CN115368234B - Synthetic method of cable Ma Lutai side chain and intermediate thereof - Google Patents
Synthetic method of cable Ma Lutai side chain and intermediate thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 37
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 37
- 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 claims abstract description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- BNJOQKFENDDGSC-UHFFFAOYSA-N octadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCC(O)=O BNJOQKFENDDGSC-UHFFFAOYSA-N 0.000 claims description 50
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 42
- 238000001953 recrystallisation Methods 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 239000012065 filter cake Substances 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 29
- 239000007787 solid Substances 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 19
- HQHCYKULIHKCEB-UHFFFAOYSA-N tetradecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCC(O)=O HQHCYKULIHKCEB-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 229940101545 mi-acid Drugs 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 10
- 239000002699 waste material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 8
- YQZVQKYXWPIKIX-UHFFFAOYSA-N 2-[2-[2-[[2-[2-(2-aminoethoxy)ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid Chemical compound NCCOCCOCC(=O)NCCOCCOCC(O)=O YQZVQKYXWPIKIX-UHFFFAOYSA-N 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- QVAQMUAKTNUNLN-ZCFIWIBFSA-N (R)-4-Amino-5-(tert-butoxy)-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)[C@H](N)CCC(O)=O QVAQMUAKTNUNLN-ZCFIWIBFSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- -1 -tert-butyl glutamate Chemical compound 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 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 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and discloses a synthesis method of an important intermediate of a cable Ma Lutai side chain, namely, mono-tert-butyl octadecanedioate. Meanwhile, the synthesis method of the cable Ma Lutai side chain adopts the octadecanedioic acid mono-tert-butyl ester as a raw material, and synthesizes the cable Ma Lutai side chain through condensation reaction, so that the yield is high, the purity is high, the impurities are few, and the three wastes are few.
Description
Technical Field
The invention relates to a synthesis method of a cable Ma Lutai side chain of an important intermediate of a cable Ma Lutai, and belongs to the technical field of drug synthesis.
Background
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 U.S. FDA for improving glycemic control in adult patients with type 2 diabetes, currently marketed worldwide for about $40 billion. Wherein, the intermediate of the cable Ma Lutai, namely a cable Ma Lutai side chain (formula 1), is used for synthesizing a cable Ma Lutai bulk drug.
1 (1)
2, 2
At present, an important intermediate of a side chain of the cable Ma Lutai, namely, octadecanedioic acid mono-tert-butyl ester (formula 2), has a disclosed process route mainly comprising three steps:
route one: the main problems are: the octadecanedioic acid is firstly converted into acyl chloride, then tert-butyl ester reaction is carried out, and finally the target product is obtained through hydrolysis. Since acid chloride is relatively active, it is difficult to obtain mono-tert-butyl monoacyl chloride intermediate with low yield. The method has poor selectivity, difficult purification and difficult application to industrial production.
Route two: the main problems are: the method comprises the steps of esterifying octadecanedioic acid with alcohol under an acidic condition to obtain diester, selectively hydrolyzing under an alkaline condition to obtain monoester, tert-butylating to obtain asymmetric diester, and selectively hydrolyzing under an alkaline condition to obtain mono-tert-butyl ester. The method has the advantages of multiple steps, poor selectivity of monoester hydrolysis, difficult purification, low yield and difficult industrialization.
Route three: the main problems are: the route has simple steps and mild reaction conditions. Although the selectivity problem still exists, the selectivity of the reaction can be effectively improved by selecting a proper tert-butyl esterification system and a proper reagent, the yield is high, and the method is suitable for industrial production. However, octadecanedioic acid as a main raw material is high in cost, less in circulation in the market and not easily available.
At present, research and development of an important intermediate-cable Ma Lutai side chain related to cable Ma Lutai has great market prospect and economic and social benefits, the prior art has a plurality of problems, a new synthesis process is urgently needed, the defects existing in the prior art are overcome, and the blank of a process route is made up.
