CN113943255A - Preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid - Google Patents
Preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid Download PDFInfo
- Publication number
- CN113943255A CN113943255A CN202110797895.6A CN202110797895A CN113943255A CN 113943255 A CN113943255 A CN 113943255A CN 202110797895 A CN202110797895 A CN 202110797895A CN 113943255 A CN113943255 A CN 113943255A
- Authority
- CN
- China
- Prior art keywords
- cyclopropyl
- propionic acid
- chiral
- dioxaimidazolin
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- IMTWAIJZPIQWEY-UHFFFAOYSA-N OC(CCC1(C2CC2)ONON1)=O Chemical compound OC(CCC1(C2CC2)ONON1)=O IMTWAIJZPIQWEY-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 9
- -1 (S) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid Chemical compound 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229940125898 compound 5 Drugs 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical class CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- BZUDZUHYBPOSMJ-UHFFFAOYSA-N tert-butyl 4-cyclopropyl-4-oxobutanoate Chemical compound C(C)(C)(C)OC(CCC(=O)C1CC1)=O BZUDZUHYBPOSMJ-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- HVCFCNAITDHQFX-UHFFFAOYSA-N 1-cyclopropylethanone Chemical compound CC(=O)C1CC1 HVCFCNAITDHQFX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and preparation, and particularly relates to a preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid. The method has the advantages of high yield, excellent product purity, low cost, contribution to industrial application and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis and preparation, and particularly relates to a preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid.
Background
Prior art CN201580070274.0 discloses a process for the preparation of compound 5 of the formula:
wherein, the compound 5 has isomers with two configurations of R and S, and the structural formula is as follows:
in the prior art, the compound 5 is resolved by adopting an SFC column separation means to obtain isomers with two configurations of R and S, so that the yield is low, the cost is high, and the further industrial application of the compound is not facilitated.
Disclosure of Invention
In view of the problems in the prior art, the invention provides a preparation method of (S) -3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid.
The invention is realized by the following technical scheme:
a preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid is characterized in that racemic 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid and chirally pure S- (-) -methylbenzylamine or R- (+) -methylbenzylamine are mixed, and a chiral compound is resolved.
As a preferred embodiment of the present invention, the chiral 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid is (S) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid, racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and chirally pure S- (-) -methylbenzylamine are mixed to resolve a chiral compound; or 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid is (R) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid, racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and chirally pure R- (-) -methylbenzylamine are mixed, and the chiral compound is resolved.
As a preferred embodiment of the present invention, the preparation process comprises:
or
As a preferred embodiment of the present invention, the mixing process is carried out in methanol as a resolution solvent.
As a preferred embodiment of the invention, the methanol is used in 12-15 v/w (mL/g) of the resolution process relative to the racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid, and the elution amount is 10v/w (mL/g)
As a preferred embodiment of the present invention, the resolution process temperature is from-2 to 17 ℃.
As a preferred embodiment of the present invention, the preparation method further comprises: dropwise adding concentrated hydrochloric acid, controlling the temperature of the system to be 0-5 ℃ in the dropwise adding process, and adjusting the pH value of the system to be about 1-2. The salt of methylbenzylamine salt in the methylbenzylamine salt of the chiral compound and hydrochloric acid is formed to obtain the chiral compound with a specific conformation.
As a preferred embodiment of the present invention, there is provided a chiral compound having a structure selected from the group consisting of:
compared with the prior art, the invention has the advantages that:
the method can simply and efficiently obtain the target chiral compound, and has the advantages of high yield, excellent product purity, low cost, contribution to industrial application and the like.
Drawings
FIG. 1 is a nuclear magnetic spectrum of compound 5 in S configuration;
FIG. 2 is a mass spectrum of compound 5 in S configuration;
FIG. 3 is an HPLC chromatogram of racemate of Compound 5;
figure 4 is an HPLC profile of compound 5 in S configuration.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
Reagents and terms used in the embodiments of the present invention:
EtOH-ethanol; MeOH-methanol; THF-tetrahydrofuran; Acetone-Acetone; 1,4-Dioxane-1, 4-Dioxane; DMF-dimethylformamide; LDA-lithium diisopropylamide; eq-equivalent; the english name of ee is enantiomeric excesses, i.e. enantiomeric excess, which indicates the excess of a certain enantiomer, and ee% ([ R ] - [ S ]/[ R ] + [ S ]) is 100%.
Example 1 synthesis of racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid:
compound 5 can be prepared according to the patent method, see CN201580070274.
