CN112939771A - Preparation method of long-chain alkyl diacid mono-tert-butyl ester - Google Patents
Preparation method of long-chain alkyl diacid mono-tert-butyl ester Download PDFInfo
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 68
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000002994 raw material Substances 0.000 claims abstract description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 117
- 239000000126 substance Substances 0.000 claims description 99
- 238000006243 chemical reaction Methods 0.000 claims description 91
- 239000002904 solvent Substances 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 61
- 238000005406 washing Methods 0.000 claims description 56
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 36
- 238000001816 cooling Methods 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 30
- 238000002390 rotary evaporation Methods 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 239000008213 purified water Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 18
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 17
- 239000012279 sodium borohydride Substances 0.000 claims description 17
- 238000004537 pulping Methods 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 15
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003929 acidic solution Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- 238000005481 NMR spectroscopy Methods 0.000 description 58
- 239000000047 product Substances 0.000 description 49
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 42
- 239000001257 hydrogen Substances 0.000 description 42
- 229910052739 hydrogen Inorganic materials 0.000 description 42
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 33
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 28
- 238000001819 mass spectrum Methods 0.000 description 28
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000004949 mass spectrometry Methods 0.000 description 24
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 24
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 24
- -1 mono-tert-butyl hexadecyl Chemical group 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 21
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 20
- 239000012535 impurity Substances 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 235000021314 Palmitic acid Nutrition 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 238000009833 condensation Methods 0.000 description 8
- 230000005494 condensation Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- AKGGVTJJNPYBQU-UHFFFAOYSA-N 16-chloro-16-oxohexadecanoic acid Chemical compound OC(=O)CCCCCCCCCCCCCCC(Cl)=O AKGGVTJJNPYBQU-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ASXKHYPKFDCKKV-UHFFFAOYSA-N 2-methyl-1,4-dioxepane-5,7-dione Chemical compound CC1COC(=O)CC(=O)O1 ASXKHYPKFDCKKV-UHFFFAOYSA-N 0.000 description 1
- SNPYVVAFTGQELD-UHFFFAOYSA-N CCCCCCCCCCCCCCC=CC=C(C(C)(C)C)C(O)=O Chemical compound CCCCCCCCCCCCCCC=CC=C(C(C)(C)C)C(O)=O SNPYVVAFTGQELD-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- 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
Abstract
A preparation method of long-chain alkyl diacid mono-tert-butyl ester belongs to the technical field of organic synthesis, wherein long-chain alkyl diacid is used as a starting raw material and reacts with oxalyl chloride to generate long-chain monoacyl chloride, and the long-chain monoacyl chloride and tert-butyl alcohol are subjected to esterification reaction to generate the long-chain alkyl diacid mono-tert-butyl ester.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of long-chain alkyl diacid mono-tert-butyl ester.
Background
The long-chain alkyl diacid mono-tert-butyl ester is mostly an important intermediate in organic synthesis, and is particularly used as an intermediate for important drug synthesis in the field of medicine.
The application of the intermediate enables the treatment of diabetes to obtain breakthrough progress, but the octadecyl diacid mono-tert-butyl ester is expensive and the raw material synthesis difficulty is high.
The hexadecyl diacid mono-tert-butyl ester is used for laboratory research and development and chemical medicine synthesis, the hexadecyl diacid mono-tert-butyl ester sold in the market at present is an imported product, the market price is expensive, the synthesis difficulty is high, and the cost is high.
The Chinese patent CN202010851914.4 provides a synthesis method of mono-tert-butyl octadecadienecarboxylic acid, which adopts expensive sebacic acid as a raw material, and concentrated sulfuric acid as a catalyst in the synthesis process, so that the operation process is dangerous, and the purity of the prepared product is not high enough.
Disclosure of Invention
In view of the above, there is a need to provide a method for preparing long-chain alkyl diacid mono-tert-butyl ester, so as to solve the problems that the existing technology for synthesizing long-chain alkyl diacid mono-tert-butyl ester is immature, the raw material price is expensive, the operation process using concentrated sulfuric acid as a catalyst is dangerous, and the purity is not high enough.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the preparation method of long-chain alkyl diacid mono-tert-butyl ester comprises the following steps:
reacting the long-chain alkyl diacid shown as A with oxalyl chloride to obtain monoacyl chloride shown as B, and reacting the monoacyl chloride shown as B with tert-butyl alcohol to generate long-chain alkyl diacid mono-tert-butyl ester shown as C; wherein n is an integer of 0 or more in the following reaction equation;
preferably, the specific steps are as follows:
(1) adding tetrahydrofuran solvent into the A for dissolving, cooling to-5-0 ℃, adding DMF, adding oxalyl chloride, moving to room temperature for reacting for 1-2 hours, and performing rotary evaporation and concentration to obtain B.
(2) And mixing the B and tert-butyl alcohol, adding dichloromethane for dissolving, reacting for 8-16 hours at room temperature, performing rotary evaporation to remove the solvent, pulping to recover the raw materials, washing the filtrate with water, performing rotary drying, and performing column chromatography purification to obtain the C.
Preferably, in the step (1), the molar ratio of A to oxalyl chloride is 1: 1 to 3.
Preferably, in the step (2), the molar ratio of B to tert-butanol is 1: 1 to 3.
Preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
hydrolyzing the heterocycle-containing alkanoic acid shown as D under an acidic condition to prepare the long-chain alkyl diacid shown as A, wherein n in the following equation is an integer which is more than or equal to 0;
preferably, the specific steps of the process for preparing A from D are as follows:
and D, adding an acid solution, heating to 90-120 ℃, refluxing, reacting for 10-15 hours, cooling to separate out a solid, filtering, top washing and drying to obtain A.
Preferably, in the specific step of preparing A by D, the acidic solution is hydrochloric acid with the concentration of 1 mol/L-7 mol/L.
Preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
reacting the substance shown as E in the presence of sodium borohydride to prepare the heterocyclic alkanoic acid shown as D, wherein in the following equation, n is an integer greater than or equal to 0;
preferably, the specific steps for producing D by the reaction of E are as follows:
and E, adding dichloromethane for dissolving, cooling to-5 ℃, adding acetic acid for stirring, adding sodium borohydride for reacting for 1-2 hours, extracting twice with a saturated sodium bicarbonate solution, washing with purified water, then with saturated salt solution, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain D.
Preferably, in the specific step of preparing D from E, the molar ratio of E to acetic acid is 1: 8-15.
Preferably, in the specific step of preparing D by E, the molar ratio of E to sodium borohydride is 1: 1 to 5.
Preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
condensing the long-chain alkyl diacid and isopropylidene malonate as shown in B' to prepare a substance shown in E, wherein n is an integer which is more than or equal to 0 in the following equation;
preferably, the specific steps for preparing C by reacting A' with F are as follows:
and mixing A 'and F, adding dichloromethane for dissolving, cooling to-10-0 ℃ under the protection of inert gas, sequentially adding a catalyst 4-dimethylaminopyridine and a condensing agent N, N' -diisopropylcarbodiimide, reacting for 8-16 hours, extracting twice with a citric acid aqueous solution, washing with purified water, washing with saturated salt water, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain E.