Disclosure of Invention
The invention aims to provide a synthesis method of a cable Ma Lutai side chain which is an important intermediate of a cable Ma Lutai, and develop a brand-new process route which takes tetradecanedioic acid as a starting material, so that the cost can be reduced, the safety can be improved, and meanwhile, the industrial production can be realized.
In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:
a synthesis method of a mono-tert-butyl octadecanedioate which is an important intermediate of a cable Ma Lutai side chain, wherein the structural formula of the mono-tert-butyl octadecanedioate is shown as the following formula 2, and the synthesis method comprises the following steps:
2, 2
(1) Synthesis of intermediate I: dissolving tetradecanedioic acid, mi's acid and DMAP in an organic solvent, cooling to 0 ℃, and then dropwise adding an EDCl dichloromethane solution, wherein after the dropwise adding reaction is completed; the reaction time is 0.5-3h; adding hydrochloric acid, washing with water for layering, drying an oil layer, performing suction filtration, and removing a solution from a filtrate to obtain an intermediate I;
(2) Synthesis of intermediate II: dissolving the intermediate I and sodium borohydride in an organic solvent, adding a catalyst, reacting at room temperature for 2-4 hours, adding water after the reaction is finished, quenching, filtering, and recrystallizing to obtain an intermediate II;
(3) Synthesis of octadecanedioic acid: reacting the intermediate II, acetic acid and 30% hydrochloric acid at room temperature for 2-12h, cooling and filtering after the reaction is finished, and recrystallizing to obtain octadecanedioic acid;
(4) Synthesis of mono-tert-butyl octadecanedioate: reacting octadecanedioic acid, DMAP and BOC anhydride in an organic solvent at room temperature for 0.5-4h, cooling and suction filtering after the reaction is finished, and recrystallizing to obtain the octadecanedioic acid mono-tert-butyl ester.
Preferably, (1) in the synthesis of the intermediate I, tetradecanedioic acid, mirabilic acid and DMAP are mixed according to the molar ratio, wherein EDCl=1:2.2, (3-4) and (3-4); the solvent used was methylene chloride.
Preferably, (2) in the synthesis of intermediate II, the molar ratio of intermediate I is sodium borohydride=1, (5-6); tetrahydrofuran is used as the solvent, and iodine is used as the catalyst.
Preferably, (2) in the synthesis of intermediate ii, the recrystallization method is: adding THF into the intermediate II crude product for recrystallization, heating to 60 ℃, completely dissolving the solid, cooling to room temperature, centrifuging, washing a filter cake with THF, and drying the filter cake.
Preferably, (3) octadecanedioic acid is synthesized, wherein the volume ratio of the intermediate II to acetic acid=1:3 and the volume ratio of acetic acid to 30% hydrochloric acid is 1:2 according to the mass volume ratio (Kg: L).
Preferably, (3) in the synthesis of octadecanedioic acid, the recrystallization method comprises the following steps: and adding n-heptane into the crude product for recrystallization, heating to 80 ℃, completely dissolving the solid, cooling to room temperature, centrifuging, washing a filter cake with the n-heptane, and drying the filter cake.
Preferably, (4) synthesis of mono-tert-butyl octadecanedioate, wherein the molar ratio of octadecanedioic acid to DMAP to BOC anhydride=1:1.1:1.1; the organic solvent is one of toluene/tertiary butanol and n-heptane/tertiary butanol.
Preferably, (4) synthesis of the mono-tert-butyl octadecanedioate, and recrystallization method is as follows: adding toluene into the crude product for recrystallization, heating to 60 ℃, completely dissolving the solid, cooling to room temperature, centrifuging, washing a filter cake with toluene, and drying the filter cake.
The invention discloses a synthesis method of a cable Ma Lutai side chain, which has a structural formula shown in the following formula 1, wherein the synthesis method of the cable Ma Lutai side chain comprises the following steps:
1 (1)
(1) And (3) dissolving the mono-tert-butyl octadecanedioate and the D-tert-butyl glutamate in an organic solvent, reacting for 2-8 hours at room temperature, filtering after the reaction is finished, and recrystallizing to obtain an intermediate 2.