Under the protection of nitrogen, anhydrous tetrahydrofuran (9.3 liters) was added to a 50L low-temperature reaction kettle, LDA (11.14 liters, 1.17eq) was added in portions, stirring was started, and the temperature was reduced to-78 ℃. Cyclopropylmethyl ketone (1600 g, 1.0eq) was diluted with tetrahydrofuran (1.7 l) and slowly added dropwise to the reaction vessel. After the dropwise addition, slowly raising the temperature to-10 to-20 ℃, and continuously reducing the temperature to-78 ℃. Tert-butyl bromoacetate (3695 g, 1.0eq) was diluted with tetrahydrofuran (2.5 l) and slowly added dropwise to the reactor. The temperature was raised to 0 to 5 ℃ and stirred for 16 hours. 10L of saturated ammonium chloride solution was added dropwise to quench the reaction, salts were precipitated, 6L of pure water was added thereto and inorganic salts were dissolved by stirring, the mixture was stirred at room temperature for 15 minutes, the mixture was allowed to stand and separate, the aqueous phase was extracted twice with ethyl acetate (6.5L), and the organic phases were combined and washed once with pure water (7.5L), saturated ammonium chloride (7.5L) and brine (7.5L), respectively. The organic phase is concentrated at 50 to 55 ℃ until no solvent is distilled off and then at 50 to 55 ℃ for about 2 hours, leaving about 7 l of concentrate. The crude product was distilled under reduced pressure by means of an oil pump at a distillation temperature of 70 to 110 ℃ to give 1400 g of t-butyl 4-cyclopropyl-4-oxobutyrate as a pale yellow liquid (yield: 39.4%).
To a 10 l autoclave, ethanol (1824 ml), tert-butyl 4-cyclopropyl-4-oxobutyrate (760 g, 1.0eq), ammonium carbonate (3132 g, 8.5eq), sodium cyanide (448 g, 2.4eq) and water (1824 ml) were added, slowly heated to 60 to 70 ℃, and the reaction was stirred for about 18 hours. The temperature was reduced to 0 to 5 ℃ and the reaction mixture was poured into a mixture of ethyl acetate (5.9 liters) and water (5.9 liters) and stirred well. The layers were separated by settling, the aqueous phase was extracted 3 times with ethyl acetate (12L), and the organic phases were combined and washed once with water (15.5L) and saturated brine (8.2L) each. The organic phase is concentrated until no solvent is distilled off, n-heptane (13.5 l) is slowly added and the temperature is raised to 50 to 55 ℃. The temperature was slowly reduced to 0 to 10 ℃ and the mixture was filtered, and the filter cake was rinsed once with n-heptane (1200 ml) and dried under vacuum to give 658 g of tert-butyl 3- (4-cyclopropyl-2, 5-dioxaimidazolidin-4-yl) propionate as a yellow-like solid (yield: 64%).
To a 1000 ml three-necked flask, 1,4-dioxane (25 ml), tert-butyl 3- (4-cyclopropyl-2, 5-dioxaimidazolidin-4-yl) propionate (50 g) was added, the temperature was lowered to 0 to 10 ℃, and 280 ml of a 6N dioxane hydrochloride solution was slowly dropped into the three-necked flask and stirred at room temperature overnight. The reaction was concentrated until no significant solvent evaporated, added (85 ml), warmed to 80 to 85 ℃, stirred for 1 hour, slowly cooled to 15 to 20 ℃, filtered, the filter cake rinsed with acetonitrile (25 ml), and dried under vacuum to give 30.5 g of 3- (4-cyclopropyl-2, 5-dioxaimidazolidin-4-yl) propionic acid as a gray solid (yield: 77.2%).
Example 2 resolution with methylbenzylamine
To a 10L three-necked flask was added racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid (1520 g, 1.0eq), and anhydrous methanol (16.72L) was added, followed by stirring to dissolve at 15. + -. 2 ℃. S-methylbenzylamine (1020 g, 1.2eq) was added dropwise to the system, and the mixture was stirred at 15 ± 2 ℃ for 1 hour, filtered, and dried by suction to obtain crude salts ((S) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and a salt formed from (S) -methylbenzylamine 1: 1) (ee% ═ 96.60%).
The crude salt was placed in a 5 l three-necked flask, methanol (2.4 l) was added, and the mixture was stirred at 15 ± 2 ℃ for 2 hours, filtered, dried by suction, and dried under vacuum at 45 to 50 ℃ to a constant weight to obtain 890 g of a white solid salt of a fine salt ((S) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and a salt formed from (S) -methylbenzylamine 1: 1) (ee% ═ 98.35%).
