CN114085244B - Preparation method of 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid - Google Patents
Preparation method of 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid Download PDFInfo
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- CN114085244B CN114085244B CN202111419337.2A CN202111419337A CN114085244B CN 114085244 B CN114085244 B CN 114085244B CN 202111419337 A CN202111419337 A CN 202111419337A CN 114085244 B CN114085244 B CN 114085244B
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- oxobutanoic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- FBWXUNCARHZYFO-UHFFFAOYSA-N C(=O)=C(C(=O)O)CCP(=O)(OCO)O Chemical compound C(=O)=C(C(=O)O)CCP(=O)(OCO)O FBWXUNCARHZYFO-UHFFFAOYSA-N 0.000 title claims description 29
- -1 3-methyl ethoxy phosphono-propanal Chemical compound 0.000 claims abstract description 39
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 24
- RWENMRCNLGQHOF-UHFFFAOYSA-N C(CP(=O)(O)OCO)C(C(=O)O)O Chemical compound C(CP(=O)(O)OCO)C(C(=O)O)O RWENMRCNLGQHOF-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- 238000007259 addition reaction Methods 0.000 claims abstract description 13
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 10
- AZXOZIJLWIODLL-UHFFFAOYSA-N CP(OCCC(O)C#N)=O Chemical compound CP(OCCC(O)C#N)=O AZXOZIJLWIODLL-UHFFFAOYSA-N 0.000 claims abstract description 8
- HVDJPRIMLGGPBH-UHFFFAOYSA-N 4-[hydroxy(hydroxymethoxy)phosphoryl]-2-oxobutanoic acid Chemical compound O=C(C(=O)O)CCP(=O)(OCO)O HVDJPRIMLGGPBH-UHFFFAOYSA-N 0.000 claims description 36
- 238000004519 manufacturing process Methods 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052720 vanadium Inorganic materials 0.000 claims description 15
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 10
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 10
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 10
- 239000003377 acid catalyst Substances 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 7
- UNTBPXHCXVWYOI-UHFFFAOYSA-O azanium;oxido(dioxo)vanadium Chemical compound [NH4+].[O-][V](=O)=O UNTBPXHCXVWYOI-UHFFFAOYSA-O 0.000 claims description 7
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical group N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 5
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 5
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000011534 incubation Methods 0.000 claims description 4
- 125000005287 vanadyl group Chemical group 0.000 claims description 4
- QUEDYRXQWSDKKG-UHFFFAOYSA-M [O-2].[O-2].[V+5].[OH-] Chemical compound [O-2].[O-2].[V+5].[OH-] QUEDYRXQWSDKKG-UHFFFAOYSA-M 0.000 claims description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 3
- PAJMKGZZBBTTOY-UHFFFAOYSA-N 2-[[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid Chemical compound C1=CC=C(OCC(O)=O)C2=C1CC1C(CCC(O)CCCCC)C(O)CC1C2 PAJMKGZZBBTTOY-UHFFFAOYSA-N 0.000 claims description 2
- LOUBVQKDBZRZNQ-UHFFFAOYSA-M [O-2].[O-2].[OH-].O.[V+5] Chemical compound [O-2].[O-2].[OH-].O.[V+5] LOUBVQKDBZRZNQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 4
- 238000001914 filtration Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid Chemical compound CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 5
- 150000004715 keto acids Chemical class 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- CNRNYORZJGVOSY-UHFFFAOYSA-N 2,5-diphenyl-1,3-oxazole Chemical compound C=1N=C(C=2C=CC=CC=2)OC=1C1=CC=CC=C1 CNRNYORZJGVOSY-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- 239000005561 Glufosinate Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- XNQULTQRGBXLIA-UHFFFAOYSA-O phosphonic anhydride Chemical compound O[P+](O)=O XNQULTQRGBXLIA-UHFFFAOYSA-O 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- FKCLZDBBWQTVIS-UHFFFAOYSA-N C(=O)=C(C(=O)O)CC=P(=O)CO Chemical compound C(=O)=C(C(=O)O)CC=P(=O)CO FKCLZDBBWQTVIS-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- YHMDGPZOSGBQRH-UHFFFAOYSA-N PPO Natural products CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC YHMDGPZOSGBQRH-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UFZOPKFMKMAWLU-UHFFFAOYSA-N ethoxy(methyl)phosphinic acid Chemical compound CCOP(C)(O)=O UFZOPKFMKMAWLU-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002351 wastewater Substances 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
-
- 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3264—Esters with hydroxyalkyl compounds
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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid, which comprises the following steps: (1) Carrying out addition reaction on 3-methyl ethoxy phosphono-propanal and cyanide to obtain (3-cyano-3-hydroxypropyl) methyl phosphinate; (2) Carrying out hydrolysis reaction on the (3-cyano-3-hydroxypropyl) methylphosphinate to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid; (3) 4- (hydroxy methyl phosphonic acid) -2-hydroxy butyric acid is subjected to oxidation reaction to obtain 4- (hydroxy methyl phosphonic acid) -2-carbonyl butyric acid. The preparation method of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid provided by the invention has the advantages of simple purification, easily obtained raw materials, high yield, and total yield of more than 90% in three steps.
Description
Technical Field
The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid.
Background
4- (hydroxy methyl phosphoryl) -2-carbonyl butyric acid, PPO or keto acid for short, is an important intermediate in the synthesis process of glufosinate-ammonium, the compound can obtain glufosinate-ammonium through steps such as ammonification reduction, and the L-glufosinate-ammonium can be obtained through fermentation by a biological enzyme method.
In 1980, the FBC company first filed patent US4399287A for preparing a keto acid intermediate, and 3- (ethoxymethylphosphono) propionate extended the carbon chain by a claisen condensation reaction to obtain a keto acid intermediate 4- (hydroxymethylphosphono) -2-carbonylbutyric acid, with an isolated yield of about 30% of 4- (hydroxymethylphosphono) -2-carbonylbutyric acid.
In 1991, hoechest reported a chemical synthesis method of 4- (hydroxy methylphosphonyl) -2-carbonyl butyric acid, wherein methyl phosphonic acid monoethyl ester and ethyl acrylate are subjected to Michael addition reaction under the action of sodium ethoxide to prepare 3- (ethoxymethylphosphonyl) -ethyl propionate, then the 3- (ethoxymethylphosphonyl) -ethyl propionate and diethyl oxalate are subjected to Crisen ester condensation reaction under the action of sodium ethoxide at-50 ℃, and then hydrochloric acid is used for hydrolysis and decarboxylation to prepare 4- (hydroxy methylphosphonyl) -2-carbonyl butyric acid. However, the method needs to be carried out at the temperature of minus 50 ℃, has low overall yield and generates a large amount of wastewater, and meanwhile, the crystallization time of the product is as long as 48 hours (J.org.chem., 1991,56,1783-1788), and the reaction formula is as follows:
patent US1583424a reports for the first time a method for preparing a ketocyanide compound by taking 2, 5-dioxo-1-oxa-2-phospholane and sodium cyanide as raw materials and obtaining the ketoacid compound through acidolysis, wherein the reaction formula is as follows:
CN103665032a discloses a preparation method of glufosinate, which uses a keto acid synthesis route to prepare an important intermediate 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid of glufosinate. Taking five-membered heterocyclic ring phosphonic anhydride containing oxygen and phosphorus and cyanide as raw materials, and performing a cyanation reaction in an organic solvent to generate a ketonitrile compound; then, the keto acid substance 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid is obtained through hydrolysis process in acid solution; finally, in the presence of an alcohol solvent and a catalyst, the glufosinate-ammonium is obtained through an ammonification and hydrogenation reduction process. However, the cyclic phosphonic anhydride used in the method is difficult to prepare, has high cost and is difficult to purify.
Therefore, how to provide a preparation method of 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid with high yield, simple purification and easily available raw materials is a problem to be solved at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid. The preparation method of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid provided by the invention has the advantages of simple purification, easily obtained raw materials, high yield, and total yield of more than 90% in three steps.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
the invention provides a preparation method of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid, which comprises the following steps:
(1) 3-methyl ethoxy phosphono-propionaldehyde and cyanide are subjected to addition reaction to obtain (3-cyano-3-hydroxypropyl) methyl phosphinate, wherein the reaction formula is shown as follows:
(2) Hydrolysis of (3-cyano-3-hydroxypropyl) methylphosphinate to give 4- (hydroxymethylphosphono) -2-hydroxybutyric acid of the formula:
(3) Oxidizing 4- (hydroxymethyl-phosphono) -2-hydroxybutyric acid to obtain 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid, wherein the reaction formula is shown as follows:
in the invention, the raw material 3-methyl ethoxy phosphono-propionaldehyde is synthesized by referring to patent CN103374030A, diethyl methylphosphonite reacts with acrolein, and then the crude product is obtained after hydrochloric acid hydrolysis, and the purity is more than 90%.
In the present invention, in step (1), the cyanide comprises sodium cyanide and/or potassium cyanide.
Preferably, in step (1), the molar ratio of 3-methyl ethoxyphosphonopropanal to cyanide is 1 (0.8-1.5), and may be, for example, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.; preferably 1 (1.0-1.1), for example, 1:1.0, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, etc.
Preferably, in step (1), the addition reaction is carried out in the presence of an acidic catalyst.
Preferably, the acidic catalyst comprises any one or a combination of at least two of sodium metabisulfite, sodium bisulphite or sodium dihydrogen phosphate, preferably sodium metabisulfite and/or sodium bisulphite.
Preferably, the molar ratio of 3-methyl ethoxyphosphonopropanal to acidic catalyst is 1 (0.5-2.0), which may be, for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, etc.; preferably 1 (0.8-1.2), for example, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, etc.
Preferably, in step (1), the addition reaction is carried out in a solvent.
Preferably, the solvent comprises any one or a combination of at least two of water, methanol or ethanol, preferably water.
In the present invention, in the step (1), the temperature of the addition reaction is 0 to 50 ℃, and for example, it may be 0 ℃,5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, etc.; preferably 5-25deg.C, for example, 5 deg.C, 7 deg.C, 9 deg.C, 11 deg.C, 13 deg.C, 15 deg.C, 17 deg.C, 19 deg.C, 21 deg.C, 23 deg.C, 25 deg.C, etc. can be used.
Preferably, in the step (1), the time of the addition reaction is 1.1-13h, for example, 1.1h, 2h, 3h, 4h, 5h, 6h, 7h, 9h, 10h, 11h, 12h, 13h, etc.; preferably 2.5-7h, for example 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, etc.
In the present invention, in the step (1), the preparation method of the (3-cyano-3-hydroxypropyl) methylphosphinate comprises the following steps: mixing 3-methyl ethoxy phosphono-propanal, acid catalyst and solvent, dropping cyanide solution, thermal insulation reaction to obtain (3-cyano-3-hydroxy propyl) methyl phosphinate.
Preferably, the mass ratio of 3-methyl ethoxyphosphono-propanal to solvent is 1 (2-5), which may be, for example, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5, etc.
Preferably, the cyanide solution is an aqueous cyanide solution.
Preferably, the aqueous cyanide solution has a mass percentage of 20-40%, for example, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, etc.
Preferably, the dropping speed is 0.5-20mL/min, for example, 0.5mL/min, 1mL/min, 2mL/min, 3mL/min, 4mL/min, 5mL/min, 6mL/min, 7mL/min, 8mL/min, 9mL/min, 10mL/min, 11mL/min, 12mL/min, 13mL/min, 14mL/min, 15mL/min, 16mL/min, 17mL/min, 18mL/min, 19mL/min, 20mL/min, etc.
Preferably, the time of the dropping is 0.1-3h, for example, 0.1h, 0.3h, 0.5h, 0.7h, 0.9h, 1.1h, 1.3h, 1.5h, 1.7h, 1.9h, 2.1h, 2.3h, 2.5h, 2.7h, 2.9h, 3h, etc.; preferably 0.5 to 2h, for example, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, 2h, etc.
Preferably, the temperature is controlled during the process of dropping cyanide solution, wherein the temperature is 0-50deg.C, such as 0deg.C, 5deg.C, 10deg.C, 15deg.C, 20deg.C, 25deg.C, 30deg.C, 35deg.C, 40deg.C, 45deg.C, 50deg.C, etc.; preferably 5-25deg.C, for example, 5 deg.C, 7 deg.C, 9 deg.C, 11 deg.C, 13 deg.C, 15 deg.C, 17 deg.C, 19 deg.C, 21 deg.C, 23 deg.C, 25 deg.C, etc. can be used.
Preferably, the temperature of the incubation reaction is 20-30deg.C, and may be, for example, 20deg.C, 21deg.C, 22deg.C, 23deg.C, 24deg.C, 25deg.C, 26deg.C, 27deg.C, 28deg.C, 29 deg.C, 30deg.C, etc.
Preferably, the time of the heat preservation reaction is 1-10h, for example, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h and the like; preferably 2 to 5h, for example, 2h, 2.2h, 2.4h, 2.6h, 2.8h, 3h, 3.2h, 3.4h, 3.6h, 3.8h, 4h, 4.2h, 4.4h, 4.6h, 4.8h, 5h, etc.
In the present invention, in the step (2), the hydrolysis reaction is performed in the presence of an acid.
Preferably, the acid comprises hydrochloric acid.
Preferably, the acid content is 25-35% by mass, for example 25%, 26%, 27%, 28%, 29%, 30%, 31%, 35%, 33%, 34%, 35% and the like.
Preferably, the molar ratio of (3-cyano-3-hydroxypropyl) methylphosphinate to acid is 1 (2-10), which may be, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc.; preferably 1 (3-5), which may be, for example, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5, etc.
In the present invention, in the step (2), the hydrolysis reaction is carried out at a temperature of 60 to 130℃and may be, for example, 60℃70℃80℃90℃100℃110℃120℃130℃or the like; preferably 90-120deg.C, for example, 90deg.C, 95deg.C, 100deg.C, 105 deg.C, 110deg.C, 115 deg.C, 120deg.C, etc.
Preferably, in the step (2), the time of the hydrolysis reaction is 1-24h, for example, 1h, 3h, 5h, 7h, 9h, 11h, 13h, 15h, 17h, 19h, 21h, 24h, etc.; preferably 3 to 6 hours, for example, 3 hours, 4 hours, 5 hours, 6 hours, etc.
In the present invention, in step (2), a post-treatment is further required after the hydrolysis reaction, and the post-treatment includes the following steps: and sequentially desolventizing, alcohol separating and filtering the reaction liquid obtained after the hydrolysis reaction, and concentrating the filtrate obtained by filtering to obtain the 4- (hydroxy methyl phosphono) -2-hydroxybutyric acid.
Preferably, the desolventizing temperature is 40-120 ℃, for example, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃ and the like; the pressure is-0.098-0.1013 MPa, for example, -0.098MPa, -0.05MPa, 0MPa, 0.1MPa, 0.1013MPa, etc.
Preferably, the solvent used for the alcohol analysis comprises methanol.
Preferably, the concentration is performed by desolventizing under reduced pressure at 25-50deg.C, such as 25deg.C, 30deg.C, 35deg.C, 40deg.C, 45deg.C, 50deg.C, etc.; the pressure is-0.098 to-0.05 MPa, and may be, for example, -0.098MPa, -0.088MPa, -0.07MPa, -0.06MPa, -0.05MPa, etc.
In the present invention, in the step (3), the oxidation reaction is performed in the presence of a vanadium-based catalyst.
Preferably, the vanadium-based catalyst comprises any one or a combination of at least two of vanadium pentoxide, vanadium trioxide, vanadium tetraoxide, ammonium metavanadate, sodium metavanadate, potassium metavanadate and bis (acetylacetonate) vanadyl, preferably any one or a combination of at least two of vanadium pentoxide, ammonium metavanadate or bis (acetylacetonate) vanadyl.
Preferably, the mass ratio of the 4- (hydroxymethyl-phosphono) -2-hydroxybutyric acid to the vanadium catalyst is 100 (0.5-20), and for example, the mass ratio can be 100:0.5, 100:1, 100:5, 100:10, 100:15, 100:20 and the like; preferably 100 (1-5), for example, 100:1, 100:2, 100:3, 100:4, 100:5, etc.
In the present invention, in the step (3), the oxidation reaction is performed in an oxygen-containing gas.
Preferably, the oxygen-containing gas comprises air and/or oxygen.
Preferably, in step (3), the oxidation reaction is carried out in a solvent comprising water.
Preferably, the mass ratio of the 4- (hydroxymethyl-phosphono) -2-hydroxybutyric acid to the solvent is 1 (3-5), and may be, for example, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5, etc.
In the present invention, in the step (3), the temperature of the oxidation reaction is 20 to 120 ℃, for example, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, etc. may be used; preferably 60-80deg.C, for example 60 deg.C, 62 deg.C, 64 deg.C, 66 deg.C, 68 deg.C, 70 deg.C, 72 deg.C, 74 deg.C, 76 deg.C, 78 deg.C, 80 deg.C, etc. can be used.
Preferably, the time of the oxidation reaction is 1-24h, and may be, for example, 1h, 3h, 5h, 7h, 9h, 11h, 13h, 15h, 17h, 19h, 21h, 24h, etc.; preferably 3 to 8h, for example, 3h, 4h, 5h, 6h, 7h, 8h, etc.
Preferably, the pressure of the oxidation reaction is 0.05-0.8MPa, for example, 0.05MPa, 0.1MPa, 0.15MPa, 0.2MPa, 0.3MPa, 0.4MPa, 0.5MPa, 0.6MPa, 0.7MPa, 0.8MPa, etc.; preferably 0.1 to 0.5MPa, for example, 0.1MPa, 0.2MPa, 0.3MPa, 0.4MPa, 0.5MPa, etc.
Preferably, in the step (3), after the oxidation reaction, a post-treatment is further required, wherein the post-treatment comprises the following steps of filtering a reaction liquid obtained after the oxidation reaction for one time, and then distilling a filtrate obtained by the one-time filtration to obtain a crude product of 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid; mixing the crude product of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid with an organic solvent A, and carrying out secondary filtration; and finally, mixing the filtrate obtained by the secondary filtration with an organic solvent B, and crystallizing to obtain a 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid product.
Preferably, the temperature of the distillation is 60-100deg.C, for example 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, etc.; the pressure is-0.098 to-0.08 MPa, and may be, for example, -0.098MPa, -0.095MPa, -0.092MPa, -0.09MPa, -0.088MPa, -0.086MPa, -0.084MPa, -0.082MPa, -0.08MPa, etc.
Preferably, the organic solvent a comprises acetone.
Preferably, the organic solvent B includes methyl isobutyl ketone.
As a preferable technical scheme of the invention, the preparation method of the 4- (hydroxy methyl phosphonic acid) -2-carbonyl butyric acid comprises the following steps:
(1) Mixing 3-methyl ethoxy phosphono-propanal, an acid catalyst and a solvent, controlling the system temperature to be between 0 and 50 ℃, dropwise adding cyanide solution at the speed of between 0.5 and 20mL/min, and reacting for 1 to 10 hours at the temperature of between 20 and 30 ℃ to obtain (3-cyano-3-hydroxypropyl) methyl phosphinate;
wherein, the mol ratio of the 3-methyl ethoxy phosphonic group propionaldehyde to the cyanide to the acid catalyst is 1 (0.8-1.5): 0.5-2.0);
(2) Mixing (3-cyano-3-hydroxypropyl) methyl phosphinate with a molar ratio of 1 (2-10) and acid, and reacting at 60-130 ℃ for 1-24h to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid;
(3) Mixing 4- (hydroxy methyl phosphono) -2-hydroxy butyric acid, vanadium catalyst and solvent, introducing oxygen-containing gas, and reacting at 20-120 deg.C and 0.05-0.8MPa for 1-24 hr to obtain 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid;
wherein the mass ratio of the 4- (hydroxy methyl phosphonic group) -2-hydroxy butyric acid to the vanadium catalyst is 100 (0.5-20).
Compared with the prior art, the invention has the following beneficial effects:
(1) The preparation method of the 4- (hydroxy methyl phosphonic acid) -2-carbonyl butyric acid provided by the invention has the advantages of simple purification method and no need of complex post-treatment operation;
(2) The preparation method of 4- (hydroxy methyl phosphonic group) -2-carbonyl butyric acid provided by the invention has the advantages of easily available raw materials, high yield, and the total yield of three steps can reach more than 90%.
Drawings
FIG. 1 is an HPLC profile of a standard sample of 4- (hydroxymethylphosphono) -2-oxobutanoic acid.
FIG. 2 is an HPLC chart of 4- (hydroxymethylphosphono) -2-oxobutanoic acid product of example 1.
FIG. 3 is a secondary mass spectrum of the 4- (hydroxymethylphosphono) -2-oxobutanoic acid product of example 1.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butanoic acid, comprising the steps of:
(1) 120g (purity 90%) of 3-methyl ethoxy phosphono-propanal is placed in 330g of water, 125g of sodium metabisulfite is added, the temperature is controlled to 24 ℃, 112.9g of sodium cyanide aqueous solution (mass content is 30%) is dropwise added at the speed of 1.9mL/min, and after about 1h of adding, the reaction is continued at 25 ℃ for 2h in a heat-preserving way, so as to obtain a feed liquid containing (3-cyano-3-hydroxypropyl) methyl phosphinate;
(2) Adding the (3-cyano-3-hydroxypropyl) methyl phosphinate-containing feed liquid obtained in the step (1) into 280g of hydrochloric acid (the mass percentage content is 30%), heating to 97 ℃ for hydrolysis reaction for 5 hours, removing acid water at minus 0.098MPa and 110 ℃, cooling to 45 ℃, adding methanol for alcohol precipitation, filtering to remove inorganic salts such as ammonium chloride generated by the reaction, and recovering methanol from filtrate at minus 0.05MPa and 50 ℃ to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid;
(3) Adding 300g of water into the 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid obtained in the step (2) in an autoclave, stirring and dissolving, adding ammonium metavanadate accounting for 2.5% of the mass of the 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid, introducing air, and reacting for 8 hours at 75 ℃ and 0.2 MPa; after the reaction is completed, the temperature is reduced to 25 ℃, the vanadium catalyst is removed by filtration, the filtrate is distilled at the temperature of 80 ℃ below zero under the pressure of-0.08 MPa to obtain a crude product, 200g of acetone is added for dissolution, insoluble salt is removed by filtration, 500g of methyl isobutyl ketone is added into the filtrate for crystallization, and 110.2g of white solid product 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid is obtained, the purity is 98.5%, and the yield is 91.6%.
And (3) structural identification:
as shown in fig. 1, the HPLC profile of the standard sample of 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid (PPO), from which it can be seen that the peak time of 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid is 4.875min; as shown in FIG. 2, the peak time of 4- (hydroxymethylphosphono) -2-carbonyl-butyric acid (PPO) product of example 1 was 4.844min; the product of example 1 was confirmed to be 4- (hydroxymethylphosphono) -2-oxobutanoic acid.
As shown in FIG. 3, the secondary mass spectrum of the 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid product of example 1, which is shown in the figure, contains M-1 (M-H) fragment peak 179.0202, M-45 (M-COOH) fragment peak 135.0284, M-73 (M-COCOOH) fragment peak 107.0319, M-101 (M-CH) 2 CH 2 COCOOH) fragment peak 78.9996, M-117 (containing CH only) 3 POH) debris peak 62.9675.
Example 2
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butanoic acid, comprising the steps of:
(1) 120g (purity 92%) of 3-methyl ethoxy phosphono-propanal is placed in 300g of water, 77g of sodium bisulphite is added, the temperature is controlled to 23 ℃, 109.9g of sodium cyanide aqueous solution (mass content is 30%) is added dropwise at the speed of 3.6mL/min, after about 0.5h of adding, the reaction is continued at 26 ℃ for 5h, and the feed liquid containing (3-cyano-3-hydroxypropyl) methyl phosphinate is obtained.
(2) Adding the (3-cyano-3-hydroxypropyl) methyl phosphinate-containing feed liquid obtained in the step (1) into 410g of hydrochloric acid (the mass percentage content is 30%), heating to 114 ℃ for hydrolysis reaction for 6 hours, removing acid water at minus 0.08MPa and 112 ℃, cooling to 44 ℃ and adding methanol for alcohol precipitation, filtering to remove inorganic salts such as ammonium chloride generated by the reaction, and recovering methanol from filtrate at minus 0.06MPa and 45 ℃ to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid;
(3) Adding 300g of water into a high-pressure kettle to stir and dissolve 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid obtained in the step (2), adding 5% vanadium pentoxide by mass of 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid, introducing oxygen to react for 5 hours at 80 ℃ and 0.5MPa, cooling to 25 ℃ after completion, filtering to remove vanadium catalyst, distilling filtrate at-0.09 MPa and 85 ℃ to obtain a crude product, adding 200g of acetone to dissolve, filtering to remove insoluble salt, adding 500g of methyl isobutyl ketone into the filtrate to crystallize, and obtaining a white solid product, namely 111.0g of 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid with the purity of 98.6% and the yield of 90.3%.
Example 3
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butanoic acid, comprising the steps of:
(1) 120g (purity 90%) of 3-methyl ethoxy phosphono-propanal is placed in 300g of water, 100g of sodium metabisulfite is added, the temperature is controlled to 22 ℃, 118.2g of sodium cyanide aqueous solution (mass content is 30%) is dropwise added at the speed of 3.9mL/min, and after the addition of about 0.5h, the reaction is continued at 24 ℃ for 3h, so as to obtain a feed liquid containing (3-cyano-3-hydroxypropyl) methyl phosphinate;
(2) Adding the (3-cyano-3-hydroxypropyl) methyl phosphinate-containing feed liquid obtained in the step (1) into 360g of hydrochloric acid (the mass percentage content is 30%), heating to 114 ℃ for hydrolysis reaction for 3 hours, removing acid water at minus 0.094MPa and 115 ℃, cooling to 45 ℃ and adding methanol for alcohol precipitation, filtering to remove inorganic salts such as ammonium chloride generated by the reaction, and recovering methanol from filtrate at minus 0.08MPa and 40 ℃ to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid;
(3) Adding 300g of water into the 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid obtained in the step (2) in an autoclave, stirring and dissolving, adding vanadium pentoxide accounting for 2.5% of the mass of the 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid, and introducing oxygen to react for 5 hours at 63 ℃ and 0.1 MPa; after the reaction is completed, the temperature is reduced to 25 ℃, the vanadium catalyst is removed by filtration, the filtrate is distilled at the temperature of minus 0.085MPa and 90 ℃ to obtain a crude product, 200g of acetone is added for dissolution, the insoluble salt is removed by filtration, 500g of methyl isobutyl ketone is added into the filtrate for crystallization, and 107.0g of white solid product 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid is obtained, the purity is 98.0%, and the yield is 88.5%.
Example 4
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butyric acid, differing from example 1 only in that in step (1), the purity of 3-methylethylphosphono-propanal is 96%, the other steps being the same as in example 1.
Example 5
This example shows a process for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid, which differs from example 1 only in that sodium metabisulfite is not added in step (1) and in that the other steps are the same as in example 1.
Example 6
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butyric acid, differing from example 1 only in that sodium metabisulfite is replaced by sodium bisulfate in the same molar amount in step (1), the other steps being the same as in example 1.
Example 7
This example provides a process for the preparation of 4- (hydroxymethylphosphono) -2-oxobutanoic acid, differing from example 1 only in that in step (1) the quality of sodium metabisulfite is reduced to 62g, the other steps being the same as in example 1.
Example 8
This example provides a process for preparing 4- (hydroxymethylphosphono) -2-oxobutanoic acid, which differs from example 1 only in that in step (2) the reaction temperature is 80℃and the reaction time is 7 hours, the other steps being the same as in example 1.
Example 9
This example provides a process for preparing 4- (hydroxymethylphosphono) -2-oxobutanoic acid, which differs from example 1 only in that in step (2), the reaction temperature is 130℃and the reaction time is 2 hours, the other steps being the same as in example 1.
Example 10
This example provides a process for the preparation of 4- (hydroxymethylphosphonyl) -2-carbonyl butyric acid, differing from example 1 only in that in step (3), ammonium metavanadate is replaced by an equivalent molar amount of vanadium trioxide, the other steps being the same as in example 1.
Example 11
This example provides a process for preparing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid, which differs from example 1 only in that in step (3), the mass of ammonium metavanadate is 0.5% of the mass of 4- (hydroxymethylphosphonyl) -2-hydroxybutyric acid, and the other steps are the same as in example 1.
Example 12
This example provides a process for preparing 4- (hydroxymethylphosphono) -2-oxobutanoic acid, which differs from example 1 only in that in step (3), the solvent water is replaced by methanol of equivalent mass, and the other steps are the same as in example 1.
Test case
Product yield and purity testing
The testing method comprises the following steps: calculating the total yield of synthesizing 4- (hydroxymethyl phosphono) -2-carbonyl butyric acid by taking 3-methyl ethoxy phosphono-propionaldehyde as a raw material, and detecting by high performance liquid chromatography to obtain the purity of the pure product;
yield (%) = [4- (hydroxymethyl phosphono) -2-carbonyl butyric acid mass x purity ]/[180× (3-methylethoxy phosphono propanal) molar amount ] ×100%;
the test results are shown in table 1:
TABLE 1
| Sample of | Purity (%) | Yield (%) |
| Example 1 | 98.5 | 91.6 |
| Example 2 | 98.6 | 90.3 |
| Example 3 | 98.0 | 88.5 |
| Example 4 | 98.5 | 91.2 |
| Example 5 | 97.8 | 25.7 |
| Example 6 | 98.0 | 77.6 |
| Example 7 | 98.3 | 83.2 |
| Example 8 | 97.9 | 45.6 |
| Example 9 | 98.1 | 78.1 |
| Example 10 | 98.5 | 81.7 |
| Example 11 | 98.2 | 68.5 |
| Example 12 | 98.1 | 75.3 |
As is clear from the data in Table 1, according to the method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid provided by the present invention (examples 1-12), the purity of 4- (hydroxymethylphosphono) -2-oxobutanoic acid was 97.8-98.6%, and the total yield of the reaction was 25.7-91.6%.
By adopting the preparation method of 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid provided by the preferred technical scheme (examples 1-3), the purity of the 4- (hydroxymethyl-phosphono) -2-carbonyl butyric acid is 98.0-98.6%, and the total reaction yield is 88.5-91.6%.
As is evident from a comparison of example 1 and example 4, the purity of the starting 3-methylethoxy-phosphonopropanal does not affect the yield of the reaction and the purity of the product.
As can be seen from a comparison of example 1 and examples 5-6, the acid catalyst significantly affected the yield of the reaction in step (1), and the overall yield of the reaction was only 25.7% when no acid catalyst was added; when sodium metabisulfite is replaced by sodium bisulfate in the same molar amount, the overall yield of the reaction is also significantly reduced.
As is clear from a comparison of example 1 and example 7, the addition amount of the acidic catalyst in step (1) affects the reaction yield, and when the addition amount is too small, the total yield of the reaction decreases.
As is evident from a comparison of example 1 and examples 8 to 9, the reaction temperature and time in step (2) affect the reaction yield.
As is clear from a comparison of example 1 and examples 10 to 11, the kind and the amount of the vanadium-based catalyst added in step (3) affect the reaction yield.
As is clear from a comparison of example 1 and example 12, in step (3), the solvent is selected to affect the reaction yield, and when methanol is used as the solvent, the esterification reaction of 4- (hydroxymethylphosphono) -2-hydroxybutyric acid may occur.
The applicant states that the process of the invention is illustrated by the above examples, but the invention is not limited to, i.e. does not mean that the invention must be carried out in dependence on the above process steps. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of selected raw materials, addition of auxiliary components, selection of specific modes, etc. fall within the scope of the present invention and the scope of disclosure.
Claims (33)
1. A process for the preparation of 4- (hydroxymethylphosphono) -2-carbonyl butanoic acid, comprising the steps of:
(1) Carrying out addition reaction on 3-methyl ethoxy phosphono-propanal and cyanide to obtain (3-cyano-3-hydroxypropyl) methyl phosphinate; the addition reaction is carried out in a solvent, wherein the solvent is any one or a combination of at least two of water, methanol or ethanol;
(2) Carrying out hydrolysis reaction on the (3-cyano-3-hydroxypropyl) methylphosphinate to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid; the hydrolysis reaction is carried out in the presence of an acid, which is hydrochloric acid;
(3) Oxidizing 4- (hydroxy methyl phosphonic acid) -2-hydroxy butyric acid to obtain 4- (hydroxy methyl phosphonic acid) -2-carbonyl butyric acid; the oxidation reaction is carried out in the presence of a vanadium-based catalyst, wherein the vanadium-based catalyst is any one or a combination of at least two of vanadium pentoxide, vanadium trioxide, vanadium tetraoxide, ammonium metavanadate, sodium metavanadate, potassium metavanadate and bis (acetylacetonate) vanadyl; the oxidation reaction is carried out in an oxygen-containing gas, wherein the oxygen-containing gas is air and/or oxygen; the oxidation reaction is carried out in a solvent, wherein the solvent is water;
in the step (1), the cyanide is sodium cyanide and/or potassium cyanide;
in the step (1), the molar ratio of the 3-methyl ethoxy phosphonic group propionaldehyde to the cyanide is 1 (0.8-1.5);
in the step (1), the addition reaction is carried out in the presence of an acidic catalyst, wherein the acidic catalyst is any one or a combination of at least two of sodium metabisulfite, sodium bisulphite, sodium bisulfate or sodium dihydrogen phosphate;
the mol ratio of the 3-methyl ethoxy phosphonic acyl propionaldehyde to the acid catalyst is 1 (0.5-2.0);
in the step (2), the temperature of the hydrolysis reaction is 90-120 ℃, and the time of the hydrolysis reaction is 3-6h;
the mass ratio of the 4- (hydroxy methyl phosphonic group) -2-hydroxy butyric acid to the vanadium catalyst is 100 (1-5).
2. The process for producing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid according to claim 1, wherein in step (1), the molar ratio of 3-methylethoxyphosphinoyl propanal to cyanide is 1 (1.0-1.1).
3. The method for producing 4- (hydroxymethylphosphono) -2-carbonyl butyric acid according to claim 1, wherein said acidic catalyst is sodium metabisulfite and/or sodium bisulphite.
4. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein the molar ratio of 3-methylethylphosphono-propanal to the acidic catalyst is 1 (0.8-1.2).
5. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein said solvent of step (1) is water.
6. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (1), the temperature of the addition reaction is 0-50 ℃.
7. The process for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 6, wherein in step (1), the temperature of the addition reaction is 5-25 ℃.
8. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (1), the time of the addition reaction is 1.1 to 13 hours.
9. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 8, wherein in step (1), the time of the addition reaction is 2.5-7 hours.
10. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (1), the method for producing (3-cyano-3-hydroxypropyl) methylphosphinate comprises the steps of: mixing 3-methyl ethoxy phosphono-propanal, acid catalyst and solvent, dropping cyanide solution, thermal insulation reaction to obtain (3-cyano-3-hydroxy propyl) methyl phosphinate.
11. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 10, wherein the mass ratio of 3-methylethylphosphono-propanal to the solvent is 1 (2-5).
12. The method for producing 4- (hydroxymethylphosphonyl) -2-carbonyl butyric acid according to claim 10, wherein said cyanide solution is an aqueous cyanide solution.
13. The method for producing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid according to claim 10, wherein the aqueous cyanide solution has a mass percentage of 20-40%.
14. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 10, wherein the dropping speed is 0.5-20mL/min.
15. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 10, wherein the time for said dropping is 0.1-3h.
16. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 15, wherein the time of said dropping is 0.5-2h.
17. The method for producing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid according to claim 10, wherein a temperature control is required during the dropwise addition of the cyanide solution, said temperature control being at a temperature of 0-50 ℃.
18. The method for producing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid according to claim 17, wherein a temperature control is required during the dropwise addition of the cyanide solution, said temperature control being at a temperature of 5-25 ℃.
19. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 10, wherein the temperature of the incubation reaction is 20-30 ℃.
20. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 10, wherein the incubation time is 1-10 hours.
21. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 20, wherein said incubation is carried out for a period of time ranging from 2 to 5 hours.
22. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein the mass percentage of the acid is 25-35%.
23. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein the molar ratio of (3-cyano-3-hydroxypropyl) methylphosphinate to acid is 1 (2-10).
24. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 23, wherein the molar ratio of (3-cyano-3-hydroxypropyl) methylphosphinate to acid is 1 (3-5).
25. The method for producing 4- (hydroxymethylphosphonyl) -2-oxobutanoic acid according to claim 1, wherein the vanadium-based catalyst is any one of or a combination of at least two of vanadium pentoxide, ammonium metavanadate or bis (acetylacetonate) vanadyl.
26. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein the mass ratio of 4- (hydroxymethylphosphono) -2-hydroxybutyric acid to the solvent is 1 (3-5).
27. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (3), the temperature of the oxidation reaction is 20-120 ℃.
28. The process for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 27, wherein in step (3), the temperature of the oxidation reaction is 60-80 ℃.
29. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (3), the time of the oxidation reaction is 1 to 24 hours.
30. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 29, wherein in step (3), the time of the oxidation reaction is 3 to 8 hours.
31. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein in step (3), the pressure of the oxidation reaction is 0.05-0.8MPa.
32. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 31, wherein in step (3), the pressure of the oxidation reaction is 0.1-0.5MPa.
33. The method for producing 4- (hydroxymethylphosphono) -2-oxobutanoic acid according to claim 1, wherein said method comprises the steps of:
(1) Mixing 3-methyl ethoxy phosphono-propanal, an acid catalyst and a solvent, controlling the system temperature to be between 0 and 50 ℃, dropwise adding cyanide solution at the speed of between 0.5 and 20mL/min, and reacting for 1 to 10 hours at the temperature of between 20 and 30 ℃ to obtain (3-cyano-3-hydroxypropyl) methyl phosphinate;
wherein, the mol ratio of the 3-methyl ethoxy phosphonic group propionaldehyde to the cyanide to the acid catalyst is 1 (0.8-1.5): 0.5-2.0);
(2) Mixing (3-cyano-3-hydroxypropyl) methyl phosphinate with a molar ratio of 1 (2-10) and acid, and reacting at 60-130 ℃ for 1-24h to obtain 4- (hydroxymethyl phosphono) -2-hydroxybutyric acid;
(3) Mixing 4- (hydroxy methyl phosphono) -2-hydroxy butyric acid, vanadium catalyst and solvent, introducing oxygen-containing gas, and reacting at 20-120 deg.C and 0.05-0.8MPa for 1-24 hr to obtain 4- (hydroxy methyl phosphono) -2-carbonyl butyric acid;
wherein the mass ratio of the 4- (hydroxy methyl phosphonic group) -2-hydroxy butyric acid to the vanadium catalyst is 100 (0.5-20).
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