(2) Dissolving the intermediate 2 and AEEA-AEEA in an organic solvent, reacting for 2-8 hours at room temperature, filtering after the reaction is finished, and recrystallizing to obtain a cable Ma Lutai side chain.
Preferably, in the step (1), the molar ratio of the mono-tert-butyl octadecanedioate to the D-tert-butyl glutamate=1 (1-2); the organic solvent is dichloromethane.
Preferably, in the step (2), the molar ratio is that the intermediate 2:aeeA-Aeea=1, (1-2); the organic solvent is dichloromethane.
Compared with the prior art, the invention has the beneficial effects that: 1. the method has the advantages that the tetradecanedioic acid condensation, reduction, ring opening and Boc single protection synthesis are adopted for the octadecyl diacid mono-tert-butyl ester, the yield and purity of the product are high, the impurities are few, the overall reaction efficiency is high due to the adoption of the molar ratio, the reaction solvent and the temperature, the reaction condition is simple, the reaction raw materials are simple and easy to obtain, and the cost is low; 2. the three wastes generated in the synthesis process of the octadecanedioic acid mono-tert-butyl ester are less; 3. the side chain of the cable Ma Lutai adopts condensation reaction, and the side chain of the cable Ma Lutai is synthesized by adopting a two-step method, so that the yield is high, the purity is high, the impurity is less, and the three wastes are less.
Drawings
FIG. 1, process scheme of example 1 of the present invention;
fig. 2, process scheme of example 2 of the present invention.
FIG. 3, liquid chromatogram of intermediate I of example 1.
FIG. 4, liquid chromatogram of intermediate II of example 1.
FIG. 5 shows a liquid chromatogram of octadecanedioic acid of example 1.
FIG. 6 is a liquid chromatogram of mono-tert-butyl octadecanedioate of example 1.
Fig. 7, liquid chromatogram of the compound of example 5.
Detailed Description
The invention is further described below. The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention.
Example 1
As shown in fig. 1, a synthesis method of the important intermediate of the side chain of the cable Ma Lutai, namely, the mono-tert-butyl octadecanedioate (formula 2) comprises the following steps:
2, 2
(1) Synthesis of intermediate I: tetradecanedioic acid (0.1 mol), mirabilic acid (0.22 mol), DMAP (0.3 mol) and methylene chloride solution (500 ml) are put into a four-mouth bottle, the temperature is reduced to 0 ℃, and EDCl (0.3 mol) methylene chloride (100 ml) solution is added dropwise for reaction for 1 h; adding 500ml of hydrochloric acid, washing and layering, adding 500ml of hydrochloric acid into an oil layer again, stirring, standing and layering, placing the oil layer into a drying bottle filled with anhydrous sodium sulfate, drying for 1h, carrying out suction filtration, and removing the solution from the filtrate to obtain an intermediate I (0.08 mol), wherein the yield is 80%.
Intermediate I is pale yellow crystalline powder with a purity of 95.5% (as shown in FIG. 3, liquid chromatogram).
(2) Synthesis of intermediate II: 500ml of intermediate I (0.08 mol), iodine (0.04 mol) and sodium borohydride (0.4 mol) THF solvent are put into a four-mouth bottle to react for 3 hours at room temperature, water is added to quench and filter after the reaction is finished, and recrystallization is carried out (the recrystallization process is that 100ml of THF is added into a crude intermediate II product to carry out recrystallization, the temperature is firstly increased to 60 ℃, the solid is completely dissolved, then the temperature is reduced to 20 ℃, the mixture is centrifuged, a filter cake is washed by 100ml of THF, and the filter cake is dried), so that intermediate II (0.05 mol) is obtained, and the yield is 63%.
Intermediate ii was a white solid with a purity of 97.7% (liquid chromatogram as shown in fig. 4).