Adding the refined salt obtained in the step into a 10-liter three-neck bottle, adding 2170 ml of pure water, cooling to 0-5 ℃, dropwise adding concentrated hydrochloric acid, controlling the temperature of the system to 0-5 ℃ in the dropwise adding process, adjusting the pH value of the system to about 1-2, continuously stirring at the temperature for 60 minutes after the dropwise adding is finished, filtering, pulping a filter cake by using ice water (2170 ml), leaching, draining, and drying in vacuum at the temperature of 50-55 ℃ to constant weight to obtain 512 white powder solid (S) -3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid (the yield is 33.7%, and the ee% is 99.86%).
1HNMR spectrogram and mass spectrum detection are shown in figures 1 and 2.
Experimental conditions using HPLC chiral columns (chiralpak, IF, 250mm 4.6mm, 5 μm): mobile phase methanol/formic acid (100:0.2), flow rate 1 ml/min, temperature 30 ℃. The (R) -5 retention time was 3.96 minutes, and the (S) -5 retention time was 7.70 minutes.
HPLC spectrograms for HPLC purity detection of compound 5 racemate and (S) -5 chiral compound are shown in FIGS. 3 and 4.
Example 3 comparative test
Regarding the method for resolving chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid, different solvents and chiral resolution conditions are as follows:
3.1 solvent species investigation
Wherein the table ee value is calculated as (R) -5.
Here, the table ee value was calculated as (S) -5.
As can be seen from the above test results, the compound 5 has better selectivity when resolved by using methanol as a solvent.
3.2 solvent (methanol) dosage and temperature considerations
Here, the table ee value was calculated as (S) -5.
The test results show that the methanol dosage is 12-15 v/w (mL/g), the leaching amount is 10v/w (mL/g), the temperature is-2-17 ℃, and the resolution effect is good.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. A preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid is characterized in that racemic 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid and chirally pure S- (-) -methylbenzylamine or R- (+) -methylbenzylamine are mixed, and a chiral compound is resolved.
2. The process according to claim 1, wherein chiral 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid is (S) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid, racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and chirally pure S- (-) -methylbenzylamine are mixed to resolve the chiral compound; or 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid is (R) -3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid, racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolin-4-yl) propionic acid and chirally pure R- (-) -methylbenzylamine are mixed, and the chiral compound is resolved.
3. The method according to claim 1 or 2, wherein the preparation process comprises:
or
4. A process according to any one of claims 1 to 3, characterized in that the mixing process is carried out in methanol as a resolving solvent.
5. The method of claim 4, wherein the methanol used in the resolution process is 12-15 v/w (mL/g) and the elution is 10v/w (mL/g) relative to the racemic 3- (4-cyclopropyl-2, 5-dioxaimidazolidin-4-yl) propionic acid.
6. The process of claim 4, wherein the resolution process temperature is from-2 to 17 ℃.
7. The method of any one of claims 1-6, further comprising: dropwise adding concentrated hydrochloric acid, controlling the temperature of the system to be 0-5 ℃ in the dropwise adding process, and adjusting the pH value of the system to be about 1-2.
8. A chiral compound having a structure selected from the group consisting of:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020106933347 | 2020-07-17 | ||
| CN202010693334 | 2020-07-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113943255A true CN113943255A (en) | 2022-01-18 |
Family
ID=79327426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110797895.6A Pending CN113943255A (en) | 2020-07-17 | 2021-07-15 | Preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113943255A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443173A (en) * | 2000-08-17 | 2003-09-17 | 辉瑞大药厂 | Substituted imidazoles as TAFI a inhibitors |
| CN1639109A (en) * | 2000-09-29 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Dynamic resolution of isomers and resolved isomers |
| US20100210699A1 (en) * | 2006-05-31 | 2010-08-19 | Francois Nique | Imidazolidine derivatives, uses therefor, preparation thereof and compositions comprising such |
| CN107108579A (en) * | 2014-12-22 | 2017-08-29 | 加拉帕戈斯股份有限公司 | It is used for the derovatives of 5 [(base of piperazine 1) 3 oxopropyls] imidazolidine 2,4 for treating osteoarthritis as ADAMTS inhibitor |
-
2021
