CN117263796A - Preparation method of mono-tert-butyl octadecanedioate - Google Patents
Preparation method of mono-tert-butyl octadecanedioate Download PDFInfo
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- CN117263796A CN117263796A CN202311233631.3A CN202311233631A CN117263796A CN 117263796 A CN117263796 A CN 117263796A CN 202311233631 A CN202311233631 A CN 202311233631A CN 117263796 A CN117263796 A CN 117263796A
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- octadecanedioic
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- WDUQJXKBWRNMKI-UHFFFAOYSA-N 18-[(2-methylpropan-2-yl)oxy]-18-oxooctadecanoic acid Chemical compound CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(O)=O WDUQJXKBWRNMKI-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- YVSRVPPXZJZGBX-UHFFFAOYSA-N oxacyclononadecane-2,19-dione Chemical compound O=C1CCCCCCCCCCCCCCCCC(=O)O1 YVSRVPPXZJZGBX-UHFFFAOYSA-N 0.000 claims abstract description 45
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 37
- BNJOQKFENDDGSC-UHFFFAOYSA-N octadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCC(O)=O BNJOQKFENDDGSC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 230000018044 dehydration Effects 0.000 claims description 11
- 238000006297 dehydration reaction Methods 0.000 claims description 11
- 150000007530 organic bases Chemical class 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims 9
- 238000000746 purification Methods 0.000 abstract description 10
- 238000000926 separation method Methods 0.000 abstract description 8
- 125000004122 cyclic group Chemical group 0.000 abstract description 7
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LCZVKKUAUWQDPX-UHFFFAOYSA-N tert-butyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate Chemical compound CC(=O)OC1=CC=CC=C1CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1=CC=CC=C1OC(C)=O LCZVKKUAUWQDPX-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of mono-tert-butyl octadecanedioate, which comprises the following steps: s1, enabling octadecanedioic acid to undergo a cyclization reaction to generate octadecanedioic anhydride; s2, enabling the octadecanedioic anhydride to react with tertiary butanol to generate the octadecanedioic anhydride mono-tertiary butyl ester. According to the preparation method of the embodiment of the invention, the cyclic octadecanedioic acid mono-tert-butyl ester can be prepared with high selectivity and high yield by preparing the cyclic octadecanedioic anhydride (II) and reacting the cyclic octadecanedioic acid mono-tert-butyl ester with tert-butyl alcohol; in addition, the synthetic route only needs two steps, and has short reaction route, simple operation and short reaction time; in addition, the separation and purification are simple, the column passing is not needed, and the recrystallization is only needed.
Description
Technical Field
The invention belongs to the technical field of compound preparation, and particularly relates to a preparation method of mono-tert-butyl octadecanedioate.
Background
Cord Ma Lutai is a novel long-acting glucagon-like peptide-1 (GLP-1) analogue, cord Ma Lutai is the first and only oral glucagon-like peptide-1 receptor agonist drug worldwide, and cord Ma Lutai tablets have been approved by the United states FDA for improving the glycemic control of adult patients with type 2 diabetes, and are novel hypoglycemic and slimming drugs. The mono-tert-butyl octadecanedioate is a key raw material for synthesizing the novel hypoglycemic and slimming medicine cable Ma Lutai, and the chemical structural formula is shown as the following formula (1):
related literature reports exist on the synthesis of mono-tert-butyl octadecanedioate, wherein in the main synthetic routes, octadecanedioic acid is firstly prepared into acyl chloride and then reacts with tert-butanol; some reaction routes are to react octadecanedioic acid with N, N-dimethylformamide di-tert-butyl acetal to directly convert one of the carboxylic acids into tert-butyl ester; there are routes to prepare the octadecanedioic acid into di-tert-butyl ester, and then selectively hydrolyze one of the tert-butyl esters to obtain the octadecanedioic acid mono-tert-butyl ester. Although the synthetic routes are more, the existing routes have the problems of poor selectivity and difficult separation and purification, so that the production cost of the mono-tert-butyl octadecanedioate is high.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of octadecanedioic acid mono-tert-butyl ester, which has good selectivity, simple separation and purification and simple operation and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the mono-tert-butyl octadecanedioate provided by the embodiment of the invention comprises the following steps:
s1, enabling octadecanedioic acid to undergo a cyclization reaction to generate octadecanedioic anhydride;
s2, enabling the octadecanedioic anhydride to react with tertiary butanol to generate the octadecanedioic anhydride mono-tertiary butyl ester.
Further, the cyclization reaction of step S1 is performed in the presence of a dehydration reagent in a first solvent.
Further, the first solvent comprises any one or more of dichloromethane, toluene, chloroform and 2-methyltetrahydrofuran; the dehydration reagent comprises any one or more of N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCL).
Further, in the step S1, the molar ratio of the octadecanedioic acid to the dehydration reagent is 1 (1.1-1.3), the reaction temperature is 0-50 ℃, and the reaction time is 2-15h.
Further, the step S1 further includes: after the cyclization reaction is finished, insoluble substances are removed by suction filtration, clear water is added for washing, an organic layer is separated, the organic layer is dried and evaporated, and then the organic layer is recrystallized by ethyl acetate to obtain the octadecanedioic anhydride.
Further, the step S2 includes:
reacting the octadecanedioic anhydride with the tert-butyl alcohol in a second solvent in the presence of an organic base to produce the octadecanedioic anhydride mono-tert-butyl ester.
Further, the second solvent comprises any one or more of dichloromethane, toluene, chloroform and 2-methyltetrahydrofuran; the organic base comprises any one or more of triethylamine, pyridine and N, N-diisopropylethylamine.
Further, the octadecanedioic anhydride: organic base: the molar ratio of the tertiary butanol is 1: (1.2-1.5): (1.1-2.0).
Further, the reaction temperature in the step S2 is 40-100 ℃, and the reaction time is 10-20h.
Further, the step S2 further includes: after the reaction is finished, adding dilute hydrochloric acid to adjust the pH to 1-2, separating out an organic layer, drying, evaporating to dryness, and recrystallizing with ethyl acetate to obtain the octadecanedioic acid mono-tert-butyl ester.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method of the embodiment of the invention, the cyclic octadecanedioic acid mono-tert-butyl ester can be prepared with high selectivity and high yield by preparing the cyclic octadecanedioic anhydride (II) and reacting the cyclic octadecanedioic acid mono-tert-butyl ester with tert-butyl alcohol;
in addition, the synthetic route only needs two steps, and has short reaction route, simple operation and short reaction time;
in addition, the separation and purification are simple, the column passing is not needed, and the recrystallization is only needed.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The preparation method of the mono-tert-butyl octadecanedioate according to the embodiment of the invention is first described in detail.
The preparation method of the rush hour embodiment comprises the following steps:
s1, enabling octadecanedioic acid to undergo a cyclization reaction to generate octadecanedioic anhydride;
s2, enabling the octadecanedioic anhydride to react with tertiary butanol to generate the octadecanedioic anhydride mono-tertiary butyl ester.
Specifically, the synthetic route is represented by the following formula (2):
that is, according to the production method of the present application, mono-tert-butyl octadecanedioate can be produced with high selectivity and high yield by producing cyclic octadecanedioic anhydride (II) and reacting it with tert-butanol; in addition, the synthetic route only needs two steps, and has short reaction route, simple operation and short reaction time; in addition, the separation and purification are simple, the column passing is not needed, and the recrystallization is only needed. The steps S1 and S2 are described in detail below.
First, in step S1, a ring-closure reaction of octadecanedioic acid is performed to produce octadecanedioic anhydride.
In some embodiments of the invention, the cyclization reaction of step S1 is performed in a first solvent in the presence of a dehydration reagent. The progress of the cyclization reaction can be promoted by using a dehydration reagent in a liquid state.
In some embodiments of the invention, the first solvent comprises any one or more of dichloromethane, toluene, chloroform, 2-methyltetrahydrofuran; the dehydration reagent comprises any one or more of N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCL). These solvents can well dissolve octadecanedioic acid as a starting material, and these dehydration reagents can remove hydrogen at the terminal of octadecanedioic acid, promoting the progress of the cyclization reaction.
Further, in the step S1, the molar ratio of the octadecanedioic acid to the dehydration reagent is 1 (1.1-1.3), the reaction temperature is 0-50 ℃, and the reaction time is 2-15h. That is, the use of a slight excess of the dehydrating reagent is advantageous in improving the yield.
Further, the step S1 further includes: after the cyclization reaction is finished, insoluble substances are removed by suction filtration, clear water is added for washing, an organic layer is separated, the organic layer is dried and evaporated, and then the organic layer is recrystallized by ethyl acetate to obtain the octadecanedioic anhydride. According to the preparation method, the separation and purification of the intermediate are also simple, and column purification is not needed.
Next, step S2 is described, and in step S2, the octadecanedioic anhydride is reacted with t-butanol to produce octadecanedioic anhydride mono-t-butyl ester.
Further, the step S2 includes:
reacting the octadecanedioic anhydride with the tert-butyl alcohol in a second solvent in the presence of an organic base to produce the octadecanedioic anhydride mono-tert-butyl ester. As is clear from the above formula (2), the presence of an organic base as an acid-binding agent is advantageous in promoting the progress of the reaction.
Further, the second solvent comprises any one or more of dichloromethane, toluene, chloroform and 2-methyltetrahydrofuran; the organic base comprises any one or more of triethylamine, pyridine and N, N-diisopropylethylamine. Octadecanedioic anhydride and tert-butanol can be well dissolved in the solvents, and organic alkali can be well dissolved in the solvents.
Further, the octadecanedioic anhydride: organic base: the molar ratio of the tertiary butanol is 1: (1.2-1.5): (1.1-2.0). The slightly excessive organic alkali and tertiary butanol are beneficial to improving the reaction rate, promoting the reaction and improving the yield.
Further, the reaction temperature in the step S2 is 40-100 ℃, and the reaction time is 10-20h.
Further, the step S2 further includes: after the reaction is finished, adding dilute hydrochloric acid to adjust the pH to 1-2, separating out an organic layer, drying, evaporating to dryness, and recrystallizing with ethyl acetate to obtain the octadecanedioic acid mono-tert-butyl ester. Therefore, the separation and purification of the target product are also simple, and column purification is not needed.
The preparation method according to the present invention is described in further detail below with reference to specific examples.
Preparation of (one) octadecanedioic anhydride (II)
Example 1
In a 2L round bottom flask, 100g (1.0 eq.) of octadecanedioic acid (I) and 500mL of dichloromethane were added under nitrogen and the temperature was controlled to 25℃and 72.2g (1.1 eq.) of N, N' -Dicyclohexylcarbodiimide (DCC) were added in portions and stirred for 12h.
After the reaction, insoluble matters are removed by suction filtration, 300mL of clear water is added for washing, drying and evaporating are carried out, and ethyl acetate is used for recrystallization, thus 68.8g of octadecanedioic anhydride (II) is obtained, and the yield is 73%.
Example 2
In a 2L round bottom flask, 120g (1.0 eq.) of octadecanedioic acid (I) and 580mL of methylene chloride were added under nitrogen and the temperature was controlled to 20℃and 62.6g (1.3 eq.) of N, N' -Diisopropylcarbodiimide (DIC) was added in portions and stirred for 8h.
After the reaction, insoluble matters are removed by suction filtration, 400mL of clear water is added for washing, drying and evaporating are carried out, and 69.0g of octadecanedioic anhydride (II) is obtained by recrystalization with ethyl acetate, and the yield is 61%.
Example 3
86g (1.0 eq.) of octadecanedioic acid (I) and 400mL of chloroform were added under nitrogen to a 1L round bottom flask, the temperature was controlled to 50℃and 68.1g (1.3 eq.) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCL) were added in portions and stirred for 15h.
After the reaction, insoluble matters are removed by suction filtration, 400mL of clear water is added for washing, drying and evaporating are carried out, and the mixture is recrystallized by ethyl acetate to obtain 54.3g of octadecanedioic anhydride (II) with the yield of 67 percent.
Preparation of mono-tert-butyl (di) octadecanedioate (III)
Example 4
In a 2L round bottom flask, 100g (1.0 eq.) of octadecanedioic anhydride (II), 1.0L of dichloromethane, 44.4g (1.3 eq.) of triethylamine, 37.5g (1.5 eq.) of t-butanol are added under nitrogen protection and the temperature is raised to 40℃and the reaction time is 20h. Cooling, adding dilute hydrochloric acid to adjust the pH value to 1-2, separating out an organic layer, drying, evaporating to dryness, recrystallizing with ethyl acetate to obtain 105g of octadecanedioic acid mono-tert-butyl ester (III), and the yield is 84%.
Example 5
In a 2L round bottom flask, 100g (1.0 eq.) of octadecanedioic anhydride (II), 1.0L of toluene, 40.0g (1.5 eq.) of pyridine, 37.5g (1.5 eq.) of t-butanol are added under nitrogen protection, the temperature is raised to 60℃and the reaction time is 10h. Cooling, adding dilute hydrochloric acid to adjust pH to 1-2, separating out an organic layer, drying, evaporating to dryness, recrystallizing with ethyl acetate to obtain 97.5g of octadecanedioic acid mono-tert-butyl ester (III), and obtaining 78% yield.
Example 6
In a 2L round bottom flask, 74g (1.0 eq.) of octadecanedioic anhydride (II), 530mL of chloroform, 38.7g (1.2 eq.) of N, N-diisopropylethylamine, 37g (2 eq.) of t-butanol were added under nitrogen protection and the reaction time was 20h at 60 ℃. Cooling, adding dilute hydrochloric acid to adjust pH to 1-2, separating out an organic layer, drying, evaporating to dryness, recrystallizing with ethyl acetate to obtain 81.4g of octadecanedioic acid mono-tert-butyl ester (III), and obtaining 88% yield.
In summary, the preparation method provided by the invention has the advantages of high selectivity, simplicity in separation and purification, and total yield of the two steps reaching more than 50%. The preparation method has the advantages of short synthetic route, simple and convenient operation, low cost and high yield.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of the mono-tert-butyl octadecanedioate is characterized by comprising the following steps of:
s1, enabling octadecanedioic acid to undergo a cyclization reaction to generate octadecanedioic anhydride;
s2, enabling the octadecanedioic anhydride to react with tertiary butanol to generate the octadecanedioic anhydride mono-tertiary butyl ester.
2. The method according to claim 1, wherein the cyclization reaction of step S1 is performed in a first solvent in the presence of a dehydration reagent.
3. The method of claim 2, wherein the first solvent comprises any one or more of dichloromethane, toluene, chloroform, 2-methyltetrahydrofuran; the dehydration reagent comprises any one or more of N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCL).
4. The method according to claim 3, wherein in the step S1, the molar ratio of the octadecanedioic acid to the dehydration reagent is 1 (1.1-1.3), the reaction temperature is 0-50 ℃ and the reaction time is 2-15h.
5. The method according to claim 2, wherein the step S1 further comprises: after the cyclization reaction is finished, insoluble substances are removed by suction filtration, clear water is added for washing, an organic layer is separated, the organic layer is dried and evaporated, and then the organic layer is recrystallized by ethyl acetate to obtain the octadecanedioic anhydride.
6. The method according to claim 1, wherein the step S2 comprises:
reacting the octadecanedioic anhydride with the tert-butyl alcohol in a second solvent in the presence of an organic base to produce the octadecanedioic anhydride mono-tert-butyl ester.
7. The method of claim 6, wherein the second solvent comprises any one or more of dichloromethane, toluene, chloroform, 2-methyltetrahydrofuran; the organic base comprises any one or more of triethylamine, pyridine and N, N-diisopropylethylamine.
8. The method of claim 7, wherein the octadecanedioic anhydride: organic base: the molar ratio of the tertiary butanol is 1: (1.2-1.5): (1.1-2.0).
9. The method according to claim 6, wherein the reaction temperature in the step S2 is 40-100 ℃ and the reaction time is 10-20h.
10. The method according to claim 6, wherein the step S2 further comprises: after the reaction is finished, adding dilute hydrochloric acid to adjust the pH to 1-2, separating out an organic layer, drying, evaporating to dryness, and recrystallizing with ethyl acetate to obtain the octadecanedioic acid mono-tert-butyl ester.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311233631.3A CN117263796A (en) | 2023-09-22 | 2023-09-22 | Preparation method of mono-tert-butyl octadecanedioate |
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