(3) Synthesis of octadecanedioic acid: adding intermediate II (0.05 mol), acetic acid 60ml and hydrochloric acid (30%) 120ml into a four-mouth bottle, reacting for 6h at room temperature, cooling and suction filtering after the reaction is finished, recrystallizing (the recrystallization process is that 100ml of n-heptane is added into a crude product for recrystallization, heating to 80 ℃ firstly, completely dissolving the solid, cooling to 25 ℃, centrifuging, washing a filter cake with 100ml of n-heptane, and drying the filter cake) to obtain octadecanedioic acid (0.026 mol), wherein the yield is 52%.
Octadecanedioic acid was a white solid with a purity of 97.8% (liquid chromatogram as shown in fig. 5).
(4) Synthesis of mono-tert-butyl octadecanedioate: octadecanedioic acid (0.026 mol), DMAP (0.029 mol), BOC anhydride (0.029 mol), tert-butyl alcohol 200ml and toluene 200ml are put into a four-mouth bottle to react for 2h at room temperature, cooling and suction filtration are carried out after the reaction is finished, recrystallization is carried out (the recrystallization process is that 100ml of toluene is added into a crude product to carry out recrystallization, the temperature is firstly increased to 60 ℃, the solid is completely dissolved, then the temperature is reduced to 25 ℃, the centrifugation is carried out, a filter cake is washed by 100ml of toluene, and the filter cake is dried) to obtain the octadecanedioic acid mono-tert-butyl ester (0.02 mol), and the yield is 77%.
The mono-tert-butyl octadecanedioate is white solid with the purity of 99.79 percent (shown in the liquid chromatogram of FIG. 6).
In this example, tetradecanedioic acid is condensed, reduced, decarboxylated, and esterified to produce the product of mono-tert-butyl octadecanedioate. The synthesized high-quality octadecanedioic acid mono-tert-butyl ester has high yield and high purity.
The content of the octadecanedioic acid mono-tert-butyl ester product is analyzed by adopting an external standard method of a high performance liquid chromatography instrument, and the content is 99.79 percent.
Example 2
A method for synthesizing a mono-tert-butyl octadecanedioate (formula 2) which is an important intermediate of a side chain of a cable Ma Lutai comprises the following steps:
(1) Synthesis of intermediate I: tetradecanedioic acid (0.2 mol), mirabilic acid (0.8 mol), DMAP (0.8 mol) and methylene chloride solution (500 ml) are put into a four-mouth bottle, the temperature is reduced to 0 ℃, and EDCl (0.8 mol) methylene chloride (100 ml) solution is added dropwise for reaction for 3 hours; adding 500ml of hydrochloric acid, washing and layering, adding 500ml of hydrochloric acid again into an oil layer, washing and layering again, putting the oil layer into a drying bottle filled with anhydrous sodium sulfate, drying for 1h, filtering, and removing the solution from the filtrate to obtain an intermediate I (0.15 mol), wherein the yield is 75%.
Intermediate I is pale yellow crystalline powder with a purity of 98.2%.
(2) Synthesis of intermediate II: 500ml of intermediate I (0.15 mol), iodine (0.075 mol) and sodium borohydride (0.9 mol) THF solvent are put into a four-mouth bottle, reacted for 2 hours at room temperature, water is added to quench and filter after the reaction is finished, recrystallization is carried out (the recrystallization process is that 100ml of THF is added into a crude intermediate II product for recrystallization, the temperature is firstly increased to 60 ℃, the solid is completely dissolved, then the temperature is reduced to 20 ℃, the centrifugation is carried out, a filter cake is washed by 100ml of THF, and the filter cake is dried), thus obtaining intermediate II (0.09 mol) with the yield of 60 percent.
Intermediate II was a white solid with a purity of 97.1%.
(3) Synthesis of octadecanedioic acid: adding intermediate II (0.09 mol), acetic acid 72ml and hydrochloric acid (30%) 120ml into a four-mouth bottle, reacting for 2h at room temperature, cooling and suction filtering after the reaction is finished, recrystallizing (the recrystallization process is that 100ml of n-heptane is added into a crude product for recrystallization, heating to 80 ℃ firstly, completely dissolving the solid, cooling to 25 ℃, centrifuging, washing a filter cake with 100ml of n-heptane, and drying the filter cake) to obtain octadecanedioic acid (0.045 mol), wherein the yield is 50%.
Octadecanedioic acid is white solid with the purity of 98.0 percent.
(4) Synthesis of mono-tert-butyl octadecanedioate: octadecanedioic acid (0.045 mol), DMAP (0.09 mol), BOC anhydride (0.09 mol), tert-butyl alcohol 200ml and n-heptane 200ml are put into a four-mouth bottle to react for 0.5h at room temperature, cooling and suction filtration are carried out after the reaction is finished, recrystallization is carried out (the recrystallization process is that 100ml of n-heptane is added into a crude product to carry out recrystallization, the temperature is firstly increased to 80 ℃, the solid is completely dissolved, then the temperature is reduced to 25 ℃, the temperature is reduced, the centrifugation is carried out, a filter cake is washed by 100ml of n-heptane, and the filter cake is dried) to obtain the octadecanedioic acid mono-tert-butyl ester (0.032 mol), and the yield is 71%.
The mono-tert-butyl octadecanedioate is white solid with the purity of 98.5 percent.
Example 3
A method for synthesizing a mono-tert-butyl octadecanedioate (formula 2) which is an important intermediate of a side chain of a cable Ma Lutai comprises the following steps:
(1) Synthesis of intermediate I: tetradecanedioic acid (0.1 mol), mirabilic acid (0.3 mol), DMAP (0.5 mol) and methylene chloride solution (500 ml) are put into a four-mouth bottle, the temperature is reduced to 0 ℃, and EDCl (0.4 mol) methylene chloride (100 ml) solution is added dropwise for reaction for 0.5 h; adding hydrochloric acid 500ml, washing with water for layering, adding hydrochloric acid 500ml again into an oil layer, washing with water again for layering, drying the oil layer in a drying bottle filled with anhydrous sodium sulfate for 1h, filtering, and removing the solution from the filtrate to obtain an intermediate I (0.071 mol), wherein the yield is 71%.
Intermediate I is pale yellow crystalline powder with a purity of 97.5%.
(2) Synthesis of intermediate II: 500ml of intermediate I (0.071 mol), iodine (0.035 mol) and sodium borohydride (0.426 mol) THF solvent are put into a four-mouth bottle to react for 4 hours at room temperature, water is added to quench and suction-filter after the reaction is finished, recrystallization is carried out (the recrystallization process is that THF100ml is added into intermediate II crude product to carry out recrystallization, the temperature is firstly increased to 60 ℃, the solid is completely dissolved, then the temperature is reduced to 20 ℃, the centrifugation is carried out, a filter cake is washed by 100ml THF, and the filter cake is dried) to obtain intermediate II (0.042 mol) with the yield of 59%.
Intermediate II was a white solid with a purity of 97.1%.
(3) Synthesis of octadecanedioic acid: adding intermediate II (0.042 mol), acetic acid 26ml and hydrochloric acid (30%) 48ml into a four-mouth bottle, reacting for 12h at room temperature, cooling and suction filtering after the reaction is finished, recrystallizing (the recrystallization process is that 100ml of n-heptane is added into a crude product for recrystallization, the temperature is firstly increased to 80 ℃, the solid is completely dissolved, the temperature is then reduced to 25 ℃, the temperature is further reduced, the centrifugation is carried out, a filter cake is washed by 100ml of n-heptane, and the filter cake is dried) to obtain octadecanedioic acid (0.020 mol), and the yield is 48%.
Octadecanedioic acid is white solid with the purity of 97.6 percent.
