ~ -methane-aminoalkane phosphonic and carboxy-methane-aminoaryl-alkane phosphonic acids are disclosed in German Patent No, 2,318,416. The alkali metal salts of these phosphonic acids are obtained by reacting the aminoalkane phosphonic acids and aminoaryl-alkane phosphonic acids with formaldehyde and an alkali metal cyanide in an alkaline medium. A disadvantage of this process is that extensive safety precautions are required when operating with alkali metal cyanides. Moreover, this pro-cess is limited to the production of carboxy-methane derivatives while higher homologues cannot be obtained in this manner.
It has now been found that said carboxylated diphos-phonic acids can be produced in a simple manner when acyl-amino-carboxylic acids or their anhydrides having the general formula o R -C-NR -CnR H2n lCOOH
wherein Rl, R2, R3 and n have the same meaning as hereinbefore, are reacted with pyrosphorous acid or phosphorous acid and phos-phorus trichloride in the molar ratio of 5:1 to 1:2 at elevatedtemperature.
~nhydride derivatives of the carbo~y-alkane-amilloalkane l~i3475 phosphonic acids which form during the reaction can be hydrolyzed to the free carboxy-phosphonic acids in a simple manner.
Instead of pyrophorous acid, phosphorous acid and phos-phorus trichloride can also be used in a molar ratio similar to that required for the formation of pyrophosphorous acid.
This manner of carrying out the reaction is all the - more surprising since it is known that in the reaction with phos-phorous acid and phosphorus trichloride the carboxylic acids and - their anhydrides readily react to form l-hydroxy-alkane-l,l-diphosphonic acids as is evident from Z. anorg. allg. Chem. 381, 247 (1971). This also applies to ~-aminopropionic acid (see laid-open German Specification 2,130,794). However, under similar con-ditions for the reaction aminoacetic acid and imino diacetic acid undergo decomposition so that the corresponding phosphonic acids are formed only in small amounts. However, in the case of the acyl-aminocarboxylic acids the phosphonylation occurs on the amide group, but not, as expected, on the carboxylic acid group.
According to the invention either the anhydrides of the acyl-aminocarboxylic acid are reacted with pyrophosphorous acid or the acyl-aminocarboxylic acid itself is reacted with phosphorous acid and PC13 in the corresponding molar ratio with or without solvents at temperatures between 50 and 100~C. One mole of pyro-phosphorous acid is used per acyl-amino group.
Since pyrophosphorous acid is in any case obtained from phosphorous trichloride and phosphorous acid, the dehydrating effect of the PC13 can be utilized for the formation of the anhydrides of acyl-aminocarboxylic acids during the reaction.
Thus, it is not absolutely necessary to use the anhydrides of the acyl-aminocarboxylic acids as the starting material. In order to simplify the process, acyl-aminocarboxylic acids can also be reacted directly with a mixture of phosphorous acid and phosphol-us trichloride. Howeverl the proportion of phosphorus trichloride ~ 347~
which must be used is higher than that required for obtaining pyrophosphorous acid. It is advantageous to use 1.5 times to twice the amount.
Acyl-aminocarboxylic acids are compounds which can be easily obtained from aminocarboxylic acids by reaction with car-boxylic anhydrides. Acetyl-amino acids can also be obtained by addition of ketene to amino acids. For the production of the formyl derivatives the reaction of aminocarboxylic acids with formic acid in the presence of acetanhydride is used. Benzoyl derivatives, for example, hippuric acid or ornithuric acid, are obtained from aminocarboxylic acid and benzoyl chloride by means of the Schotten-Baumann reaction.
N-carboxy-acyl-aminocarboxylic acidswhich areparticularly suitable for the reactionwith phosphorousacid and phosphorus tri-chloride or pyrophosphorous acid are derived from the followinc3 amino acids: glycine, sarcosine, phenyl glycine, ~- and ~-alanine, phenyl alanine, ~- and ~-aminobutyric acid, lysine, ornithine, methionine, proline, imino-diacetic acid, imino-dipropionic acid, aspartic acid and glutamic acid.