- 2021-07-15 CN CN202110797895.6A patent/CN113943255A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443173A (en) * | 2000-08-17 | 2003-09-17 | 辉瑞大药厂 | Substituted imidazoles as TAFI a inhibitors |
| CN1639109A (en) * | 2000-09-29 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Dynamic resolution of isomers and resolved isomers |
| US20100210699A1 (en) * | 2006-05-31 | 2010-08-19 | Francois Nique | Imidazolidine derivatives, uses therefor, preparation thereof and compositions comprising such |
| CN107108579A (en) * | 2014-12-22 | 2017-08-29 | 加拉帕戈斯股份有限公司 | It is used for the derovatives of 5 [(base of piperazine 1) 3 oxopropyls] imidazolidine 2,4 for treating osteoarthritis as ADAMTS inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| FRANCK BREBION ET AL.,: "Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS‑5 Inhibitor for the Treatment of Osteoarthritis", 《J.MED.CHEM.》, vol. 64, 15 March 2021 (2021-03-15), pages 2937 - 2952, XP093054372, DOI: 10.1021/acs.jmedchem.0c02008 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112020498B (en) | Buvalracetam intermediate, preparation method thereof and preparation method of Buvalracetam | |
| Collum et al. | Substituent effects on the stereochemistry of substituted cyclohexanone dimethylhydrazone alkylations. An x-ray crystal structure of lithiated cyclohexanone dimethylhydrazone | |
| CN101772475B (en) | Process for the resolution of zopiclone and intermediate compounds | |
| CN111099989B (en) | S-3-cyclohexene carboxylic acid and refining method thereof | |
| EP1135357B1 (en) | Process for the resolution of tramadol | |
| Pakulski et al. | Enantioselective reduction of ketoxime ethers with borane–oxazaborolidines and synthesis of the key intermediate leading to (S)-rivastigmine | |
| CN113508120A (en) | Process for preparing cannabidiol | |
| WO2014038665A1 (en) | Method for producing optically active 2,3-dihydrofarnesal | |
| CN113943255A (en) | Preparation method of chiral 3- (4-cyclopropyl-2, 5-dioxaimidazoline-4-yl) propionic acid | |
| Csuk et al. | Enantioselective Dreiding-Schmidt reactions: asymmetric synthesis and analysis of α-methylene-γ-butyrolactones | |
| EP3625237B1 (en) | A method for separating optically active hydroxy cineole derivatives | |
| HUE025113T2 (en) | Method for enzymatic synthesis of (7S)-1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl) N-methyl methanamine, and use for the synthesis of Ivabradine and the salts thereof | |
| CN108239091B (en) | Resolution of 1-cyclohexyl-2- (5H-imidazo [5,1-a ] isoindol) ethyl-1-one | |
| US7829702B2 (en) | Racemic separation of 2,6-trans-dimethymorpholine | |
| CN109651437B (en) | Chiral nitrogen-phosphorus ligand, preparation method thereof and method for resolving racemic menthol | |
| CN112341413A (en) | Intermediate for synthesizing brivaracetam and preparation method thereof | |
| WO2021044230A1 (en) | Process for the synthesis of the sodium salt of 4-[[(lr)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)-phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-l(2h)-pyrimidinyl]-l- phenylethyl]amino]-butanoic acid (elagolix sodium salt) and intermediates of said process | |
| AU2017332937B2 (en) | Method for producing (R)-5-(3,4-difluorophenyl)-5-[(3-methyl-2-oxopyridin-1(2H)-yl)methyl]imidazolidine-2,4-dione and intermediate for producing same | |
| US6818778B2 (en) | Process for preparing (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid, and (-)-chiral stationary phases for resolution of racemic compounds using the same | |
| Kinbara et al. | Chiral discrimination of 2‐arylalkanoic acids by (1S, 2S)‐1‐aminoindan‐2‐ol and (1S, 2S)‐2‐aminoindan‐1‐ol: Correlation of the relative configuration of the amino and hydroxy groups with the pattern of a supramolecular hydrogen‐bond network in the less‐soluble diastereomeric salt | |
| EP3068746B1 (en) | Process for the preparation of enantiomerically pure 1-aminoindan | |
| MXPA06004650A (en) | New process for preparing an optically pure 2-morphinol derivative. | |
| JPH05506008A (en) | A method for producing a homochiral amine, a method for producing an intermediate for producing the amine, and an intermediate produced according to the method | |
| EP3339300B1 (en) | Method for preparing thienyl alanine having optical activity | |
| JP5704182B2 (en) | Process for producing optically active tetrahydrofuran-2-carboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information |
Address after: Area A, 4th Floor, Digital Peninsula, No. 2, Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen, Guangdong, 518017 Applicant after: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Address before: 518040 37th floor, chegongmiao Lvjing Plaza, 6009 Shennan Avenue, Futian District, Shenzhen City, Guangdong Province Applicant before: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |