CN108558728A - A kind of N- hydroxysuccinimides preparation method - Google Patents
A kind of N- hydroxysuccinimides preparation method Download PDFInfo
- Publication number
- CN108558728A CN108558728A CN201810237272.1A CN201810237272A CN108558728A CN 108558728 A CN108558728 A CN 108558728A CN 201810237272 A CN201810237272 A CN 201810237272A CN 108558728 A CN108558728 A CN 108558728A
- Authority
- CN
- China
- Prior art keywords
- acid
- reaction
- preparation
- succinic acid
- azanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 title claims description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 53
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000001384 succinic acid Substances 0.000 claims description 16
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 12
- 239000004327 boric acid Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000012970 cakes Nutrition 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 abstract description 19
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- JDXQWYKOKYUQDN-UHFFFAOYSA-N 3-hydroxypyrrolidine-2,5-dione Chemical class OC1CC(=O)NC1=O JDXQWYKOKYUQDN-UHFFFAOYSA-N 0.000 abstract 2
- 230000007423 decrease Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000010992 reflux Methods 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 235000011121 sodium hydroxide Nutrition 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000001816 cooling Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000007788 liquid Substances 0.000 description 16
- FHHJDRFHHWUPDG-UHFFFAOYSA-N peroxysulfuric acid Chemical compound OOS(O)(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-N 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 208000005156 Dehydration Diseases 0.000 description 11
- 230000018044 dehydration Effects 0.000 description 11
- 238000006297 dehydration reaction Methods 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 229940014800 succinic anhydride Drugs 0.000 description 7
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000002443 hydroxylamines Chemical class 0.000 description 6
- ZBTUYCUNQBRXOR-UHFFFAOYSA-L sodium succinate hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-]C(=O)CCC([O-])=O ZBTUYCUNQBRXOR-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000013019 agitation Methods 0.000 description 4
- -1 amino, carboxyl Chemical group 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 230000003068 static effect Effects 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- QUTGXAIWZAMYEM-UHFFFAOYSA-N 2-cyclopentyloxyethanamine Chemical compound NCCOC1CCCC1 QUTGXAIWZAMYEM-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 125000002237 D-aspartyl group Chemical group [H]OC(=O)[C@]([H])(N([H])[H])C([H])([H])C(*)=O 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Substances CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000002473 artificial blood Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 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 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of N hydroxysuccinimides preparation method, is raw material with succinic acid, reacts preparation N hydroxysuccinimides in the presence of acidulous material with azanol.Reaction yield is more than 85%, further decreases production cost, eliminates security risk present in production process.
Description
Technical field
The present invention relates to a kind of N- hydroxysuccinimides preparation methods, specially succinic acid, azanol and boric acid are used to make
Catalyst synthesizes N- hydroxysuccinimide synthetic methods, belongs to organic fine and synthesizes field.
Background technology
N- hydroxysuccinimides (NHS), English name:N-Hydroxy succinimide, also referred to as:N- hydroxysuccinimidyls
Acid imide (HOSU), CAS:6066-82-6, EINECS:228-001-3, molecular formula:C4H5NO3, molecular weight:115.0874.
N- hydroxysuccinimides are a kind of particularly important fine chemicals and industrial chemicals, due to containing work in structure
Bold and vigorous nitrogen hydroxyl, can with the amino, carboxyl or glycosyl covalent bond of antigen, antibody, enzyme and its nucleic acid, in conjunction with rear and do not influence
Their activity, therefore the diagnosis for the precursor and affinity chromatography, tumour that synthetic peptide, antibiotic, amino acid, protein can be commonly used for etc.
Imaging and treatment.
N- hydroxysuccinimides prepare active ester, can inhibit the generation of its racemic light action when peptide is coupled,
There is very extensive purposes in terms of medical production.Such as it is used for biomedical material (such as artificial blood vessel);Exist in radiopharmaceutical
99Tcm label in application because its shorter half-life period, good physical property, it is cheap and easy to get and become current nuclear medicine
The most frequently used in inspection, foreground one of radionuclide the most wide;Amikacin is synthesized, before the column for synthesizing reverse-phase chromatography
Derivative reagent, the numerous areas such as synthesis glue crosslinking agent.