Acyl-aminocarboxylic acids and their anhydrides, which are used for the reaction, preferably contain formyl, acetyl, chloro-acetyl, phenyl-acetyl, propionyl, succinyl, cyclohexanoyl and benzoyl radicals as the acyl group.
The carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane amino-aryl-alkane diphosphonic acids and their alkali salts which are obtained by neutralizing the free acid with alkali liquor are readily water-soluble. Their solubility is substantially higher than that o~ the aminophosphonic acids from which .hey are derived. They are distinguished as good com-plexing agents for metal cations such as calcium,magnesium, iron, copper and manganese.
Since they are resistant to hydrolysis cven ~t tClnpCra-_ 3 1~1347~
tures above 100C, they can also be used with advantage in cases in which polyphosphates cannot beused because of the hydrolysis.
The present invention will be further illustrated by way of the following Examples.
Example l 58.3 g of N-acetyl glycine are suspended in 250 ml of dimethyl diglycol and 62 g of phosphorous acid are added, where-upon 45 ml of phosphorus trichloride are added dropwise while stirring vigorously. After the addition of the phosphorous tri-chloride the mixture is heated to 70-80C and maintained at this temperature for three hours while stirring, whereupon 150 ml of H2O are added, followed by boiling for 15 minutes. The mixture is then evaporated to dryness in a water-jet vacuum, taken up with 50 ml of water and mixed with 200 ml of isopropanol while a white precipitate consisting substantially of N-carboxy-methane-aminoethane diphosphonic acid is deposited.
Yield: 119.5 g For the purification a portion of the precipitate is dissolved in water and treated with an intensely acid cation exchanger. The solution is then concentrated and the acid is precipitated with i-propanol.
Analysis o~tained: C 18.6% N 5.4~ P 23.9%
computed: C 18.25% N 5.32% P 23~55o Example 2 55 ml of phosphorus trichloride are added dropwise to a mixture of 70 g of N-acetyl glycine and 70 g of phosphorous acid while stirring slowly. The mixture is gradually heated to 75C
and maintained at this temperature for 3 to 4 hours, whereupon the mixture is cooled and 120 ml of water are added. The mixture is then boiled for a short time and concentrated by evaporation in the vacuum of a water-jet pump. 140 g of a residue having a 1~1347;~
slightly yellow colour are obtained. This residue contains pri-marily N-carboxy-methane-aminoethane-l,l-diphosphonic acid in addition to a small amount of 2-amino-1-hydroxy-ethane-1,1-di-phosphonic acid~
~nalysis obtained: C 18.4~ N 5.9% P 24.2%
computed: C 18. 25% N 5. 32r~ p 23 ~ 55rO
Example 3 /
-29~ 5 g of glutamic acid are gradually added to 60 ml of 1~ acetanhydride containing 0.4 g of p-toluene sulphonic acid while - stirring. The mixture is then held at a temperature of 100 to 110C for one hour. Acetic acid formed and excess acetanhydride are distilled off in the vacuum of a water-jet pump. The viscous oil obtained as the residue is dissolved in 50 ml of dimethyl di-glycol ether, whereupon 80 g of phosphorus trichloride are added.
Next, a solution of 20 g of phosphorous acid in 30 ml of dimethyl diglycol ether is added dropwise while stirring vigorously.
While stirring is continued the temperature is increased to 90-95C and this temperature is maintained for 3 to 4 hours. This is followed by heating with 50 ml of water for 30 minutes. The solvent is then distilled off in vacuo and the reaction product is precipitated by taking it up in alcohol.
