CN114591187A - Preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane - Google Patents
Preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane Download PDFInfo
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- CN114591187A CN114591187A CN202210106789.3A CN202210106789A CN114591187A CN 114591187 A CN114591187 A CN 114591187A CN 202210106789 A CN202210106789 A CN 202210106789A CN 114591187 A CN114591187 A CN 114591187A
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- compound
- bis
- propane
- hydroxymethyl
- methylamino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 229940125782 compound 2 Drugs 0.000 claims abstract description 23
- 238000000746 purification Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 229940125904 compound 1 Drugs 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 5
- 230000005494 condensation Effects 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 8
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000006177 biological buffer Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 description 31
- 239000000047 product Substances 0.000 description 25
- 239000012043 crude product Substances 0.000 description 19
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 229960000281 trometamol Drugs 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 239000007810 chemical reaction solvent Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 5
- 229940035437 1,3-propanediol Drugs 0.000 description 5
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 5
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 3
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- 238000009007 Diagnostic Kit Methods 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 description 1
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- BRRRIZHWQMAVLQ-UHFFFAOYSA-N [2-amino-3-hydroxy-2-(hydroxymethyl)propyl] dihydrogen phosphate Chemical compound OCC(N)(CO)COP(O)(O)=O BRRRIZHWQMAVLQ-UHFFFAOYSA-N 0.000 description 1
- 238000002479 acid--base titration Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane, which comprises the steps of carrying out a self reaction on a compound 1, or reacting the compound 1 with a condensation reagent to obtain a compound 2; reacting the compound 2 with a compound 2A to obtain the 1,3-bis (tri (hydroxymethyl) methylamino) propane; the method has the advantages of improving the yield of the product, being simple, reducing the cost of the product and being suitable for industrial production by optimizing the initial raw materials and optimizing the preparation and purification steps, and the prepared 1,3-bis (tri (hydroxymethyl) methylamino) propane has high purity, low water content and dryness, meets the requirements of the biological buffer field on the purity, impurity content, cost and the like of the product and is suitable for application in the biological buffer field.
Description
Technical Field
The invention belongs to the technical field of biological buffers, and particularly relates to a preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane.
Background
1,3-BIS (TRIS (hydroxymethyl) methylamino) propane, known by the english name 1,3-BIS (TRIS (hydroxymethyl) methyliminon) propane, also known as BIS-TRIS propane, is a white crystalline powder, and belongs to one of the TRIS series of biological buffers. The buffer range of BIS-TRIS propane is 6.3-9.5, and its first-order acid dissociation constant pKa is at 25 deg.C16.8, second acid dissociation constant pKa29.0. BIS-TRIS propane has been applied to biochemical diagnostic kits, DNA/RNA extraction kits, PCR diagnostic kits and other kits, and belongs to one of the most deeply applied reagents in TRIS series products.
In the preparation of BIS-TRIS propane, Chinese patent CN200810200543.2 discloses a preparation method, which comprises the steps of taking TRIS (hydroxymethyl) aminomethane and 1, 3-dibromopropane as main reaction raw materials, carrying out reflux reaction in an ethanol solution for a certain time, respectively carrying out acidification and alkalization treatment to obtain a crude product, and recrystallizing to obtain a pure 1,3-BIS (tri (hydroxymethyl) methylamino) propane product. However, the number of patents in particular in 1,3-bis (tris (hydroxymethyl) methylamino) propane is relatively small, and there are various problems associated with the preparation process in the prior patents, such as: low yield, low purity and the like. The above problems, if not solved, would prevent their large-scale use, especially as materials in the field of biological buffers.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane, the raw materials of the preparation and purification process are easy to obtain, the product manufacturing cost is low, the preparation method is simple, mass large-scale production can be realized, and the preparation method has important industrial application value in the field of biological buffers.
The purpose of the invention can be achieved by adopting the following technical scheme:
a preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane is characterized by comprising the following steps:
preparation step S1: the compound 1 is reacted by itself, or the compound 1 is reacted with a condensation reagent to obtain a compound 2;
preparation step S2: and (3) reacting the compound 2 with a compound 2A to obtain the 1,3-bis (tri (hydroxymethyl) methylamino) propane.
Wherein, the compound 1 is a compound with a general structure shown in a formula I:
compound 2 is a compound having the general structure shown in formula II:
compound 2A is a compound having the general structure shown in formula III:
wherein, in the structural formula of the compound 1, Z1、Z2Respectively at least one of halogen, OH and NH; in the structural formula of the compound 2, Y is at least one of-O-, -NH-.
The reaction equation of the preparation step S1 is shown by the following formula (1):
the reaction equation of the preparation step S2 is shown in the following formula (2):
further, the compound 2A is a corresponding salt formed by a compound having a general structure shown in formula III and an inorganic acid, and is preferably a composition of one or more of sulfate, phosphate, hydrochloride and nitrate.
Further, in the structural formula of the compound 2, Y is-O-CO-O-, -O-SO2-O-、-O-SO-O-、-NH-CO-NH-、-NH-SO2At least one of-NH-, -NH-SO-NH-.
Further, in the preparation step S1, the condensation reagent is at least one of ammonia gas, ammonia water, urea, dihalo sulfoxide, sulfonyl halide, and N, N' -carbonyldiimidazole.
Further, in the step S1, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 h.
Further, in the step S2, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa (gauge pressure), and the reaction time is 0.1-72 hours.
Further, in step S2, the molar ratio of compound 2 to compound 2A is 1: (0.1-10).
Further, step S1 is performed in a solvent a, wherein the solvent a is one or a combination of two or more selected from methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
Further, step S2 is performed in a solvent B, wherein the solvent B is one or a combination of two or more selected from methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
Further, the method also comprises the following preparation steps:
the crude 1,3-bis (tris (hydroxymethyl) methylamino) propane obtained in production step S2 is dissolved in a purification solvent, and then recrystallized and dried to obtain a purified 1,3-bis (tris (hydroxymethyl) methylamino) propane.
Further, the purifying solvent is one or a combination of more than two of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, water and dimethyl sulfoxide.
Compared with the prior art, the invention has the beneficial effects that:
1. the application provides a preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane, which improves the yield of products by optimizing the starting materials and optimizing the preparation and purification steps, is simple, reduces the cost of the products, is suitable for industrial production, has the advantages of high purity of the prepared 1,3-bis (tri (hydroxymethyl) methylamino) propane, low water content and dryness, meets the requirements of the biological buffer field on the purity, impurity content, cost and the like, and is suitable for application in the biological buffer field.
2. The by-products and impurities generated by the preparation method are easy to purify and separate, and the impurities in the product can reach the high-purity practical application standard without a complex purification process, so that the preparation process of the product is simplified, the product purity is high, and the yield and quality requirements of large-scale application can be met.
Detailed Description
The present invention will be further described with reference to the following embodiments, which are not intended to limit the scope of the present invention, but are defined by the following examples, which are provided for illustration of the principles of the present invention; that is, the following description is only a part of the preferred embodiment of the present invention, and it is not intended to limit the scope of the present invention, and it will be apparent to those skilled in the art that various changes, modifications and variations can be made in the present invention without departing from the spirit, principle and scope of the invention, additional features of the invention may be included alone or in any combination, and these changes, modifications and variations should also be considered to be within the scope of the claimed invention. In addition, the raw materials used in the invention are all common commercial products, so that the sources of the raw materials do not need to be particularly limited.
The purity of the product was analyzed by acid-base titration.
Nuclear magnetic analysis was performed using an AVANCE 400 mega nuclear magnetic resonance spectrometer from Bruker (Bruker).
The pressure values mentioned in this patent application, if not specified otherwise, are gauge pressures, and gauge pressures refer to the total absolute pressure exceeding the ambient atmospheric pressure or the pressure at a point in the liquid above atmospheric pressure.
The yield, as a percentage ratio of actual product mass to theoretical product mass, and theoretical product mass, were calculated as the raw materials in the reaction equation were not in excess.
Example 1
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
under the condition of stirring, 100g of 3-chloropropanol is added into a 1L drying reactor, the reaction temperature is 200 ℃, the reaction pressure is 1MPa (gauge pressure), and the compound is obtained after 24h of reaction
Preparation step S2:
to a 1L dry reactor was added 100g of the above compound with stirring
Tetrahydrofuran, tromethamine, compound as reaction solvent
And ammoniaThe molar ratio of the triol is 1:3, the reaction temperature is 70 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 5 h. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tris (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tris (hydroxymethyl) methylamino) propane is 68%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent ethanol by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 2
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
under the condition of stirring, 100g of 3-amino-1-propanol is added into a 1L drying reactor, the reaction temperature is 180 ℃, the reaction pressure is 0.5MPa (gauge pressure), and the compound is obtained after 36h of reaction
Preparation step S2:
to a 1L dry reactor was added, with stirring, 100g of the above compound
Reaction solvents acetonitrile, tromethamine, compounds
The molar ratio of the ammonia to the tromethamine is 1:5 respectively, the reaction temperature is 85 ℃, the reaction pressure is 0.3MPa (gauge pressure), and the reaction time is 10 h. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 61%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 into a purification solvent methanol by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 3
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
adding 100g of 3-bromo-1-propanol into a 1L drying reactor under stirring, dissolving in acetone solution, reacting at 60 deg.C and 0.1MPa (gauge pressure) for 72h to obtain compound
Preparation step S2:
to a 1L dry reactor was added, with stirring, 100g of the above compound
Reaction solvents of ethyl acetate, tromethamine and compound
The molar ratio of the ammonia to the tromethamine is 1:7 respectively, the reaction temperature is 80 ℃, the reaction pressure is 0.5MPa (gauge pressure), and the reaction time is 24 h. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 71%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 into a purification solvent dimethyl carbonate by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.5%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 4
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
adding 100g of 3-chloropropylamine into a 1L dry reactor under stirring, dissolving in DMF at 130 deg.C under 0MPa (gauge pressure), and reacting for 12h to obtain the compound
Preparation step S2:
to a 1L dry reactor was added, with stirring, 100g of the above compound
Reaction solvent ethanol, tromethamine phosphate, compound
The molar ratio of the ammonia to the tromethamine is 1:9 respectively, the reaction temperature is 80 ℃, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 12 h. And after the reaction is finished, cooling to normal temperature, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 62%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent diethyl carbonate by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 5
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
to a 1L dry reactor, 100g of 1, 3-dibromopropane and urea were charged with stirring, dissolved in dioxane, 1, 3-dibromopropaneThe molar ratio of propane to urea is 1: 1; the reaction temperature is 110 ℃, the reaction pressure is 0.8MPa (gauge pressure), and the compound is obtained after 48 hours of reaction
Preparation step S2:
100g of the above compound 2, dioxane as a reaction solvent, tromethamine, and compound 2 and tromethamine were charged into a 1L dry reactor under stirring at a reaction temperature of 110 ℃ and a reaction pressure of 0.2MPa (gauge pressure) for 3 hours, at a molar ratio of 1:3, respectively. And after the reaction is finished, cooling to normal temperature, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 56%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent acetone by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.5%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 6
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
100g of 1, 3-propanediamine and thionyl chloride were added to a 1L dry reactor with stirring and dissolved in carbonic acidDiethyl ester, the molar ratio of 1, 3-propanediamine to thionyl chloride being 1: 1; the reaction temperature is 130 ℃, the reaction pressure is 0.7MPa (gauge pressure), and the compound is obtained after 24 hours of reaction
Preparation step S2:
100g of the above-mentioned compound 2, a reaction solvent DMF, and tromethamine were charged into a 1L dry reactor under stirring, at a reaction temperature of 150 ℃ and a reaction pressure of 0.7MPa (gauge pressure) for 16 hours, at a molar ratio of 1:4 for each of the compound 2 and the tromethamine. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 51%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent ethanol by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.0%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 7
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
100g of 1, 3-propanediol and dichloro were added to a 1L dry reactor with stirringSulfoxide dissolved in dimethyl sulfoxide, wherein the molar ratio of 1, 3-propylene glycol to thionyl chloride is 1: 1; the reaction temperature is 190 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the compound is obtained after 6 hours of reaction
Preparation step S2:
100g of the compound 2, ethanol as a reaction solvent, and tromethamine were added to a 1L dry reactor under stirring, at a reaction temperature of 80 ℃ and a reaction pressure of 0.9MPa (gauge pressure) for 36 hours, in a molar ratio of 1:2 for each of the compound 2 and the tromethamine. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 51%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent ethanol by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 8
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
to a 1L dry reactor, 100g was charged with stirringDissolving 1, 3-propanediol and sulfonyl chloride in ethyl acetate, wherein the molar ratio of the 1, 3-propanediol to the sulfonyl chloride is 1: 1; the reaction temperature is 200 ℃, the reaction pressure is 1MPa (gauge pressure), and the compound is obtained after 24 hours of reaction
Preparation step S2:
100g of the above compound 2, acetonitrile as a reaction solvent, and tromethamine were charged into a 1L dry reactor under stirring at 85 ℃ under a reaction pressure of 0.5MPa (gauge pressure) for 8 hours, at a molar ratio of 1:2 for the compound 2 and the tromethamine, respectively. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 55%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent tetrahydrofuran by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data were as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
example 9
A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane comprises the following preparation steps:
preparation step S1:
drying reaction to 1L under stirring100g of 1, 3-propanediol and N, N '-carbonyldiimidazole are added into a reactor and dissolved in dimethyl carbonate, and the molar ratio of the 1, 3-propanediol to the N, N' -carbonyldiimidazole is 1: 1; the reaction temperature is 90 ℃, the reaction pressure is 0.9MPa (gauge pressure), and the compound is obtained after 24 hours of reaction
Preparation step S2:
100g of the above-mentioned compound 2, a reaction solvent DMF, and tromethamine were charged into a 1L dry reactor under stirring, at a reaction temperature of 150 ℃ and a reaction pressure of 0.1MPa (gauge pressure) for 1 hour, in a molar ratio of 1:3, respectively. And (3) cooling to normal temperature after the reaction is finished, filtering to remove insoluble substances, performing rotary evaporation on the filtrate under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane, wherein the yield of the crude product of the 1,3-bis (tri (hydroxymethyl) methylamino) propane is 61%.
Preparation step S3:
under the drying condition, dissolving the crude 1,3-bis (tri (hydroxymethyl) methylamino) propane obtained in the preparation step S2 in a purification solvent ethanol by using a drying closed device, and then recrystallizing and drying to obtain refined 1,3-bis (tri (hydroxymethyl) methylamino) propane; the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.6ppm、2.6ppm、1.6ppm。
the embodiment shows that the 1,3-bis (tri (hydroxymethyl) methylamino) propane prepared in the embodiment has high purity and less impurity content, can meet the requirements of the application field, and the preparation method of the invention has the product yield up to 71 percent, improves the product yield and has the product purity up to 99.9 percent.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (11)
1. A preparation method of 1,3-bis (tri (hydroxymethyl) methylamino) propane is characterized by comprising the following steps:
preparation step S1: the compound 1 is reacted by itself, or the compound 1 is reacted with a condensation reagent to obtain a compound 2;
preparation step S2: reacting the compound 2 with a compound 2A to obtain the 1,3-bis (tri (hydroxymethyl) methylamino) propane;
wherein, the compound 1 is a compound with a general structure shown in a formula I:
compound 2 is a compound having the general structure shown in formula II:
compound 2A is a compound having the general structure shown in formula III:
wherein, in the structural formula of the compound 1, Z1、Z2Respectively at least one of halogen, OH and NH; in the structural formula of the compound 2, Y is at least one of-O-, -NH-.
2. The method for preparing 1,3-bis (tris (hydroxymethyl) methylamino) propane according to claim 1, wherein the compound 2A is a composition of one or more of sulfate, hydrochloride, phosphate and nitrate of a compound having a general structure shown in formula III.
3. The method according to claim 1, wherein Y in the formula of Compound 2 is-O-CO-O-, -O-SO2-O-、-O-SO-O-、-NH-CO-NH-、-NH-SO2At least one of-NH-, -NH-SO-NH-.
4. The method according to claim 1, wherein in step S1, the condensation reagent is at least one of ammonia, water, urea, dihalo sulfoxide, sulfonyl halide, and N, N' -carbonyldiimidazole.
5. The process according to any one of claims 1 to 4, wherein the reaction temperature in step S1 is-50 to 200 ℃, the reaction pressure is-0.05 to 1MPa, and the reaction time is 0.1 to 72 hours.
6. The process according to any one of claims 1 to 4, wherein the reaction temperature in step S2 is-50 to 200 ℃, the reaction pressure is-0.05 to 1MPa, and the reaction time is 0.1 to 72 hours.
7. The method for preparing 1,3-bis (tris (hydroxymethyl) methylamino) propane according to any one of claims 1 to 4, wherein in step S2, the molar ratio of Compound 2 to Compound 2A is 1: (0.1-10).
8. The method according to any one of claims 1 to 4, wherein step S1 is performed in a solvent A selected from one or a combination of two or more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
9. The method according to any one of claims 1 to 4, wherein step S2 is performed in a solvent B selected from one or a combination of two or more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
10. The method for preparing 1,3-bis (tris (hydroxymethyl) methylamino) propane according to any one of claims 1 to 4, characterized by comprising the following steps:
the crude 1,3-bis (tris (hydroxymethyl) methylamino) propane obtained in preparation step S2 is dissolved in a purification solvent, and then recrystallized and dried to obtain refined 1,3-bis (tris (hydroxymethyl) methylamino) propane.
11. The process according to claim 10, wherein the reaction mixture is a mixture of 1,3-bis (tris (hydroxymethyl) methylamino) propane,
the purifying solvent is one or a composition of more than two of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, water and dimethyl sulfoxide.
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| 吴萍;王靖宇;许振良;殷神军;: "一步碱化后处理法制备1,3-双[(三羟甲基)甲基氨基]丙烷", 化学世界, no. 06, pages 358 - 360 * |
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