Many document report N- hydroxysuccinimide synthetic methods are all made of succinic anhydride and azanol obtains, such as Henan
Work, 1995. (5) 18;Applied chemistry, 2003.20 (6) 611;Jiangxi chemical industry 2002, (1) 37;Chemical reagent 2006,28 (2) 121
With chemical industry system of the Northwest University Master's thesis in 2009 such as Zhang Chunge.These papers are prepared by succinic anhydride and azanol reaction
, main contents are process optimization.
Patent CN101372473B discloses a kind of preparation method of N- hydroxy diimides.One kind is used in preparation method
Novel catalyst-acetic anhydride/trifluoracetic acid/organic base so that substitution dicarboxylic anhydride and the reaction condition of azanol complex salt are more
Mildly, reaction yield and product purity improve, and reduce production cost.
N- hydroxysuccinimides synthetic method generally uses succinic anhydride and oxyammonia reaction to prepare in the prior art.
Concrete operation step is as follows:100g (1.0mol) succinic anhydrides and 70g (1.0mol) hydroxylamine hydrochloride are heated together,
Make reaction system that negative pressure be kept to extract the volatile matter of generation, is heated rapidly to 125 DEG C or more, 160 DEG C are slowly risen to after 1h.Stop
Liquid reactant is poured into 400ml ether simultaneously high degree of agitation by heating when temperature is down to 125 DEG C.Second is gone in product solidified hypsokinesis
Ether layer, for heat to boiling, heat filter, filtrate is rapidly cooled to 0 DEG C to solidfied material altogether with 400ml butanol.It is filtered after 1h, fourth is used in crystallization successively
Alcohol, ether washing, gained crude product re-crystallizing in ethyl acetate obtain 50g finished products, yield 44%.The reaction the disadvantage is that yield is low, at
This height.In addition, avoiding using low boiling point organic solvent in process of production as possible, to eliminate safe hidden trouble.And this technique is a large amount of
Using ether (boiling point is 34.5 DEG C, standard pressure), there is high safety hidden danger in process of production.In addition, making in the prior art
It is raw material with succinic anhydride, chemical hazard is big, and price is high, seriously constrains N- hydroxysuccinimides into production cost.
Such as patent CN103145601A discloses a kind of preparation method of N- hydroxysuccinimides, and hydroxylamine hydrochloride is hanged
Float in ether organic solvent, control temperature, instills the methanol of inorganic base of the concentration in 5~30% ranges under nitrogen protection
Solution, then filters off the NaCl solid salts of generation under nitrogen protection, and obtained filtrate is added succinic anhydride and answers at room temperature
Acid catalyst is closed, temperature reaction is carried out and first steams methanol during temperature reaction, then rise to 105~130 DEG C, when reaction
Between control within the scope of 1~20hr, decompression boil off ether organic solvent, obtain HOSU crude products;It will add in obtained crude product HOSU
Enter ethyl acetate, temperature rising reflux to HOSU crude products dissolves, and is then filtered to remove a small amount of solid insoluble while hot, cooling, HOSU knots
Partial crystallization goes out, and required HOSU products are obtained by filtration.
Yield is improved, production cost is further decreased, eliminating security risk present in production process becomes N- hydroxyl fourths
The important goal of imidodicarbonic diamide production.
Invention content
The present invention is directed to introduce a kind of raw material to be easy to get, cheap succinic acid substitutes the N- maloyls of succinic anhydride
Imines synthetic method, high income.
Goal of the invention to realize the present invention, the present invention provide the following technical solutions:
A kind of N- hydroxysuccinimides preparation method, with succinic acid be raw material, with azanol in the presence of acidulous material
Reaction prepares N- hydroxysuccinimides.
The reaction mechanism mechanism of reaction is as follows:
Azanol used in this reaction process should be free azanol, can add to obtain free hydroxylamine in reaction process
Enter alkaline matter acquisition, sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate, sodium hydroxide and hydrogen can be selected in alkaline matter used
Potassium oxide.Consider that it is that optimal selection, bicarbonate and carbonate were using to select sodium hydroxide from safe to use and economics
Great amount of carbon dioxide is released in journey easily causes security risk.