Example 4 35 ml of phosphorus trichloride and 52 g OL N-acetyl-3-aminopropionic acid are added to 32 g of phosphorous acid while excluding the moisture. The components are mixed with the aid of a slowly rotating stirrer. The mixture is then heated for 4 hours to 80C, whereupon 100 ml of water are added. The mixture is then boiled with reflux for 1 to 2 hours and the N-carboxy-ethane-l-aminoethane-l,l-diphosphonic acid containing a small amount of ~-alanine as an inpurity is precipitated and dried.
Yield: r~ 7 6 g 15 ~347~
Example 5 40 g of hippuric acid are dissolved with 18 g of phos-phorous acid and 25 ml of PC13 in 150 ml of tetramethylene sul-phone and kept at a temperature of 80C for 3 to 4 hours, where-upon 50 ml of E~2O are added. The mixture is then heated for 1 hour to a temperature of 100 to 110C and freed from most of the water in vacuo while a portion of the N-carboxy-methane-phenyl-amino-methane diphosphonic acid precipitates. The precipitation is completed by adding isopropanol. The precipitate is filtered off and washed with isopropanol several times in order to free the crystallizate from adhering sulphone.
Yield: 56 g Analysis obtained: C 32.6% N 4 .1% P 18.8go computed: C 33.23% N 4.31% P 19.05%
~xample 6 39.5 g of acetyl sarcosine and 38 g of phosphorous acid are suspended in 150 ml of diglycol dimethyl ether. 38 ml of PC13 are added dropwise while stirring whereby the mixture is slightly heated. After increasing the temperature to 70C this temperature is maintained for four hours. The mixture is then hydrolized while adding 50 ml of water. After evaporating the solvent in vacuo the mixture is again taken up in 50 ml of water and mixed with 150 ml of ethanol. After drying the difficultly soluble residue its weight was 73.5 g.
Analysis obtained: C 22.0% N 5. 4o P 22 . 9~o computed: C 21.65% N 5.06% P 22. 36o On proceeding in the same manner 69 ~ 2 g of N-carboxy-ethane-amino-methane diphosphonic acid ~ere obtained from 35.5 y of N-formyl alanine.
~1347~
Example 7 A solution of 35 g of N-formyl-~-alanine anhydride in 100 ml of tetramethylene sulphone is added dropwise to a solution of 40 g of pyrophosphorous acid in 50 ml of tetramethylene sul-phone while stirring. The temperature of this mixture is main-tained at 90C for four hours. After adding 20 ml of water the mixture is heated once more for one hour to a temperature of 100 to 110C. The mixture is then cooled and mixed with 200 ml of acetone in order to precipitate the N-carboxy-ethane-aminomethane diphosphonic acid.
Analysis obtained: C 18.6% N 5.2% P 23.1%
computed: C 18.25% N 5.32% P 23.55%
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a carboxy-alkane amino-alkane diphosphonic acid and a carboxy-alkane-aminoaryl-alkane diphosphonic acid having the general formula wherein R1 is H, CH3, C2H5, C6H5, C6H11 or HOOC CmH2m where m is 2 to 5, R2 is H, CH3, C2H5, C6H5, CH2COOH or C2H4COOH, R3 is H, CH3, C2H5, -CH2C6H5, -C2H4SCH3, -CH2COOH, -C2H4COOH, or R2 + R3 is , or R1 + R2 is CmH2mCO - where m is 2 - 5 and n is 1 - 4, which comprises reacting an acyl-aminocarboxylic acid or an anhydride thereof having the general formula wherein R1, R2, n and R3 have the meaning as above, with pyrophos-phorous acid or phosphorous acid and phosphorus trichloride in the molar ratio of 5:1 to 1:2 at elevated temperature.
2. A process according to claim 1, in which the anhy-drides of the acyl-aminocarboxylic acids are produced during the reaction by means of phosphorus trichloride and reacted with the pyrophosphorous acid thus formed.
3. A process according to claim 1 in which the reaction is carried out in a polar aprotic solvent.
4. A process according to claim 1, 2 or 3 in which the reaction temperature is from 50 to 100°C.
5. A process as claimed in claim 1 in which the acyl amino acid is derived from an amino acid selected from glycine, sarcosine, phenyl glycine, .alpha.- and .beta.-alanine, phenyl alanine, .alpha.-and .gamma.-aminobutyric acid, lysine, ornithine, methionine, proline, imino-diacetic acid, imino-dipropionic acid, aspartic acid and glutamic acid.
6. A process as claimed in claim 1 in which the acyl amino acid is derived from an amino acid selected from glycine, sarcosine, phenyl glycine, .alpha.- and .beta.-alanine, phenyl alanine, .alpha.-and .gamma.-aminobutyric acid, lysine, ornithine, methionine, proline, imino-diacetic acid, imino-dipropionic acid, aspartic acid and glutamic acid and the acyl group is selected from formyl, acetyl, chloro-acetyl, phenyl-acetyl, propionyl, succinyl, cyclohexanoyl and benzoyl radicals.
7. A process as claimed in claim 1, 2 or 3 in which the reaction temperature is from 70°C to 95°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782846835 DE2846835A1 (en) | 1978-10-27 | 1978-10-27 | METHOD FOR PRODUCING CARBOXYLALKANE-AMINOALKANE DIPHOSPHONIC ACIDS AND AMINOARYLALKANE DIPHOSPHONIC ACIDS |
| DEP2846835.1 | 1978-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113475A true CA1113475A (en) | 1981-12-01 |
Family
ID=6053296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA337,563A Expired CA1113475A (en) | 1978-10-27 | 1979-10-15 | Process for producing carboxy-alkane-aminoalkane diphosphonic acids and carboxy-alkane-aminoaryl- alkane diphosphonic acids |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0012194B1 (en) |
| AT (1) | ATE648T1 (en) |
| CA (1) | CA1113475A (en) |
| DE (2) | DE2846835A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3047107A1 (en) * | 1980-12-13 | 1982-07-29 | Hoechst Ag, 6000 Frankfurt | METHOD FOR PRODUCING 1-AMINO-ALKANE-1,1-DIPHOSPHONIC ACIDS |
| IT1196315B (en) * | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | PROCEDURE FOR THE PREPARATION OF DIPHOSPHONIC ACIDS |
| GB8825589D0 (en) * | 1988-11-02 | 1988-12-07 | Albright & Wilson | Purification |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1958124C3 (en) * | 1969-11-19 | 1978-08-17 | Henkel Kgaa, 4000 Duesseldorf | Process for the preparation of aminomethanediphosphonic acid or its salts |
| DE1958123C3 (en) * | 1969-11-19 | 1978-09-28 | Henkel Kgaa, 4000 Duesseldorf | Process for the preparation of 1-aminoalkane-1,1-diphosphonic acids or their salts |
| 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 |
| DE2203340C3 (en) * | 1972-01-25 | 1974-06-12 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | Process for the preparation of 1-aminoethane-l-diphosphonic acid and derivatives thereof substituted on the nitrogen |
| DE2722539C3 (en) * | 1977-05-18 | 1981-11-19 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | Process for the preparation of N, N-dimethylaminomethane-diphosphonic acid |
-
1978
- 1978-10-27 DE DE19782846835 patent/DE2846835A1/en not_active Withdrawn
-
1979
- 1979-10-15 CA CA337,563A patent/CA1113475A/en not_active Expired
- 1979-10-26 EP EP79104159A patent/EP0012194B1/en not_active Expired
- 1979-10-26 DE DE7979104159T patent/DE2962064D1/en not_active Expired
- 1979-10-26 AT AT79104159T patent/ATE648T1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0012194A1 (en) | 1980-06-25 |
| EP0012194B1 (en) | 1982-02-03 |
| DE2846835A1 (en) | 1980-05-08 |
| ATE648T1 (en) | 1982-02-15 |
| DE2962064D1 (en) | 1982-03-11 |
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