(4) Synthesis of mono-tert-butyl octadecanedioate: octadecanedioic acid (0.02 mol), DMAP (0.02 mol), BOC anhydride (0.02 mol), tert-butyl alcohol 200ml and toluene 200ml are put into a four-mouth bottle to react for 4h at room temperature, cooling and suction filtration are carried out after the reaction is finished, recrystallization is carried out (the recrystallization process is that 100ml of toluene is added into a crude product to carry out recrystallization, the temperature is firstly increased to 80 ℃, the solid is completely dissolved, then the temperature is reduced to 25 ℃, the solution is centrifuged, a filter cake is washed by 100ml of toluene, and the filter cake is dried) to obtain the octadecanedioic acid mono-tert-butyl ester (0.014 mol) with the yield of 70 percent.
The mono-tert-butyl octadecanedioate is white solid with the purity of 98.6 percent.
Example 4
In example 1, 50kg of sodium sulfate waste residue is produced by kg of the product, and a small amount of methylene chloride and the like are contained. About 50kg of dichloromethane waste liquid is produced by kg of the product, and water, dichloromethane and inorganic salts (such as sodium chloride and the like) are contained in the dichloromethane waste liquid; about 20kg of tetrahydrofuran waste liquid is produced by kg of products, and a large amount of tetrahydrofuran, water, inorganic salts and the like are contained.
Example 5
As shown in fig. 2, the synthesis method of the cable Ma Lutai side chain (formula 1) comprises the following steps:
1 (1)
(1) Synthesis of intermediate 2: put octadecanedioic acid mono-tert-butyl ester (intermediate 1) (0.1 mol), D-glutamic acid tert-butyl ester (0.12 mol) and methylene dichloride (500 ml) into a four-mouth bottle for reaction at room temperature for 4 hours, suction filtration is carried out after the reaction is finished, and the ethylene dichloride is recrystallized to obtain intermediate 2 (0.08 mol) with the yield of 80 percent.
(2) Synthesis of the pendant of cord Ma Lutai: intermediate 2 (0.08 mol), AEEa-AEEa (0.096 mol) and methylene chloride (500 ml) were put into a four-necked flask and reacted at room temperature for 4 hours, and after the reaction was completed, suction filtration and recrystallization of dichloroethane gave a side chain of cable Ma Lutai (0.06 mol) in a yield of 75% and a purity of 99.93% (liquid chromatogram shown in FIG. 7).
In this example, the mono-tert-butyl octadecanedioate was condensed to form the pendant chain of cord Ma Lutai. The two-step method is adopted to synthesize the side chain of the cable Ma Lutai, so that the yield is high, the purity is high, the impurities are few, and the three wastes are few.
Example 6
A method for synthesizing a side chain (formula 1) of a cable Ma Lutai, which comprises the following steps:
(1) Synthesis of intermediate 2: put octadecanedioic acid mono-tert-butyl ester (intermediate 1) (0.2 mol), D-glutamic acid tert-butyl ester (0.2 mol) and methylene dichloride (500 ml) into a four-mouth bottle for reaction at room temperature for 2 hours, suction filtration is carried out after the reaction is finished, and intermediate 2 (0.15 mol) is obtained through recrystallization, wherein the yield is 75%, and the purity is 97.6%.
(2) Synthesis of the pendant of cord Ma Lutai: intermediate 2 (0.15 mol), AEEA-AEEA (0.15 mol) and methylene chloride (500 ml) were put into a four-necked flask and reacted at room temperature for 2 hours, and after the reaction was completed, the mixture was suction-filtered and recrystallized to obtain a side chain of cable Ma Lutai (0.10 mol), the yield was 67% and the purity was 97.2%.
Example 7
A method for synthesizing a side chain (formula 1) of a cable Ma Lutai, which comprises the following steps:
(1) Synthesis of intermediate 2: put octadecanedioic acid mono-tert-butyl ester (intermediate 1) (0.1 mol), D-glutamic acid tert-butyl ester (0.2 mol) and methylene dichloride (500 ml) into a four-mouth bottle for reaction at room temperature for 8 hours, suction filtration is carried out after the reaction is finished, and intermediate 2 (0.072 mol) is obtained through recrystallization, wherein the yield is 72%, and the purity is 97.5%.
(2) Synthesis of the pendant of cord Ma Lutai: intermediate 2 (0.072 mol), AEEA-AEEA (0.144 mol) and methylene chloride (500 ml) are put into a four-mouth bottle to react for 8 hours at room temperature, and after the reaction is finished, suction filtration and recrystallization are carried out to obtain a cable Ma Lutai side chain (0.049 mol), the yield is 68 percent, and the purity is 97.1 percent.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and variations could be made by those skilled in the art without departing from the technical principles of the present invention, and such modifications and variations should also be regarded as being within the scope of the invention.
Claims (1)
1. A method for synthesizing a mono-tert-butyl octadecanedioate (formula 2) which is an important intermediate of a cable Ma Lutai side chain is characterized by comprising the following steps: the method comprises the following steps:
，
2, 2
(1) Synthesis of intermediate I: adding 0.1mol of tetradecanedioic acid, 0.22mol of Mi's acid, 0.3mol of DMAP and 500ml of dichloromethane solution into a four-mouth bottle, cooling to 0 ℃, dropwise adding 100ml of dichloromethane solution of 0.3mol of EDCl, and reacting for 1 h; adding hydrochloric acid 500ml, washing with water, layering, adding hydrochloric acid 500ml again into the oil layer, stirring, standing for layering, drying the oil layer in a drying bottle filled with anhydrous sodium sulfate for 1h, suction filtering, removing the solution from the filtrate to obtain intermediate I0.08 mol,
(2) Synthesis of intermediate II: adding 0.08mol of intermediate I, 0.04mol of iodine, 0.4mol of sodium borohydride and 500ml of THF solvent into a four-mouth bottle, reacting for 3 hours at room temperature, adding water after the reaction is finished, quenching, filtering, recrystallizing, and recrystallizing: adding 100ml of THF into the crude intermediate II for recrystallization, heating to 60 ℃, completely dissolving the solid, cooling to 20 ℃, centrifuging, washing the filter cake with 100ml of THF, drying the filter cake to obtain 0.05mol of intermediate II,
(3) Synthesis of octadecanedioic acid: adding 0.05mol of intermediate II, 60ml of acetic acid and 120ml of 30% hydrochloric acid into a four-mouth bottle, reacting for 6 hours at room temperature, cooling and filtering after the reaction is finished, recrystallizing, and recrystallizing: adding 100ml of n-heptane into the crude product for recrystallization, heating to 80 ℃, completely dissolving the solid, cooling to 25 ℃, centrifuging, washing a filter cake with 100ml of n-heptane, drying the filter cake to obtain 0.026mol of octadecanedioic acid,
(4) Synthesis of mono-tert-butyl octadecanedioate: octadecanedioic acid 0.026mol, DMAP0.029mol, BOC anhydride 0.029mol, tertiary butanol 200ml and toluene 200ml are put into a four-mouth bottle to react for 2h at room temperature, and after the reaction is finished, the temperature is reduced, suction filtration is carried out, and the recrystallization process is that: adding 100ml of toluene into the crude product for recrystallization, heating to 60 ℃, completely dissolving the solid, cooling to 25 ℃, centrifuging, washing a filter cake with 100ml of toluene, and drying the filter cake to obtain 0.02mol of octadecanedioic acid mono-tert-butyl ester.
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| CN113461519A (en) * | 2021-08-12 | 2021-10-01 | 浙江泽瑞生物医药有限公司 | Preparation method of octadecanedioic acid mono-tert-butyl ester-PFP |
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| WO2021034815A1 (en) * | 2019-08-19 | 2021-02-25 | Eli Lilly And Company | Methods of making incretin analogs |
| CN112939771A (en) * | 2021-01-28 | 2021-06-11 | 宁夏蓝博思化学技术有限公司 | Preparation method of long-chain alkyl diacid mono-tert-butyl ester |
| CN113461519A (en) * | 2021-08-12 | 2021-10-01 | 浙江泽瑞生物医药有限公司 | Preparation method of octadecanedioic acid mono-tert-butyl ester-PFP |
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