It is preferred that free hydroxylamine can be obtained by hydroxylamine hydrochloride or hydroxyl sulfate and sodium hydroxide reaction.
The molal weight ratio of succinic acid and alkali (sodium hydroxide) is 1 in reaction process:1~1.2, optimal proportion 1:1.05
~1.1.
The molal weight of succinic acid and azanol ratio is 1 in reaction process:1~1.5, optimal proportion 1:1.2~1.3.
Succinic acid and toluene dosage (mass/volume) are than being 1:1.5~3, generally select 1:2~2.5.
The activity that succinic acid reacts in this method is poorer than succinic anhydride, and the activation energy for reacting required is high, in order to make reaction
Smoothly through row, need to use catalyst, catalyst that should select acidic materials during the reaction, and be acidulous material, it cannot
Highly acid substance is selected, because highly acid substance generates hydroxylamine salt with azanol reaction first in the reaction system.In reaction process
Middle hydroxylamine salt is difficult to be dissociated into free azanol or free hydroxy lamine concentration is too low and cannot or be unfavorable for reacting.And weak acid and hydroxyl
The hydroxylamine salt that amine is formed is easy to be dissociated into active free hydroxylamine substance at a certain temperature.
Catalyst is acidulous material in this reaction system, and available acidulous material has phosphorous acid, hypophosphorous acid, boron
Acid, niter cake, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium acid sulfate, acetic acid, propionic acid, butyric acid, formic acid, etc..
It can be used, can also be used in mixed way with single substance when stating weak acid substance in use.Usage amount control is being reacted
Object amount 0.5%--5%, optimum amount are controlled in 2%-2.5%.Use out of range is ineffective.
When using catalyst, weak inorganic acid is more better than organic acid.
Weak acid catalyst effect is carbonyl reaction activity in enhancing succinic acid structure during the reaction, and is accelerated in reaction
Dewatering speed, this effect are conducive to nitrogen-atoms in free hydroxylamine and react.
It has a certain amount of water in the reaction process that the present invention is introduced to generate, since the presence of water is to reacting unfavorable, institute
It is removed with the water that must be at any time generated reaction in reaction system, life is removed using solvent azeotropy process in reaction process of the present invention
Cheng Shui such as selects toluene solvant.It can also select hexahydrotoluene, benzene, hexamethylene, etc..Due to being more toxic for benzene, should use up
Amount avoids using.
This reaction is could to be reacted under the conditions of certain temperature, therefore the boiling point of reaction dehydrated solvent is selected to must be over 70
℃.No more than 180 DEG C, more than 180 DEG C product yields significantly reduce reaction temperature.Optimal reaction temperature should be at 100 DEG C to 150
℃。
There are two types of feed way in reaction process:
The first feed way be according to certain mass ratio by succinic acid, hydroxylamine salt (hydroxyl sulfate or hydroxylamine hydrochloride),
Catalyst such as boric acid, sodium hydroxide, solvent toluene mix, with 130 DEG C of progress dehydrations.Reaction yield 70%, should
Yield is slightly lower, and main cause is sodium hydroxide and hydroxylamine salt preferential reaction in the feed way, and it is several that hydroxylamine salt is generated in the short time
It is converted to free azanol, azanol is unstable at high temperature causes yield low.
Second of feed way is that succinic acid and sodium hydroxide are now carried out reaction to generate succinic acid sodium salt, later succinic acid
Sodium salt, hydroxylamine salt (hydroxyl sulfate or hydroxylamine hydrochloride), catalyst such as boric acid, solvent toluene mix, and are taken off with 130 DEG C
Water reacts.Reaction yield 85%.Second of feed way is higher than the product yield that the first feed way is obtained.Main cause
It is gradual formation for azanol free during the reaction, rather than is quickly formed in the short time.
Occur without generating water in reaction process, you can illustrate that reaction terminates.Since product does not dissolve in toluene, it is easy into
Row is separated by solid-liquid separation.After isolating toluene, remaining solid is dissolved with ethyl alcohol, removes the salt that reaction process generates.Last crude product
Use re-crystallizing in ethyl acetate.
Specific implementation mode
Following embodiments can be used to further illustrate the present invention, but be not intended to limit the present invention.