Preferably, in the specific step of preparing C by reacting A 'with F, the molar ratio of A' to F is 1: 1 to 1.3.
Preferably, in the specific step of preparing C by reacting A ' with F, the molar ratio of A ' to N, N ' -diisopropylcarbodiimide is 1: 1 to 1.3.
Preferably, in the specific step of preparing C by reacting A 'with F, the molar ratio of A' to 4-dimethylaminopyridine is 1: 1 to 2.
Preferably, n in the equation for the reaction of A to B, B to C, D to A, E to D and the reaction of A' to E is an integer of 6 or more.
Preferably, n is 6 or n is 7 in the formula where a reacts to form B, B, C, D reacts to form A, E, D and a' reacts to form E.
According to the technical scheme, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester has the beneficial effects that: a new synthesis route is adopted, firstly, long-chain alkyl diacid and oxalyl chloride are subjected to mono-substitution reaction, secondly, the generated product and tertiary butanol are subjected to esterification reaction to generate long-chain alkyl diacid mono-tertiary butyl ester, the reaction is completed through two steps, the reaction process is simple, the conditions are mild, the operation is safe and easy, the production efficiency is high, the purity of the prepared product is high, and the route suitable for industrial production is created.
Drawings
FIG. 1 is a drawing showing the preparation of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -14-hydroxytetradecanoic acid prepared in example 1, example 2 and example 31H NMR spectrum.
FIG. 2 is a mass spectrum of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -14-hydroxytetradecanoic acid prepared in example 1, example 2 and example 3.
FIG. 3 shows the reaction product of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid prepared in example 1, example 2 and example 31H NMR spectrum.
FIG. 4 is a mass spectrum of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid prepared in example 1, example 2 and example 3.
FIG. 5 is a schematic representation of the hexadecyl diacids prepared in example 1, example 2 and example 31H NMR spectrum.
FIG. 6 is a diagram of the preparation of hexadecyl diacids of example 1, example 2 and example 313C NMR spectrum.
FIG. 7 is a mass spectrum of hexadecyl diacid prepared in example 1, example 2 and example 3.
FIG. 8 shows the mono-tert-butyl hexadecyl diacid ester prepared in example 1, example 2 and example 31H NMR spectrum.
FIG. 9 shows examples 1,2 andpreparation of mono-tert-butyl hexadecyldiacid ester from example 313C NMR spectrum.
FIG. 10 is a mass spectrum of mono-tert-butyl hexadecyl diacid prepared in example 1, example 2 and example 3.
FIG. 11 is a drawing showing the reaction product of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -16-hydroxyhexadecanoic acid prepared in example 4, example 5 and example 61H NMR spectrum.
FIG. 12 is a mass spectrum of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -16-hydroxyhexadecanoic acid prepared in example 4, example 5 and example 6.
FIG. 13 shows the preparation of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-) hexadecanoic acid prepared in example 4, example 5 and example 61H NMR spectrum.
FIG. 14 is a mass spectrum of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-) hexadecanoic acid prepared in example 4, example 5 and example 6.
FIG. 15 is a drawing of the preparation of the octadecyl diacid of example 4, example 5 and example 61H NMR spectrum.
FIG. 16 is a chart of the preparation of the octadecyl diacid of examples 4, 5 and 613C NMR spectrum.
FIG. 17 is a mass spectrum of the octadecyl diacid prepared in example 4, example 5, and example 6.
FIG. 18 shows the preparation of mono-tert-butyl octadecyl diacid ester prepared in example 4, example 5 and example 61H NMR spectrum.
FIG. 19 is a graph of the mono-tert-butyl octadecyl diacid prepared in example 4, example 5 and example 613C NMR spectrum.
Detailed Description
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following examples are briefly introduced, and the experimental methods without specifying specific conditions in the following examples are performed according to conventional methods and conditions.
The technical solutions and effects of the embodiments of the present invention will be further described in detail below with reference to the accompanying drawings of the present invention.
The preparation method of long-chain alkyl diacid mono-tert-butyl ester comprises the following steps:
reacting the long-chain alkyl diacid shown as A with oxalyl chloride to obtain monoacyl chloride shown as B, and reacting the monoacyl chloride shown as B with tert-butyl alcohol to generate long-chain alkyl diacid mono-tert-butyl ester shown as C; wherein n is an integer of 0 or more in the following reaction equation;
further, the method comprises the following specific steps:
(1) adding tetrahydrofuran solvent into the A for dissolving, cooling to-5-0 ℃, adding DMF, adding oxalyl chloride, moving to room temperature for reacting for 1-2 hours, and performing rotary evaporation and concentration to obtain B.
(2) And mixing the B and tert-butyl alcohol, adding dichloromethane for dissolving, reacting for 8-16 hours at room temperature, performing rotary evaporation to remove the solvent, pulping to recover the raw materials, washing the filtrate with water, performing rotary drying, and performing column chromatography purification to obtain the C.
Preferably, in the step (1), the molar ratio of A to oxalyl chloride is 1: 1-3, optimally, the molar ratio of A to oxalyl chloride is 1: 2.
preferably, in the step (2), the molar ratio of B to tert-butanol is 1: 1-3, optimally, the molar ratio of B to tertiary butanol is 1: 2.
preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
hydrolyzing the heterocycle-containing alkanoic acid shown as D under an acidic condition to prepare the long-chain alkyl diacid shown as A, wherein n in the following equation is an integer which is more than or equal to 0;
preferably, the specific steps of the process for preparing A from D are as follows:
and D, adding an acid solution, heating to 90-120 ℃, refluxing, reacting for 10-15 hours, cooling to separate out a solid, filtering, top washing and drying to obtain A.
Preferably, in the specific step of preparing A by D, the acidic solution is hydrochloric acid with the concentration of 1 mol/L-7 mol/L, and optimally, the hydrochloric acid concentration is 3.2 mol/L.
Preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
reacting the substance shown as E in the presence of sodium borohydride to prepare the heterocyclic alkanoic acid shown as D, wherein in the following equation, n is an integer greater than or equal to 0;
preferably, the specific steps for producing D from E are as follows:
and E, adding dichloromethane for dissolving, cooling to-5 ℃, adding acetic acid for stirring, adding sodium borohydride for reacting for 1-2 hours, extracting twice with a saturated sodium bicarbonate solution, washing with purified water, then with saturated salt solution, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain D.
Preferably, in the specific step of preparing D from E, the molar ratio of E to acetic acid is 1: 8-15, optimally, the molar ratio of E to acetic acid is 1: 10.
preferably, in the specific step of preparing D by E, the molar ratio of E to sodium borohydride is 1: 1-5, optimally, the molar ratio of E to sodium borohydride is 1: 3.
preferably, the preparation method of the long-chain alkyl diacid mono-tert-butyl ester further comprises the following steps:
condensing the long-chain alkyl diacid and isopropylidene malonate as shown in B' to prepare a substance shown in E, wherein n is an integer which is more than or equal to 0 in the following equation;
preferably, the specific steps for preparing C by reacting A' with F are as follows:
and mixing A 'and F, adding dichloromethane for dissolving, cooling to-10-0 ℃ under the protection of inert gas, sequentially adding a catalyst 4-dimethylaminopyridine and a condensing agent N, N' -diisopropylcarbodiimide, reacting for 8-16 hours, extracting twice with a citric acid aqueous solution, washing with purified water, washing with saturated salt water, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain E.
Preferably, in the specific step of preparing C by reacting A 'with F, the molar ratio of A' to F is 1: 1-1.3 optimally, the molar ratio of A' to F is 1: 1.1.
preferably, in the specific step of preparing C by reacting A ' with F, the molar ratio of A ' to N, N ' -diisopropylcarbodiimide is 1: 1 to 1.3, and optimally, the molar ratio of A 'to N, N' -diisopropylcarbodiimide is 1: 1.1.
preferably, in the specific step of preparing C by reacting A 'with F, the molar ratio of A' to 4-dimethylaminopyridine is 1: 1-2, optimally, the molar ratio of A' to 4-dimethylamino pyridine is 1: 1.5.
preferably, in the formula of the reaction product a B, B C, D A, E D and the reaction product a' E, n is an integer of 6 or more, and most preferably, n is 6 or 7.
Firstly, the long-chain alkyl diacid and oxalyl chloride are subjected to mono-substitution reaction, the reaction condition is mild, the operation is simple, secondly, the generated product and tert-butyl alcohol are subjected to esterification reaction to generate long-chain alkyl diacid mono-tert-butyl ester, the method is simple to operate, and the prepared product has high purity.
The high-grade long-chain alkyl diacid with high price can be prepared by the reaction of low-grade long-chain alkyl diacid with low price, wherein the low-grade long-chain alkyl diacid is condensed with isopropylidene malonate, the condensation product is reduced under the condition of sodium borohydride, and the reduction product is hydrolyzed under the acid condition to obtain the high-grade long-chain alkyl diacid.
The technical scheme and technical effects of the invention are further explained by the specific examples below.
Example 1
Preparing hexadecyl diacid mono-tert-butyl ester by taking tetradecyl diacid as a raw material:
(1) condensation of tetradecyl diacid and isopropylidene malonate to prepare 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, respectively adding 20g (77mmol) of tetradecyl diacid, 11.1g (77mmol) of isopropylidene malonate and 400ml of dichloromethane into a reaction bottle, stirring, cooling to-2 to-6 ℃, adding 9.4g (77mmol) of 4-dimethylaminopyridine, reacting for 8 to 12min, then adding 9.7g (77mmol) of N, N' -diisopropylcarbodiimide, moving to room temperature for reacting for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, purifying (200ml) water, washing with saturated saline water (200ml), and drying the organic phase with anhydrous sodium sulfate (20 g); the solvent was removed by rotary evaporation to give crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -14-hydroxytetradecanoic acid, which was slurried with methyl tert-butyl ether (50ml) and was calculated to give a yield of 86%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIG. 1-2.
As can be seen from fig. 1:1h NMR (400MHz, CDCl3) δ 15.28(s,1H), 3.08-3.03 (m,2H), 1.75-1.66 (m,10H),1.27(d, J ═ 14.3Hz,14H),1.16(d, J ═ 6.5Hz,4H), where chemical shift 7.26 is a deuterated chloroform solvent peak, hydrogen on carboxyl group with chemical shift around 11 is not shown, peak with chemical shift 0 is for calibration, negligible, chemical shifts 3.8 and 2.35 are impurity peaks, suspected of being an impurity intermediate with incomplete condensation or a raw material peak with incomplete reaction;
as can be seen from fig. 2: the molecular weight of the compound is 384.46, ES-looks for a hydrogen reduction peak 383.28.
(2) Preparation of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid by reduction of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 15g (39mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid into a reaction bottle under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 18.9g (312mmol) of acetic acid, stirring, adding 1.5g (39mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline water (150ml), and drying an organic phase by using anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 46% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 3 to 4.
As can be seen from fig. 3:1h NMR (400MHz, CDCl3) δ 3.49(t, J ═ 5.0Hz,1H),2.16 to 2.04(m,2H),1.75(dd, J ═ 18.9,8.4Hz,8H),1.44(dd, J ═ 10.2,5.7Hz,2H),1.33 to 1.17(m,20H), where chemical shift 7.26 is a deuterated chloroform solvent peak, chemical shift 0 is a peak for calibration, negligible, chemical shift 11 is not shown for hydrogen on the carboxyl group, chemical shift 15.3 is a peak for hydrogen on the enol bond on the incompletely reduced raw material, chemical shifts 3.1 and 3.8 are impurity peaks, suspected of incompletely reduced impurity intermediates or incompletely reduced raw material peaks;
as can be seen from fig. 4: the molecular weight of the compound is 370.48, ES-looks for a hydrogen reduction peak 369.26.
(3) Preparation of hexadecyl diacid by acid condition hydrolysis of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 4.4g (12mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid into a reaction bottle, adding 100ml of 4.4% hydrochloric acid aqueous solution (1.23mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the hexadecyl diacid, wherein the yield is 71%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 5 to 7.
As can be seen from fig. 5:1h NMR (400MHz, DMSO) δ 11.97(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.44 (m,4H),1.24(s,20H) with chemical shift 2.50 for the deuterated DMSO solvent peak and chemical shift 3.33 for the water peak;
as can be seen from fig. 6:13c NMR (101MHz, DMSO) δ 174.96,34.11,29.52,29.49,29.41,29.24,29.03,24.96, with a 7-fold peak around a chemical shift of 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 7: the molecular weight of the compound is 286.41, ES-looks for a hydrogen reduction peak 285.23.
(4) Hexadecyl diacid and oxalyl chloride react to prepare 16-chloro-16-oxycetanoic acid, and 16-chloro-16-oxycetanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl hexadecyl diacid ester
The specific reaction process is as follows:
adding 3.5g (12mmol) of hexadecyl diacid into a reaction bottle, adding tetrahydrofuran (70ml), stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 1.5g (12mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 h; after the reaction is finished, the 16-chloro-16-oxycetanoic acid is directly obtained by rotary evaporation and concentration, and the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
And (3) quickly adding 4g (13mmol) of the product 16-chloro-16-oxohexadecanoic acid into a reaction bottle, then adding 1g (14mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, carrying out rotary evaporation to remove the solvent, adding dichloromethane, pulping, recovering the raw material, washing the filtrate with water, and carrying out rotary drying to obtain a crude product of the hexadecyl diacid mono-tert-butyl ester, wherein the yield is 74.5%, and the purity of the hexadecyl diacid mono-tert-butyl ester is 98.5% after column chromatography purification.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 8 to 10.
As can be seen from fig. 8:1h NMR (400MHz, DMSO) δ 11.97(s,1H),2.17(dd, J ═ 15.4,7.5Hz,4H),1.48(d, J ═ 2.6Hz,4H),1.39(s,9H),1.24(s,20H), with chemical shift 2.50 for the deuterated DMSO solvent peak and 3.33 for the water peak;
as can be seen from fig. 9:13c NMR (101MHz, DMSO) δ 174.94,172.73,79.75,35.22,34.11,29.50,29.47,29.41,29.40,29.33,29.12,29.03,28.82,28.20,25.07,24.96, wherein the 7-fold peak with chemical shift around 39.6 is the deuterated DMSO solvent peak;
as can be seen from fig. 10: the molecular weight of the compound is 342.51, ES-looks for a hydrogen reduction peak 341.29.
Example 2
Preparing hexadecyl diacid mono-tert-butyl ester by taking tetradecyl diacid as a raw material:
(1) condensation of tetradecyl diacid and isopropylidene malonate to prepare 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, respectively adding 20g (77mmol) of tetradecyl diacid, 12.2g (84.7mmol) of isopropylidene malonate and 400ml of dichloromethane into a reaction bottle, stirring, cooling to-2 to-6 ℃, adding 14g (115.5mmol) of 4-dimethylaminopyridine, reacting for 8-12 min, then adding 10.7g (84.7mmol) of N, N' -diisopropylcarbodiimide, moving to room temperature for reacting for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, washing with purified water (200ml) once, washing with saturated saline water (200ml), and drying the organic phase with anhydrous sodium sulfate (20 g); the solvent was removed by rotary evaporation to give crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -14-hydroxytetradecanoic acid, which was slurried with methyl tert-butyl ether (50ml) and was calculated to give a yield of 87%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIG. 1-2.
As can be seen from fig. 1:1h NMR (400MHz, CDCl3) δ 15.28(s,1H), 3.08-3.03 (m,2H), 1.75-1.66 (m,10H),1.27(d, J ═ 14.3Hz,14H),1.16(d, J ═ 6.5Hz,4H), where chemical shift 7.26 is a deuterated chloroform solvent peak, hydrogen on carboxyl group with chemical shift around 11 is not shown, peak with chemical shift 0 is for calibration, negligible, chemical shifts 3.8 and 2.35 are impurity peaks, suspected of being an impurity intermediate with incomplete condensation or a raw material peak with incomplete reaction;
as can be seen from fig. 2: the molecular weight of the compound is 384.46, ES-looks for a hydrogen reduction peak 383.28.
(2) Preparation of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid by reduction of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 15g (39mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid into a reaction bottle under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 23.6g (390mmol) of acetic acid, stirring, adding 4.4g (117mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline water (150ml), and drying an organic phase by using anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 46% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 3 to 4.
As can be seen from fig. 3:1h NMR (400MHz, CDCl3) δ 3.49(t, J ═ 5.0Hz,1H),2.16 to 2.04(m,2H),1.75(dd, J ═ 18.9,8.4Hz,8H),1.44(dd, J ═ 10.2,5.7Hz,2H),1.33 to 1.17(m,20H), where chemical shift 7.26 is a deuterated chloroform solvent peak, chemical shift 0 is a peak for calibration, negligible, chemical shift 11 is not shown for hydrogen on the carboxyl group, chemical shift 15.3 is a peak for hydrogen on the enol bond on the incompletely reduced raw material, chemical shifts 3.1 and 3.8 are impurity peaks, suspected of incompletely reduced impurity intermediates or incompletely reduced raw material peaks;
as can be seen from fig. 4: the molecular weight of the compound is 370.48, ES-looks for a hydrogen reduction peak 369.26.
(3) Preparation of hexadecyl diacid by acid condition hydrolysis of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 4.4g (12mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid into a reaction bottle, adding 110ml of 10% hydrochloric acid aqueous solution (3.2mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the hexadecyl diacid, wherein the yield is 72%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 5 to 7.
As can be seen from fig. 5:1H NMR(400MHz, DMSO) δ 11.97(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.44 (m,4H),1.24(s,20H), with chemical shift 2.50 being the deuterated DMSO solvent peak and chemical shift 3.33 being the water peak;
as can be seen from fig. 6:13c NMR (101MHz, DMSO) δ 174.96,34.11,29.52,29.49,29.41,29.24,29.03,24.96, with a 7-fold peak around a chemical shift of 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 7: the molecular weight of the compound is 286.41, ES-looks for a hydrogen reduction peak 285.23.
(4) Hexadecyl diacid and oxalyl chloride react to prepare 16-chloro-16-oxycetanoic acid, and 16-chloro-16-oxycetanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl hexadecyl diacid ester
The specific reaction process is as follows:
adding 3.5g (12mmol) of hexadecyl diacid into a reaction bottle, adding 70ml of tetrahydrofuran, stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 3g (24mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 hours; after the reaction is finished, the 16-chloro-16-oxycetanoic acid is directly obtained by rotary evaporation and concentration, and the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
And (3) quickly adding 4g (13mmol) of the product 16-chloro-16-oxohexadecanoic acid into a reaction bottle, then adding 1.9g (26mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, performing rotary evaporation to remove the solvent, adding dichloromethane, pulping, recovering the raw material, washing the filtrate with water, and performing rotary drying to obtain a crude product of the hexadecyl diacid mono-tert-butyl ester, wherein the yield is 75%, and the purity of the hexadecyl diacid mono-tert-butyl ester is 98.8% after column chromatography purification.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 8 to 10.
As can be seen from fig. 8:1h NMR (400MHz, DMSO) δ 11.97(s,1H),2.17(dd, J ═ 15.4,7.5Hz,4H),1.48(d, J ═ 2.6Hz,4H),1.39(s,9H),1.24(s,20H), where chemical shift 2.50 is deuteratedDMSO solvent peak, chemical shift 3.33 is water peak;
as can be seen from fig. 9:13c NMR (101MHz, DMSO) δ 174.94,172.73,79.75,35.22,34.11,29.50,29.47,29.41,29.40,29.33,29.12,29.03,28.82,28.20,25.07,24.96, wherein the 7-fold peak with chemical shift around 39.6 is the deuterated DMSO solvent peak;
as can be seen from fig. 10: the molecular weight of the compound is 342.51, ES-looks for a hydrogen reduction peak 341.29.
Example 3
Preparing hexadecyl diacid mono-tert-butyl ester by taking tetradecyl diacid as a raw material:
(1) condensation of tetradecyl diacid and isopropylidene malonate to prepare 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, respectively adding 20g (77mmol) of tetradecyl diacid, 11.7g (81mmol) of isopropylidene malonate and 400ml of dichloromethane into a reaction bottle, stirring, cooling to-2 to-6 ℃, adding 18.8g (153.8mmol) of 4-dimethylamino pyridine, reacting for 8 to 12min, then adding 12.5g (99mmol) of N, N' -diisopropyl carbodiimide, moving to room temperature, reacting for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, washing with purified water (200ml) once, washing with saturated saline water (200ml), and drying the organic phase with anhydrous sodium sulfate (20 g); the solvent was removed by rotary evaporation to give crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxan-5-enyl) -14-hydroxytetradecanoic acid, which was slurried with methyl tert-butyl ether (50ml) and was calculated to give a yield of 87%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIG. 1-2.
As can be seen from fig. 1:1h NMR (400MHz, CDCl3) δ 15.28(s,1H), 3.08-3.03 (m,2H), 1.75-1.66 (m,10H),1.27(d, J ═ 14.3Hz,14H),1.16(d, J ═ 6.5Hz,4H), with chemical shift 7.26 deuterated chloroformSolvent peaks, where no hydrogen is present on the carboxyl group at chemical shift around 11, peaks at chemical shift 0 for calibration, which are negligible, impurity peaks at chemistry 3.8 and 2.35, suspected of being uncondensed complete impurity intermediates or unreacted complete starting material peaks;
as can be seen from fig. 2: the molecular weight of the compound is 384.46, ES-looks for a hydrogen reduction peak 383.28.
(2) Preparation of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid by reduction of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 15g (39mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -14-hydroxytetradecanoic acid into a round-bottom flask under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 34.9g (576.8mol) of acetic acid, stirring, adding 7.17g (189.5mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline (150ml), and drying an organic phase by using anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 46% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 3 to 4.
As can be seen from fig. 3:1h NMR (400MHz, CDCl3) δ 3.49(t, J ═ 5.0Hz,1H), 2.16-2.04 (m,2H),1.75(dd, J ═ 18.9,8.4Hz,8H),1.44(dd, J ═ 10.2,5.7Hz,2H), 1.33-1.17 (m,20H), where chemical shift 7.26 is the deuterated chloroform solvent peak, chemical shift 0 peak is for calibration, negligible, chemical shift 11 or so hydrogen on the carboxyl group is not shown, chemical shift 15.3 peak is for hydrogen on the enol bond on the unreduced complete raw material, chemical shift is 15.3 peak, chemical shift is for hydrogen on the enol bond on the unreduced complete raw material, chemical shift is not shownShifts 3.1 and 3.8 are impurity peaks, which are suspected of being unreduced completely impurity intermediates or unreacted completely raw material peaks;
as can be seen from fig. 4: the molecular weight of the compound is 370.48, ES-looks for a hydrogen reduction peak 369.26.
(3) Preparation of hexadecyl diacid by acid condition hydrolysis of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid
The specific reaction process is as follows:
adding 4.4g (12mmol) of 14- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) tetradecanoic acid into a reaction bottle, adding 100ml of 22.3% hydrochloric acid aqueous solution (6.78mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the hexadecyl diacid, wherein the yield is 72%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 5 to 7.
As can be seen from fig. 5:1h NMR (400MHz, DMSO) δ 11.97(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.44 (m,4H),1.24(s,20H) with chemical shift 2.50 for the deuterated DMSO solvent peak and chemical shift 3.33 for the water peak;
as can be seen from fig. 6:13c NMR (101MHz, DMSO) δ 174.96,34.11,29.52,29.49,29.41,29.24,29.03,24.96, with a 7-fold peak around a chemical shift of 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 7: the molecular weight of the compound is 286.41, ES-looks for a hydrogen reduction peak 285.23.
(4) Hexadecyl diacid and oxalyl chloride react to prepare 16-chloro-16-oxycetanoic acid, and 16-chloro-16-oxycetanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl hexadecyl diacid ester
The specific reaction process is as follows:
adding 3.5g (12.4mmol) of hexadecyl diacid into a reaction bottle, adding 70ml of tetrahydrofuran, stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 4.67g (36.8mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 h; after the reaction is finished, the 16-chloro-16-oxycetanoic acid is directly obtained by rotary evaporation and concentration, and the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
Quickly adding 4g (13.1mmol) of 16-chloro-16-oxohexadecanoic acid into a reaction bottle, then adding 2.89g (39mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, carrying out rotary evaporation to remove a solvent, adding dichloromethane, pulping, recovering a raw material, washing a filtrate with water, carrying out rotary drying to obtain a crude product of the mono-tert-butyl hexadecyldiacid, wherein the yield is 75%, and purifying by column chromatography to obtain the mono-tert-butyl hexadecyldiacid with the purity of 98.6%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 8 to 10.
As can be seen from fig. 8:1h NMR (400MHz, DMSO) δ 11.97(s,1H),2.17(dd, J ═ 15.4,7.5Hz,4H),1.48(d, J ═ 2.6Hz,4H),1.39(s,9H),1.24(s,20H), with chemical shift 2.50 for the deuterated DMSO solvent peak and 3.33 for the water peak;
as can be seen from fig. 9:13c NMR (101MHz, DMSO) δ 174.94,172.73,79.75,35.22,34.11,29.50,29.47,29.41,29.40,29.33,29.12,29.03,28.82,28.20,25.07,24.96, wherein the 7-fold peak with chemical shift around 39.6 is the deuterated DMSO solvent peak;
as can be seen from fig. 10: the molecular weight of the compound is 342.51, ES-looks for a hydrogen reduction peak 341.29.
Example 4
Preparing octadecyl diacid mono-tert-butyl ester by taking hexadecyl diacid as a raw material:
(1) condensation of hexadecyl diacid and isopropylidene malonate to prepare 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, adding 20g (69.8mmol) of hexadecyl diacid and 10g (69.8mmol) of propylene malonate into a reaction bottle, adding dichloromethane (400ml), stirring, cooling to-2-6 ℃, adding 8.6g (70.4mmol) of 4-dimethylamino pyridine, reacting for 8-12 min, adding 8.9g (70.5mmol) of N, N' -diisopropylcarbodiimide, moving to room temperature, reacting for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, washing with purified water (200ml) once, washing with saturated saline water (200ml), and drying the organic phase with anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid; the crude product was slurried with methyl tert-butyl ether (50ml) to give the product in 79% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 11 to 12.
As can be seen from fig. 11:1h NMR (400MHz, CDCl3) δ 15.29(s,1H),3.83(dt, J ═ 12.8,6.4Hz,2H),3.11 to 3.01(m,2H),1.75 to 1.67(m,8H),1.37 to 1.04(m,22H), where chemical shift 7.26 is a deuterated chloroform solvent peak, no hydrogen is shown on the carboxyl group at chemical shift around 11, and a peak at chemical shift 0 is used for calibration;
as can be seen from fig. 12: the molecular weight of the compound is 412.52, ES-looks for a hydrogen reduction peak 411.27.
(2) Preparation of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid by reduction of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid
The specific reaction process is as follows:
adding 15g (36.4mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid into a reaction bottle under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 17.6g (290mmol) of acetic acid, stirring, adding 1.5g (39.6mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline (150ml), and drying by using anhydrous sodium sulfate (20g) for an organic phase; removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 40% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 13 to 14.
As can be seen from fig. 13:1h NMR (400MHz, CDCl3) δ 3.56-3.40 (m,1H), 2.12-2.01 (m,2H), 1.82-1.54 (m,10H), 1.51-1.34 (m,4H),1.21(s,20H), where chemical shift 7.26 is a deuterated chloroform solvent peak, hydrogen on carboxyl group with chemical shift around 11 is not shown, peak with chemical shift 0 is for calibration, peak with chemical shift 15.29 is hydrogen on enol bond on raw material that is not completely reduced, chemical shifts 3.1 and 5.3 are impurity peaks, suspected of being an impurity intermediate that is not completely condensed or a raw material that is not completely reacted;
as can be seen from fig. 14: the molecular weight of the compound is 398.53, and ES-looks for a hydrogen reduction peak 397.31.
(3) Preparation of octadecyl diacid by 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxa-5-) hexadecanoic acid condition hydrolysis
The specific reaction process is as follows:
adding 4.4g (11.1mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid into a reaction bottle, adding 100ml of 4.4% hydrochloric acid aqueous solution (1.23mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the octadecyl diacid with the yield of 70%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 15 to 17.
As can be seen from fig. 15:1h NMR (400MHz, DMSO) δ 11.96(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.43 (m,4H),1.23(s,24H) with chemical shift 2.50 for the deuterated DMSO solvent peak and chemical shift 3.33 for the water peak;
as can be seen from fig. 16:13c NMR (101MHz, DMSO) δ 174.32,33.46,28.84,28.80,28.72,28.55,28.35,24.30, with a 7-fold peak around chemical shift 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 17: the molecular weight of the compound is 314.46, ES-looks for a hydrogen reduction peak 313.13.
(4) Octadecyl diacid and oxalyl chloride react to prepare 18-chloro-18-oxooctadecanoic acid, 18-chloro-18-oxooctadecanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl ester of octadecyl diacid
The specific reaction process is as follows:
adding 3.5g (11.2mmol) of octadecyl diacid into a reaction bottle, adding tetrahydrofuran (70ml), stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 1.5g (11.8mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 h; directly carrying out rotary evaporation and concentration after the reaction is finished to obtain the 18-chloro-18-oxooctadecanoic acid, wherein the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
Quickly adding 4g (12mmol) of 18-chloro-18-oxooctadecanoic acid into a reaction bottle, then adding 0.9g (12.1mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, performing rotary evaporation to remove the solvent, adding dichloromethane, pulping, recovering the raw materials, washing the filtrate with water, performing rotary drying to obtain a crude product of the mono-tert-butyl octadecyl diacid, wherein the yield is 70%, and performing column chromatography purification to obtain the mono-tert-butyl octadecyl diacid with the purity of 98.8%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1H NMR spectrum and13the C NMR spectrum is as shown in the figure18-19.
As can be seen from fig. 18:1h NMR (400MHz, DMSO) δ 2.20-2.13 (m,4H),1.47(s,4H),1.38(s,9H),1.23(s,24H), with chemical shift 2.50 as the deuterated DMSO solvent peak; the chemical shift 3.33 is a water peak, and the chemical shift of the water peak is slightly shifted, and hydrogen on the carboxyl group having a chemical shift of about 11 is not shown.
As can be seen from fig. 19:13c NMR (101MHz, DMSO) δ 174.96,172.72,79.74,35.22,34.15,29.51,29.47,29.40,29.33,29.24,29.11,29.04,28.82,28.20,25.06,24.98, with the 7-fold peak around chemical shift 39.6 being the deuterated DMSO solvent peak.
Example 5
Preparing octadecyl diacid mono-tert-butyl ester by taking hexadecyl diacid as a raw material:
(1) condensation of hexadecyl diacid and isopropylidene malonate to prepare 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, adding 20g (69.8mmol) of hexadecyl diacid and 11g (76.8mmol) of isopropylidene malonate into a reaction bottle, adding 400ml of dichloromethane, stirring, cooling to-2-6 ℃, adding 12.7g (104mmol) of 4-dimethylaminopyridine, reacting for 8-12 min, adding 9.6g (76.8mmol) of N, N' -diisopropylcarbodiimide, moving to room temperature for reaction for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, washing once with purified water (200ml), washing with saturated saline water (200ml), and drying an organic phase with anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid; the crude product was slurried with methyl tert-butyl ether (50ml) to give the product in 80% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 11 to 12.
From FIG. 11, the following steps:1h NMR (400MHz, CDCl3) δ 15.29(s,1H),3.83(dt, J ═ 12.8,6.4Hz,2H),3.11 to 3.01(m,2H),1.75 to 1.67(m,8H),1.37 to 1.04(m,22H), where chemical shift 7.26 is a deuterated chloroform solvent peak, no hydrogen is shown on the carboxyl group at chemical shift around 11, and a peak at chemical shift 0 is used for calibration;
as can be seen from fig. 12: the molecular weight of the compound is 412.52, ES-looks for a hydrogen reduction peak 411.27.
(2) Preparation of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid by reduction of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid
The specific reaction process is as follows:
adding 15g (36.4mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid into a reaction bottle under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 22g (364mmol) of acetic acid, stirring, adding 4.1g (109mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline water (150ml), and drying an organic phase by using anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 40% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 13 to 14.
As can be seen from fig. 13:1h NMR (400MHz, CDCl3) delta 3.56-3.40 (m,1H), 2.12-2.01 (m,2H), 1.82-1.54 (m,10H), 1.51-1.34 (m,4H),1.21(s,20H), wherein chemical shift 7.26 is a deuterated chloroform solvent peak, hydrogen on carboxyl group with chemical shift of about 11 is not shown, peak with chemical shift 0 is for calibration, peak with chemical shift 15.29 is a raw material which is not completely reducedHydrogen on the enol bond, chemical shifts of 3.1 and 5.3 are impurity peaks suspected of being an impurity intermediate which is not completely condensed or a raw material peak which is not completely reacted;
as can be seen from fig. 14: the molecular weight of the compound is 398.53, and ES-looks for a hydrogen reduction peak 397.31.
(3) Preparation of octadecyl diacid by 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxa-5-) hexadecanoic acid condition hydrolysis
The specific reaction process is as follows:
adding 4.4g (11.1mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid into a reaction bottle, adding 110ml of 10% hydrochloric acid aqueous solution (3.2mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the octadecyl diacid with the yield of 71 percent.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 15 to 17.
As can be seen from fig. 15:1h NMR (400MHz, DMSO) δ 11.96(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.43 (m,4H),1.23(s,24H) with chemical shift 2.50 for the deuterated DMSO solvent peak and chemical shift 3.33 for the water peak;
as can be seen from fig. 16:13c NMR (101MHz, DMSO) δ 174.32,33.46,28.84,28.80,28.72,28.55,28.35,24.30, with a 7-fold peak around chemical shift 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 17: the molecular weight of the compound is 314.46, ES-looks for a hydrogen reduction peak 313.13.
(4) Octadecyl diacid and oxalyl chloride react to prepare 18-chloro-18-oxooctadecanoic acid, 18-chloro-18-oxooctadecanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl ester of octadecyl diacid
The specific reaction process is as follows:
adding 3.5g (11.2mmol) of octadecyl diacid into a reaction bottle, adding tetrahydrofuran (70ml), stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 2.8g (22.4mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 h; directly carrying out rotary evaporation and concentration after the reaction is finished to obtain the 18-chloro-18-oxooctadecanoic acid, wherein the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
Quickly adding 4g (12mmol) of 18-chloro-18-oxooctadecanoic acid into a reaction bottle, then adding 1.7g (24mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, performing rotary evaporation to remove the solvent, adding dichloromethane, pulping, recovering the raw materials, washing the filtrate with water, and performing rotary drying to obtain a crude product of the octadecyl diacid mono-tert-butyl ester, wherein the yield is 72%, and purifying by column chromatography to obtain the octadecyl diacid mono-tert-butyl ester with the purity of 99%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1H NMR spectrum and13the C NMR spectrum is shown in FIGS. 18 to 19.
As can be seen from fig. 18:1h NMR (400MHz, DMSO) δ 2.20-2.13 (m,4H),1.47(s,4H),1.38(s,9H),1.23(s,24H), with chemical shift 2.50 as the deuterated DMSO solvent peak; the chemical shift 3.33 is a water peak, and the chemical shift of the water peak is slightly shifted, and hydrogen on the carboxyl group having a chemical shift of about 11 is not shown.
As can be seen from fig. 19:13c NMR (101MHz, DMSO) δ 174.96,172.72,79.74,35.22,34.15,29.51,29.47,29.40,29.33,29.24,29.11,29.04,28.82,28.20,25.06,24.98, with the 7-fold peak around chemical shift 39.6 being the deuterated DMSO solvent peak.
Example 6
Preparing octadecyl diacid mono-tert-butyl ester by taking hexadecyl diacid as a raw material:
(1) condensation of hexadecyl diacid and isopropylidene malonate to prepare 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid
The specific reaction process is as follows:
under the protection of nitrogen, adding 20g (69.8mmol) of hexadecyl diacid and 13.1g (90.7mmol) of isopropylidene malonate into a reaction bottle, adding 400ml of dichloromethane, stirring, cooling to-2-6 ℃, adding 17g (139mmol) of 4-dimethylaminopyridine, reacting for 8-12 min, adding 11.4g (90.7mmol) of N, N' -diisopropylcarbodiimide, moving to room temperature for reaction for 12h, extracting the post-treatment with 10% citric acid aqueous solution (200ml) twice, washing once with purified water (200ml), washing with saturated saline water (200ml), and drying an organic phase with anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid; pulping the crude product with methyl tert-butyl ether (50ml) to obtain product with yield of 80%, and subjecting the prepared product to nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 11 to 12.
As can be seen from fig. 11:1h NMR (400MHz, CDCl3) δ 15.29(s,1H),3.83(dt, J ═ 12.8,6.4Hz,2H),3.11 to 3.01(m,2H),1.75 to 1.67(m,8H),1.37 to 1.04(m,22H), where chemical shift 7.26 is a deuterated chloroform solvent peak, no hydrogen is shown on the carboxyl group at chemical shift around 11, and a peak at chemical shift 0 is used for calibration;
as can be seen from fig. 12: the molecular weight of the compound is 412.52, ES-looks for a hydrogen reduction peak 411.27.
(2) Preparation of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid by reduction of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid
The specific reaction process is as follows:
adding 15g (36mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-alkenyl) -16-hydroxyhexadecanoic acid into a round-bottom flask under the protection of nitrogen, adding dichloromethane, stirring for dissolving, cooling to 2-0 ℃, adding 32.5g (537mmol) of acetic acid, stirring, adding 6.8g (179mmol) of sodium borohydride, continuing to react for 2-3 h, extracting the reaction solution twice by using saturated sodium bicarbonate (150ml), washing once by using purified water (150ml), washing by using saturated saline water (150ml), and drying an organic phase by using anhydrous sodium sulfate (20 g); removing the solvent by rotary evaporation to obtain crude 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid; the crude product was slurried with methyl tert-butyl ether (35ml) to give the product in 40% yield.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1The H NMR spectrum and the mass spectrum are shown in FIGS. 13 to 14.
As can be seen from fig. 13:1h NMR (400MHz, CDCl3) δ 3.56-3.40 (m,1H), 2.12-2.01 (m,2H), 1.82-1.54 (m,10H), 1.51-1.34 (m,4H),1.21(s,20H), where chemical shift 7.26 is a deuterated chloroform solvent peak, hydrogen on carboxyl group with chemical shift around 11 is not shown, peak with chemical shift 0 is for calibration, peak with chemical shift 15.29 is hydrogen on enol bond on raw material that is not completely reduced, chemical shifts 3.1 and 5.3 are impurity peaks, suspected of being an impurity intermediate that is not completely condensed or a raw material that is not completely reacted;
as can be seen from fig. 14: the molecular weight of the compound is 398.53, and ES-looks for a hydrogen reduction peak 397.31.
(3) Preparation of octadecyl diacid by 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxa-5-) hexadecanoic acid condition hydrolysis
The specific reaction process is as follows:
adding 4.4g (11.1mmol) of 16- (2, 2-dimethyl-4, 6-dioxy-1, 3-dioxanyl-5-) hexadecanoic acid into a reaction bottle, adding 100ml of 22.3% hydrochloric acid aqueous solution (6.78mol/L), and heating and refluxing at 90-110 ℃ for 8-12 h; cooling to separate out a large amount of white solid, washing with purified water to be neutral, and top washing with dichloromethane to obtain the octadecyl diacid with the yield of 70%.
Taking the above prepared products, and respectively carrying out nucleationMagnetic resonance and mass spectrometry; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 15 to 17.
As can be seen from fig. 15:1h NMR (400MHz, DMSO) δ 11.96(s,2H),2.18(t, J ═ 7.4Hz,4H), 1.51-1.43 (m,4H),1.23(s,24H) with chemical shift 2.50 for the deuterated DMSO solvent peak and chemical shift 3.33 for the water peak;
as can be seen from fig. 16:13c NMR (101MHz, DMSO) δ 174.32,33.46,28.84,28.80,28.72,28.55,28.35,24.30, with a 7-fold peak around chemical shift 39.6 as the deuterated DMSO solvent peak;
as can be seen from fig. 17: the molecular weight of the compound is 314.46, ES-looks for a hydrogen reduction peak 313.13.
(4) Octadecyl diacid and oxalyl chloride react to prepare 18-chloro-18-oxooctadecanoic acid, 18-chloro-18-oxooctadecanoic acid and tert-butyl alcohol react to prepare mono-tert-butyl ester of octadecyl diacid
The specific reaction process is as follows:
adding 3.5g (11.2mmol) of octadecyl diacid into a reaction bottle, adding tetrahydrofuran (70ml), stirring for dissolving, cooling to-5-0 ℃, adding 2 drops of DMF, adding 4.2g (33mmol) of oxalyl chloride, and moving to room temperature for reaction for 2-3 h; directly carrying out rotary evaporation and concentration after the reaction is finished to obtain the 18-chloro-18-oxooctadecanoic acid, wherein the product is unstable at normal temperature and needs to be put into the next reaction as soon as possible.
Quickly adding 4g (12mmol) of 18-chloro-18-oxooctadecanoic acid into a reaction bottle, then adding 2.6g (35.9mmol) of tert-butyl alcohol and 17.75ml of dichloromethane, reacting for 8-12 h, performing rotary evaporation to remove the solvent, adding dichloromethane, pulping, recovering the raw materials, washing the filtrate with water, performing rotary drying to obtain a crude product of the mono-tert-butyl octadecyl diacid, wherein the yield is 70%, and performing column chromatography purification to obtain a product with the purity of 98.8%.
Taking the prepared product to perform nuclear magnetic resonance and mass spectrometry respectively, wherein1H NMR spectrum and13the C NMR spectrum is shown in FIGS. 18 to 19.
As can be seen from fig. 18:1h NMR (400MHz, DMSO) δ 2.20-2.13 (m,4H),1.47(s,4H),1.38(s,9H),1.23(s,24H), with chemical shift 2.50 as the deuterated DMSO solvent peak; the chemical shift 3.33 is a water peak, and the chemical shift of the water peak is slightly shifted, and hydrogen on the carboxyl group having a chemical shift of about 11 is not shown.
As can be seen from fig. 19:13c NMR (101MHz, DMSO) δ 174.96,172.72,79.74,35.22,34.15,29.51,29.47,29.40,29.33,29.24,29.11,29.04,28.82,28.20,25.06,24.98, with the 7-fold peak around chemical shift 39.6 being the deuterated DMSO solvent peak.
When the long-chain alkyl diacid mono-tert-butyl ester is prepared by the method, the larger the value of n is, the easier the reaction is to realize theoretically.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
Claims (18)
1. The preparation method of the long-chain alkyl diacid mono-tert-butyl ester is characterized by comprising the following steps:
reacting the long-chain alkyl diacid shown as A with oxalyl chloride to obtain monoacyl chloride shown as B, and reacting the monoacyl chloride shown as B with tert-butyl alcohol to generate long-chain alkyl diacid mono-tert-butyl ester shown as C; wherein n is an integer of 0 or more in the following reaction equation;
2. the method for preparing long-chain alkyl diacid mono-tert-butyl ester according to claim 1, characterized by comprising the following steps:
(1) adding tetrahydrofuran solvent into the A for dissolving, cooling to-5-0 ℃, adding DMF, adding oxalyl chloride, reacting for 1-2 hours at room temperature, and performing rotary evaporation and concentration to obtain B;
(2) and mixing the B and tert-butyl alcohol, adding dichloromethane for dissolving, reacting for 8-16 hours at room temperature, performing rotary evaporation to remove the solvent, pulping to recover the raw materials, washing the filtrate with water, performing rotary drying, and performing column chromatography purification to obtain the C.
3. The process for the preparation of mono-tert-butyl ester of long-chain alkyl diacid according to claim 2, characterized in that in step (1), the molar ratio of a to oxalyl chloride is 1: 1 to 3.
4. The method for preparing mono-tert-butyl ester of long-chain alkyl diacid according to claim 2, wherein in step (2), the molar ratio of B to tert-butanol is 1: 1 to 3.
5. The method of claim 1, further comprising the steps of:
hydrolyzing the heterocycle-containing alkanoic acid shown as D under an acidic condition to prepare the long-chain alkyl diacid shown as A, wherein n in the following equation is an integer which is more than or equal to 0;
6. the method for preparing mono-tert-butyl long-chain alkyl diacid according to claim 5, wherein the process for preparing A from D comprises the following steps:
and D, adding an acid solution, heating to 90-120 ℃, refluxing, reacting for 10-15 hours, cooling to separate out a solid, filtering, top washing and drying to obtain A.
7. The method of claim 6, wherein the acidic solution is hydrochloric acid with a concentration of 1mol/L to 7mol/L in the step of preparing A.
8. The method of claim 5, further comprising the steps of:
reacting the substance shown as E in the presence of sodium borohydride to prepare the heterocyclic alkanoic acid shown as D, wherein in the following equation, n is an integer greater than or equal to 0;
9. the method of claim 8, wherein the step of reacting E to form D comprises the steps of:
and E, adding dichloromethane for dissolving, cooling to-5 ℃, adding acetic acid for stirring, adding sodium borohydride for reacting for 1-2 hours, extracting twice with a saturated sodium bicarbonate solution, washing with purified water, then with saturated salt solution, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain D.
10. The method of claim 9, wherein in the step of preparing D from E, the molar ratio of E to acetic acid is 1: 8-15.
11. The method for preparing mono-tert-butyl long-chain alkyl diacid according to claim 9, wherein in the step of preparing D from E, the molar ratio of E to sodium borohydride is 1: 1 to 5.
12. The method of claim 8, wherein the method further comprises the steps of:
condensing the long-chain alkyl diacid and isopropylidene malonate as shown in B' to prepare a substance shown in E, wherein n is an integer which is more than or equal to 0 in the following equation;
13. the method of claim 12, wherein the step of preparing C from a' and F comprises:
and mixing A 'and F, adding dichloromethane for dissolving, cooling to-10-0 ℃ under the protection of inert gas, sequentially adding a catalyst 4-dimethylaminopyridine and a condensing agent N, N' -diisopropylcarbodiimide, reacting for 8-16 hours, extracting twice with a citric acid aqueous solution, washing with purified water, washing with saturated salt water, drying with anhydrous sodium sulfate, and pulping with methyl tert-butyl ether as a solvent to obtain E.
14. The method of claim 13, wherein in the step of reacting a 'with F to produce C, the molar ratio of a' to F is 1: 1 to 1.3.
15. The method of claim 13, wherein in the step of reacting a ' with F to produce C, the molar ratio of a ' to N, N ' -diisopropylcarbodiimide is 1: 1 to 1.3.
16. The method of claim 13, wherein in the step of reacting a 'with F to produce C, the molar ratio of a' to 4-dimethylaminopyridine is 1: 1 to 2.
17. The method for producing mono-tert-butyl ester of a long-chain alkyl diacid as claimed in claim 1 or 5 or 8 or 12, characterized in that n in the equation is an integer of 6 or more.
18. The method of claim 17, wherein n is 6 or 7.
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| CN113603588A (en) * | 2021-09-14 | 2021-11-05 | 郑州猫眼农业科技有限公司 | Refining method of mono-tert-butyl glutarate |
| CN113773200A (en) * | 2021-09-14 | 2021-12-10 | 郑州猫眼农业科技有限公司 | Preparation method of mono-tert-butyl glutarate |
| CN115368234A (en) * | 2022-08-19 | 2022-11-22 | 淄博矿业集团有限责任公司 | Synthesis method of important intermediate of Somaloutide side chain |
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| CN115368234A (en) * | 2022-08-19 | 2022-11-22 | 淄博矿业集团有限责任公司 | Synthesis method of important intermediate of Somaloutide side chain |
| CN115368234B (en) * | 2022-08-19 | 2024-01-26 | 淄博矿业集团有限责任公司 | Synthetic method of cable Ma Lutai side chain and intermediate thereof |
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