Embodiment 1:
160 grams of succinic acid and 59.5 grams of sodium hydroxide reactions are first generated into succinic acid sodium salt.
Mechanical agitation, spherical condensation tube and thermometer with water knockout drum are installed in four round flask, are added
400mL toluene.(140 DEG C of temperature) is heated to reflux dehydration in oil bath, until not having water abjection.Cooling reaction system is to room
Temperature continues to add succinic acid sodium salt, hydroxyl sulfate 144g, boric acid 4.5g, continues to be heated to reflux dehydration, is not dehydrated substantially to reaction.
Cooling reaction system is transferred out of toluene, adds absolute ethyl alcohol 400ml reflux extraction products 20-30 minutes, and cooling reaction system is simultaneously taken out
Sodium sulfate byproduct is filtered out, filter cake infiltrates washing three times with absolute ethyl alcohol.
The above-mentioned mother liquor that obtains is subjected to normal pressure concentration, distillation speed becomes smaller or when very little changes vacuum distillation, removes second as possible
Alcohol.Then plus 4 times of (residual quantity) amount ethyl acetate (500ml), refluxing extraction 30min.It is static to be cooled to 55 DEG C, it is transferred out of second
Ester, then 200ml ethyl esters is added to repeat to extract once, it is 180ml or so that combining extraction liquid, which is distilled to liquid, stops distillation and is stirring
It is cooling under the conditions of mixing, white solid object is obtained, filters, drying (50 DEG C), weigh, solid weight is 132g or so, yield 85%,
Liquid chromatographic detection content 99.36%, 95-97 DEG C of fusing point.
Embodiment 2:
Mechanical agitation, spherical condensation tube and thermometer with water knockout drum are installed in four round flask, are added
400mL toluene.(140 DEG C of temperature) is heated to reflux dehydration in oil bath, until not having water abjection.Cooling reaction system is to room
Temperature continues to add 160 grams of succinic acid, hydroxyl sulfate 144g, boric acid 4.5g, 59.5 grams of sodium hydroxide, continues to be heated to reflux dehydration, arrive
Reaction is not dehydrated substantially.Cooling reaction system is transferred out of toluene, adds absolute ethyl alcohol 400ml reflux extraction products 20-30 minutes,
Cooling reaction system simultaneously filters removing sodium sulfate byproduct, and filter cake infiltrates washing three times with absolute ethyl alcohol.
The above-mentioned mother liquor that obtains is subjected to normal pressure concentration, distillation speed becomes smaller or when very little changes vacuum distillation, removes second as possible
Alcohol.Then plus 4 times of (residual quantity) amount ethyl acetate (500ml), refluxing extraction 30min.It is static to be cooled to 55 DEG C, it is transferred out of second
Ester, then 200ml ethyl esters is added to repeat to extract once, it is 180ml or so that combining extraction liquid, which is distilled to liquid, stops distillation and is stirring
It is cooling under the conditions of mixing, white solid object is obtained, filters, drying (50 DEG C), weigh, solid weight is 110g or so, yield 70%,
Liquid chromatographic detection content 99%, 94.5-97 DEG C of fusing point.
Embodiment 3:
Succinic acid 1180g, sodium hydroxide 440g, hydroxyl sulfate 1066g, boric acid 33g, succinic acid feed at twice, generate
Product NHS830g, yield 72%, liquid chromatographic detection content 99.48%, 95-97 DEG C of fusing point.
Concrete operations:Then succinic acid 649g, sodium hydroxide 440g, toluene 2000mL reflux dewatering 1 hour adds succinic acid
531g, hydroxyl sulfate 1066g, boric acid 33g, then toluene 1000ml is added to be dehydrated, dewatering time 6.5 hours.Toluene is poured out, so
It afterwards with 2000ml absolute ethyl alcohols dissolved solid (being heated to reflux 30min), condenses and filters, filter cake is washed three times with absolute ethyl alcohol.
By ethyl alcohol evaporated under reduced pressure, add ethyl acetate 2000ml heating extraction products, flow back 30min, static to be cooled to 60 DEG C, separates acetic acid
Ethyl ester continues to cool to room temperature, and mother liquor is returned and continues extract product, and solid is retained in bottle, and extraction three times afterwards carries out mother liquor
It is concentrated into stoste a quarter, is then cooled down, is filtered after solid is precipitated, is dried, weighs.
Embodiment 4:
880g sodium hydroxides, 2360g succinic acid, 2130g hydroxyl sulfate, 66g boric acid, 50g hypophosphorous acid obtain product
2049g, yield 85.5%, liquid chromatographic detection content 99%, 95-97 DEG C of fusing point.
Concrete operations:880g sodium hydroxides, 700g succinic acid, toluene 4800ml carry out heating reaction, temperature rise to 95
DEG C stopping heating, reaction after five minutes starts violent, when reaction reflux becomes smaller or do not flow back almost, then adds 700g succinic acid,
Reaction immediately begins to and releases big calorimetric, and reflux is violent, reheats dehydration, cooling, under stirring conditions plus 960g succinic acid,
2130g hydroxyl sulfate, 66g boric acid, 50g hypophosphorous acid are heated to reflux toluene band water, stop heating and be cooled to room temperature, be transferred out of
Toluene.Absolute ethyl alcohol 4500ml, reflux half an hour is added to be cooled to 40 DEG C, suction filtration isolates solid, and solid invades profit with absolute ethyl alcohol
Washing three times, merge mother liquor and carry out distillation separate ethyl alcohol (being depressurized after first normal pressure).
Embodiment 5:
880g sodium hydroxides, 2360g succinic acid, 2130g hydroxyl sulfate, 66g boric acid obtain product 2050g, yield
85.5%, liquid chromatographic detection content 99.4%, 95-97 DEG C of fusing point.
Concrete operations:880g sodium hydroxides, 700g succinic acid, toluene 4800ml carry out heating reaction, temperature rise to 95
DEG C stopping heating, reaction after five minutes starts violent, when reaction reflux becomes smaller or do not flow back almost, then adds 700g succinic acid,
Reaction immediately begins to and releases big calorimetric, and reflux is violent, reheats dehydration, cooling, under stirring conditions plus 960g succinic acid,
2130g hydroxyl sulfate, 66g boric acid are heated to reflux toluene band water, stop heating and be cooled to room temperature, be transferred out of toluene.Add anhydrous
Ethyl alcohol 4500ml, reflux half an hour are cooled to 40 DEG C, and suction filtration isolates solid, and solid is invaded rinse with absolute ethyl alcohol and washed three times, closes
And mother liquor and carry out distillation separate ethyl alcohol (being depressurized after first normal pressure).
Embodiment 6:
880g sodium hydroxides, 2360g succinic acid, 2130g hydroxyl sulfate, 66g glacial acetic acid obtain product 1606g, yield
67%, liquid chromatographic detection content 95.2%, 88-95 DEG C of fusing point.
Concrete operations:880g sodium hydroxides, 700g succinic acid, toluene 4800ml carry out heating reaction, temperature rise to 95
DEG C stopping heating, reaction after five minutes starts violent, when reaction reflux becomes smaller or do not flow back almost, then adds 700g succinic acid,
Reaction immediately begins to and releases big calorimetric, and reflux is violent, reheats dehydration, cooling, under stirring conditions plus 960g succinic acid,
2130g hydroxyl sulfate, 66g glacial acetic acid are heated to reflux toluene band water, stop heating and be cooled to room temperature, be transferred out of toluene.Add nothing
Water-ethanol 4500ml, reflux half an hour are cooled to 40 DEG C, and suction filtration isolates solid, and solid is invaded rinse with absolute ethyl alcohol and washed three times,
Merge mother liquor and carry out distillation and separates ethyl alcohol (being depressurized after first normal pressure).
Embodiment 7:
800g sodium hydroxides, 2360g succinic acid, 2130g hydroxyl sulfate obtain product 1677g, yield 70%, liquid phase color
Compose detection level 97.1%, 92-97 DEG C of fusing point.
Concrete operations:800g sodium hydroxides, 700g succinic acid, toluene 4800ml carry out heating reaction, temperature rise to 95
DEG C stopping heating, reaction after five minutes starts violent, when reaction reflux becomes smaller or do not flow back almost, then adds 700g succinic acid,
Reaction immediately begins to and releases big calorimetric, and reflux is violent, reheats dehydration, cooling, under stirring conditions plus 960g succinic acid,
2130g hydroxyl sulfate is heated to reflux toluene band water, stops heating and be cooled to room temperature, be transferred out of toluene.Add absolute ethyl alcohol
4500ml, reflux half an hour are cooled to 40 DEG C, and suction filtration isolates solid, and solid is invaded rinse with absolute ethyl alcohol and washed three times, merges female
Liquid and carry out distillation separate ethyl alcohol (being depressurized after first normal pressure).
Embodiment 8:
160 grams of succinic acid and 59.5 grams of sodium hydroxide reactions are first generated into succinic acid sodium salt.
Mechanical agitation, spherical condensation tube and thermometer with water knockout drum are installed in four round flask, are added
400mL toluene.(140 DEG C of temperature) is heated to reflux dehydration in oil bath, until not having water abjection.Cooling reaction system is to room
Temperature continues to add succinic acid sodium salt, hydroxyl sulfate 144g, niter cake 4.5g, continues to be heated to reflux dehydration, do not taken off substantially to reaction
Water.Cooling reaction system is transferred out of toluene, adds absolute ethyl alcohol 400ml reflux extraction products 20-30 minutes, cooling reaction system
And removing sodium sulfate byproduct is filtered, filter cake infiltrates washing three times with absolute ethyl alcohol.
The above-mentioned mother liquor that obtains is subjected to normal pressure concentration, distillation speed becomes smaller or when very little changes vacuum distillation, removes second as possible
Alcohol.Then plus 4 times of (residual quantity) amount ethyl acetate (500ml), refluxing extraction 30min.It is static to be cooled to 55 DEG C, it is transferred out of second
Ester, then 200ml ethyl esters is added to repeat to extract once, it is 180ml or so that combining extraction liquid, which is distilled to liquid, stops distillation and is stirring
It is cooling under the conditions of mixing, white solid object is obtained, filters, drying (50 DEG C), weigh, solid weight is 87g or so, yield 56%,
Liquid chromatographic detection content 97.2%, 90-97 DEG C of fusing point.
Claims (10)
1. a kind of N- hydroxysuccinimides preparation method, which is characterized in that with succinic acid be raw material, with azanol in faintly acid object
Reaction prepares N- hydroxysuccinimides in the presence of matter.
2. preparation method according to claim 1, which is characterized in that the azanol is the azanol to dissociate.
3. preparation method according to claim 2, which is characterized in that the free hydroxylamine can be added alkaline matter and obtain
, sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide can be selected in alkaline matter used.
4. preparation method according to claim 3, which is characterized in that the molal weight of succinic acid and alkaline matter ratio is 1:
1~1.2.
5. according to claim 1-4 any one of them preparation methods, which is characterized in that the molal weight of succinic acid and azanol ratio
It is 1:1~1.5.
6. according to claim 1-5 any one of them preparation methods, which is characterized in that the acidulous material is selected from phosphorous
In acid, hypophosphorous acid, boric acid, niter cake, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium acid sulfate, acetic acid, propionic acid, butyric acid, formic acid
It is one or more.
7. according to claim 1-5 any one of them preparation methods, which is characterized in that the acidulous material is inorganic acid.
8. preparation method according to claim 6, which is characterized in that the catalyst amount control is in reaction volume (matter
Amount) 0.5%-5%.
9. according to claim 1-5 any one of them preparation methods, which is characterized in that use solvent azeotropic side in reaction process
Method, which removes, generates water.
10. according to claim 1-5 any one of them preparation methods, which is characterized in that reaction temperature is no more than 180 DEG C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810237272.1A CN108558728B (en) | 2018-03-21 | 2018-03-21 | Preparation method of N-hydroxysuccinimide |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810237272.1A CN108558728B (en) | 2018-03-21 | 2018-03-21 | Preparation method of N-hydroxysuccinimide |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108558728A true CN108558728A (en) | 2018-09-21 |
CN108558728B CN108558728B (en) | 2021-10-15 |
Family
ID=63533013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810237272.1A Active CN108558728B (en) | 2018-03-21 | 2018-03-21 | Preparation method of N-hydroxysuccinimide |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108558728B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110818607A (en) * | 2019-11-20 | 2020-02-21 | 常州吉恩药业有限公司 | Method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by one-pot two-phase method |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1953963A (en) * | 2004-05-17 | 2007-04-25 | 大赛璐化学工业株式会社 | Process for producing cyclic N-hydroxyimide compound |
CN101372473A (en) * | 2008-10-16 | 2009-02-25 | 复旦大学 | Preparation of N-hydroxy diimide |
CN103145601A (en) * | 2013-03-22 | 2013-06-12 | 上海其新生物科技有限公司 | Preparation method of N-hydroxysuccinimide |
-
2018
- 2018-03-21 CN CN201810237272.1A patent/CN108558728B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1953963A (en) * | 2004-05-17 | 2007-04-25 | 大赛璐化学工业株式会社 | Process for producing cyclic N-hydroxyimide compound |
CN101372473A (en) * | 2008-10-16 | 2009-02-25 | 复旦大学 | Preparation of N-hydroxy diimide |
CN103145601A (en) * | 2013-03-22 | 2013-06-12 | 上海其新生物科技有限公司 | Preparation method of N-hydroxysuccinimide |
Non-Patent Citations (2)
Title |
---|
MANUEL PETROSELLI ET AL.: "Lipophilic N-Hydroxyphthalimide Catalysts for the Aerobic Oxidation of Cumene: Towards Solvent-Free Conditions and Back", 《CHEM.EUR.J.》 * |
吴雁斌 等: "N-羟基丁二酰亚胺的合成新工艺研究", 《化学试剂》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110818607A (en) * | 2019-11-20 | 2020-02-21 | 常州吉恩药业有限公司 | Method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by one-pot two-phase method |
Also Published As
Publication number | Publication date |
---|---|
CN108558728B (en) | 2021-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105646606B (en) | Sugar-based sulfonates and its synthetic method | |
JP5395908B2 (en) | Process for producing 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid ester | |
CN101735123A (en) | Method for synthesizing valnemulin hydrochloride | |
CN106565858A (en) | Purification method for sugammadex sodium | |
CN108558728A (en) | A kind of N- hydroxysuccinimides preparation method | |
CN102351933A (en) | Method for preparing hydroxycobalamin salt | |
CN107513065B (en) | Preparation method of entecavir intermediate IV | |
CN101643418A (en) | Preparation method of gallic acid alcohol ester | |
CN109694359B (en) | Synthetic method of nitrofuran metabolite-furazolidone AOZ-D4 | |
CN105732700B (en) | A kind of method for preparing β sodium glycero-phosphates | |
CN105753732B (en) | Crystal form of AHU377 and preparation method thereof and purposes | |
CN110804022B (en) | Preparation method of dexrazoxane | |
CN102010345A (en) | Method for preparing D-phenylalanine through dynamic kinetic resolution | |
CN109060473A (en) | A kind of preparation method of ambroxol hydrochloride impurity reference substance | |
CN107188816A (en) | A kind of synthetic method of improved fatty monoethanol amide | |
CN115703691B (en) | 13 Synthesis method of C-p-methoxybenzoic acid | |
CN114380750B (en) | Synthetic method of deuterated albendazole | |
CN115160170B (en) | Caffeic acid micromolecule active probe and preparation method and application thereof | |
CN115215780B (en) | Method for preparing heterobifunctional crosslinking agent SMCC by using N, N-disuccinimidyl carbonate | |
CN108299163B (en) | Method for hydrolyzing aromatic ester under mild condition | |
CN102030688B (en) | Method for preparing monosodium sulfosuccinate | |
KR101921484B1 (en) | Norbornene-based compound and method of preparing the norbornene-based compound | |
KR810001104B1 (en) | Process for preparation of n-methyl moranoline | |
JP2022074008A (en) | Treprostinil monohydrate crystals and methods for preparation thereof | |
ES2669564T3 (en) | Method for the preparation of (2R, 3S) -2- (hydroxymethyl) -5-methoxytetrahydrofuran-3-ol free of pyranose compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |