CN116178220A - Method for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide - Google Patents
Method for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 22
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 title abstract description 22
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 title abstract description 22
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 title abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 229940125782 compound 2 Drugs 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 claims abstract description 9
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- AIHIHVZYAAMDPM-QMMMGPOBSA-N [(2s)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@H]2OC2)=C1 AIHIHVZYAAMDPM-QMMMGPOBSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 150000007529 inorganic bases Chemical class 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 9
- 235000011152 sodium sulphate Nutrition 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract 1
- 239000005977 Ethylene Substances 0.000 abstract 1
- MNOJRWOWILAHAV-UHFFFAOYSA-N 3-bromophenol Chemical compound OC1=CC=CC(Br)=C1 MNOJRWOWILAHAV-UHFFFAOYSA-N 0.000 description 8
- 206010019280 Heart failures Diseases 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KECCFSZFXLAGJS-UHFFFAOYSA-N 4-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=C(O)C=C1 KECCFSZFXLAGJS-UHFFFAOYSA-N 0.000 description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- 206010003119 arrhythmia Diseases 0.000 description 5
- 230000006793 arrhythmia Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229960002429 proline Drugs 0.000 description 5
- MRZXZRGNTXHLKA-UHFFFAOYSA-N 3-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=CC(O)=C1 MRZXZRGNTXHLKA-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229930182821 L-proline Natural products 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000001879 copper Chemical class 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 231100000956 nontoxicity Toxicity 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IUUZMZHMHDVICT-SECBINFHSA-N (2S)-2-[(3-methylsulfonylphenoxy)methyl]oxirane Chemical compound CS(=O)(=O)C=1C=C(OC[C@H]2OC2)C=CC=1 IUUZMZHMHDVICT-SECBINFHSA-N 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 2
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YMYKXUBZPNRRQD-UHFFFAOYSA-N 1-methoxy-3-methylsulfonylbenzene Chemical compound COC1=CC=CC(S(C)(=O)=O)=C1 YMYKXUBZPNRRQD-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- ONMOULMPIIOVTQ-UHFFFAOYSA-N 98-47-5 Chemical compound OS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 ONMOULMPIIOVTQ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
- C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
-
- 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
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ]]Methyl group]A method for synthesizing ethylene oxide, which belongs to the field of medicine synthesis. The method comprises the following steps: (1) Taking the compound 1 and sodium methylsulfinate as raw materials for reaction to obtain a compound 2; (2) The compound 2 and (S) - (+) -m-nitrobenzenesulfonic acid glycidyl ester are taken as raw materials to react to obtain a compound 3, namely (2S) -2- [ [3- (methylsulfonyl L) phenoxy group]Methyl group]Ethylene oxide. The invention prepares (2S) -2- [ [3- (methylsulfonyl L) phenoxy ]]Methyl group]Process for preparing ethylene oxideThe obtained (2S) -2- [ [3- (methylsulfonyl L) phenoxy) can be obviously improved]Methyl group]The yield and purity of the ethylene oxide are wide in application prospect.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a method for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide.
Background
Heart failure (abbreviated heart failure) is a clinical syndrome of progression of various cardiovascular diseases to the end stage, and despite the continuous progress of therapeutic measures, the mortality rate is still high, wherein the occurrence rate of arrhythmia and sudden cardiac death accounts for 50% -60% of the total mortality rate. The research shows that various mechanisms such as abnormal hemodynamics, nerve secretion activation, and myocardial cell electrophysiological abnormality during heart failure are involved in the occurrence and development of heart failure and arrhythmia, wherein the regulation of beta adrenergic receptors (beta-adrenergic receptor, beta-AR) plays an important role in heart failure and arrhythmia. A large number of basic and clinical researches find that the expression of beta 3 adrenergic receptors (beta 3-adrenergic receptor, beta 3-AR) is obviously increased during heart failure, and the beta 3-AR and a plurality of links of a downstream signal path thereof are changed and participate in the occurrence and development of heart failure and arrhythmia. Beta 3-AR has attracted attention as a new therapeutic target, and provides a new idea for clinically treating heart failure and arrhythmia.
(2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane is an important intermediate for the synthesis of beta 3-AR modulators. The patent application publication No. CN109563103A discloses a method for synthesizing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane, which specifically comprises the following two steps:
step A: 3- (methylsulfonyl) phenol was prepared. To 1-methoxy-3- (methylsulfonyl) benzene (2.58 g,13.86 mmol) under nitrogen at a temperature below-20deg.C 2 Cl 2 To the solution (12 mL) was slowly added a boron tribromide solution (2.63 mL,27.72 mmol). The reaction color changed from pale yellow to red. The reaction is slowed downSlowly warm to room temperature overnight. After completion of the reaction, the mixture was cooled to-20 ℃, then quenched with MeOH, and then with CH 2 Cl 2 And (5) diluting. By slow addition of saturated NaHCO 3 Aqueous solution of NaHCO 3 The reaction mixture was neutralized and then NaHCO was added 3 A solid. The organic layer was separated and taken up with CH 2 Cl 2 The aqueous layer was back-extracted. The combined organic layers were washed with Na2SO 4 Dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give 3- (methylsulfonyl) phenol (2.46 g,103% yield) as a white solid.
And (B) step (B): (S) -2- ((3- (methylsulfonyl) phenoxy) methyl) oxirane was prepared. To a solution of 3- (methylsulfonyl) phenol (2.46 g,14.29 mmol) in acetone (70 mL) was added potassium carbonate (3.95 g,28.57 mmol). The reaction was stirred at room temperature for 10 minutes. Then 3-nitrobenzenesulfonic acid (S) -2-ylmethyl ester (3.70 g,14.29 mmol) was added. The reaction was heated at 70 ℃ overnight under nitrogen. After cooling to room temperature, the mixture was passed through
The pad was filtered, washed with acetone and concentrated. The residue was purified by silica gel column chromatography to give (S) -2- ((3- (methylsulfonyl) phenoxy) methyl) oxirane (3.03 g,93% yield) as a colorless oil.
However, the above method has the following problems: 1. the method adopts a toxic, inflammable and environmentally-friendly raw material boron tribromide reagent in the step A; 2. the step A adopts silica gel column chromatography to purify the product 3- (methylsulfonyl) phenol, and the purification operation is complex.
Disclosure of Invention
In order to solve the above problems, the present invention provides a novel process for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane.
The present invention provides a process for preparing compound 2, comprising the steps of: taking the compound 1 and sodium methylsulfinate as raw materials for reaction to obtain a compound 2;
further, the reaction is carried out in the presence of a cuprous catalyst, a catalyst ligand and an inorganic base.
Further, the cuprous catalyst is one or a mixture of more than two of cuprous iodide, cuprous chloride and cuprous bromide;
the catalyst ligand is L proline;
the inorganic base is one or more of cesium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
Further, the equivalent ratio of compound 1 to sodium methylsulfinate is 1: (1.5-6.0), preferably 1: (3.9-4.9);
the equivalent ratio of the compound 1 to the cuprous catalyst, the catalyst ligand and the inorganic base is 1: (0.3-0.9): (0.9-1.5): (0.2-0.8), preferably 1:0.6:1.2:0.5.
further, the temperature of the reaction is 75-100 ℃, preferably 80-95 ℃; the reaction time is 10 to 30 hours, preferably 16 to 24 hours; the solvent for the reaction is an organic solvent, preferably dimethylsulfoxide.
Further, after the reaction is finished, the method further comprises the following purification steps: pouring the system after the reaction is finished into ice water, adding ethyl acetate, filtering with diatomite, separating liquid, extracting the water phase with ethyl acetate, mixing organic phases, washing with saturated saline water, drying with sodium sulfate, filtering with silica gel, concentrating the filtrate to dryness, adding n-heptane, cooling, crystallizing, filtering, and drying the solid to obtain a compound 2; preferably, the temperature of the cooling crystallization is-5-0 ℃.
The present invention also provides a process for preparing compound 3, comprising the steps of:
(1) Compound 2 was obtained according to the above-described method;
(2) Taking the compound 2 and (S) - (+) -m-nitrobenzenesulfonic acid glycidyl ester as raw materials to react to obtain a compound 3;
further, in the step (2), the reaction is carried out in the presence of an inorganic base, preferably one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate.
Further, in step (2), the equivalent ratio of compound 2 to glycidyl (S) - (+) -m-nitrobenzenesulfonate is 1: (0.85-1.05), preferably 1:0.95;
the equivalent ratio of the compound 2 to the inorganic base is 1: (1.0-2.0), preferably 1:1.5;
the temperature of the reaction is 40-70 ℃, preferably 50-60 ℃; the reaction time is 20 to 30 hours, preferably 24 hours; the solvent for the reaction is an organic solvent, preferably acetone.
Further, in the step (2), after the reaction is finished, the method further comprises the following purification steps: filtering the system after the reaction is finished, stirring and washing a filter cake with acetone, taking filtrate, concentrating to be dry, adding ethyl acetate, methyl tertiary butyl ether and water, stirring, separating liquid, extracting the water phase once again with the methyl tertiary butyl ether, combining organic phases, washing with saturated saline water, drying with sodium sulfate, decoloring with active carbon, filtering with silica gel, concentrating the filtrate to be dry, adding ethanol, heating, dissolving, clarifying, cooling to room temperature, filtering, taking solid, and drying to obtain the compound 3.
The novel method for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide has the following beneficial effects:
1. the initial raw material compound 1 adopted by the invention is cheap and easy to obtain, the cost is low, the reaction condition is mild, and the steps are simple;
2. the invention avoids using the toxic raw material boron tribromide which has strong irritation to skin and eyes, and the adopted reagent has no toxicity to human body and is environment-friendly;
3. the method of the invention uses the compound 1 as a raw material to carry out methane sulfonation reaction to obtain the compound 2, wherein the yield is 74%, the purity is as high as 98.2%, the purification operation is simple, the purification by a chromatographic column is not needed, and the industrial production is easy to realize;
4. the purity of the final product (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide prepared by the method is up to 99%.
In a word, the method for preparing the (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide has the advantages of easily obtained raw materials, mild reaction conditions, simple steps, low cost, safety, no toxicity, easy mass production, capability of obviously improving the yield and purity of the target product (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide and wide application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The route for the preparation of (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane (i.e., compound 3) in the examples of the invention is shown below:
example 1: preparation of (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane
Step 1:
m-bromophenol (5.00 kg,1.0 eq) and DMSO (25.0 kg, 5V) were charged to a 50L reaction vessel. Sodium methylsulfinate (11.50 kg,3.9 eq), L-proline (4.00 kg,1.2 eq), cuprous iodide (3.31 kg,0.6 eq) and cesium carbonate (4.75 kg,0.5 eq) were then added in sequence. Heating to 80 ℃ to react for 24 hours until the m-bromophenol is less than 1%, and cooling to 25 ℃; pouring ice water (125.0 kg), adding ethyl acetate (23.0 kg), adding 1kg of diatomite, filtering to remove copper salt, separating liquid, extracting aqueous phase with 36kg of ethyl acetate, mixing organic phases, washing with 50kg of saturated saline solution, adding 5kg of sodium sulfate, drying, adding 1kg of silica gel, filtering, and concentrating the filtrate under reduced pressure at 45-50 ℃ until dryness; 25kg of n-heptane is added, the temperature is reduced to-5 to 0 ℃ for crystallization, filtration and drying are carried out, and 3.64kg of solid, namely 4-methanesulfonyl phenol, with the HPLC purity of 98.2 percent and the yield of 74 percent is obtained.
HNMR(400M,CDCl 3 ):δ＝7.12-7.15(dt,1H),7.45-7.48(t,1H),7.45-7.48
(m,2H),3.08(s,3H)。
Step 2:
acetone (60.0 kg) is added into a 100L reaction kettle, 4-methanesulfonyl phenol (5.0 kg,1 eq), (S) - (+) -m-nitrobenzenesulfonic acid glycidyl ester (7.26 kg,0.95 eq) prepared in the step 1 is added, after stirring and dissolving evenly, potassium carbonate (7.2.0 kg,1.5 eq) is added and stirred, the system is in an almost white suspension, and the system is heated to 50-60 ℃ for reaction for 24 hours. After the reaction is stopped, the system is cooled to 20-30 ℃, filtered, the filter cake is stirred with acetone, the filtrate is concentrated to dryness, ethyl acetate (16 kg) and methyl tertiary butyl ether (30 kg) are added, water (28 kg) is added, the stirring and the liquid separation are carried out, the water phase is extracted once again by 30kg of methyl tertiary butyl ether, the organic phases are combined, washed once by saturated saline water, dried by adding sodium sulfate, decolorized by adding activated carbon, silica gel H is filled for filtration, and the organic phases are concentrated until a large amount of solids are separated out. Adding 32kg of ethanol, heating to 50-60 ℃, dissolving and clarifying, naturally cooling to room temperature, filtering, repeating for two times, and drying to obtain 4.0kg of target product, namely (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide, wherein the HPLC purity is 99%, and the yield is 61%.
HNMR(400M,CDCl 3 ):δ＝7.53-7.56(dt,1H),7.48-7.51(d,1H),7.46-7.47
(t,1H),7.20-7.23(m,1H),4.35-4.38(dd,1H)，3.96-4.00(q,1H)，3.35-3.39(m,1H)，3.04-3.06(s,3H)，2.92-2.94(t,1H)，2.77-2.79(q,1H)。
Example 2: preparation of (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane
Step 1:
m-bromophenol (5.00 kg,1.0 eq) and DMSO (25.0 kg, 5V) were added to a 50L reactor followed by sodium methylsulfinate (8.84 kg,2.9 eq), L-proline (4.00 kg,1.2 eq), cuprous iodide (3.31 kg,0.6 eq), cesium carbonate (4.75 kg,0.5 eq); heating to 90 ℃ to react for 18-20 hours until the m-bromophenol is less than 1%, and cooling to 25 ℃; pouring ice water (125.0 kg), adding ethyl acetate (23.0 kg), adding 1kg of diatomite, filtering to remove copper salt, separating liquid, extracting aqueous phase with 36kg of ethyl acetate, mixing organic phases, washing with 50kg of saturated saline solution, adding 5kg of sodium sulfate, drying, adding 1kg of silica gel, filtering, and concentrating the filtrate under reduced pressure at 45-50 ℃ until dryness; 25kg of n-heptane is added, the temperature is reduced to-5 to 0 ℃ for crystallization, filtration and drying are carried out, 2.60kg of solid, namely 4-methanesulfonyl phenol, with the HPLC purity of 95.3 percent and the yield of 53 percent is obtained.
HNMR(400M,CDCl 3 ):δ＝7.12-7.15(dt,1H),7.45-7.48(t,1H),7.45-7.48
(m,2H),3.08(s,3H).
Step 2:
as in example 1.
Example 3: preparation of (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane
Step 1:
m-bromophenol (5.00 kg,1.0 eq) and DMSO (25.0 kg, 5V) were added to a 50L reactor followed by sodium methylsulfinate (14.45 kg,4.9 eq), L-proline (4.00 kg,1.2 eq), cuprous iodide (3.31 kg,0.6 eq), cesium carbonate (4.75 kg,0.5 eq); heating to 95 ℃ to react for 16-18 hours until the m-bromophenol is less than 1%, and cooling to 25 ℃; pouring ice water (125.0 kg), adding ethyl acetate (23.0 kg), adding 1kg of diatomite, filtering to remove copper salt, separating liquid, extracting aqueous phase with 36kg of ethyl acetate, mixing organic phases, washing with 50kg of saturated saline solution, adding 5kg of sodium sulfate, drying, adding 1kg of silica gel, filtering, and concentrating the filtrate at 45-50deg.C under reduced pressure to dry; 25kg of n-heptane is added, the temperature is reduced to-5 to 0 ℃ for crystallization, filtration and drying are carried out, and 3.59kg of solid, namely 4-methanesulfonyl phenol, with the HPLC purity of 98.0 percent and the yield of 73.3 percent is obtained.
HNMR(400M,CDCl 3 ):δ＝7.12-7.15(dt,1H),7.45-7.48(t,1H),7.45-7.48
(m,2H),3.08(s,3H).
Step 2:
as in example 1.
Example 4: preparation of (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane
Step 1:
m-bromophenol (5.00 kg,1.0 eq) and DMSO (25.0 kg, 5V) were added to a 50L reactor followed by sodium methylsulfinate (11.50 kg,1.9 eq), L-proline (4.00 kg,1.2 eq), cuprous iodide (3.31 kg,0.6 eq), cesium carbonate (4.75 kg,0.5 eq); heating to 95 ℃ to react for 16-20 hours until the m-bromophenol is less than 1%, and cooling to 25 ℃; pouring ice water (125.0 kg), adding ethyl acetate (23.0 kg), adding 1kg of diatomite, filtering to remove copper salt, separating liquid, extracting aqueous phase with 36kg of ethyl acetate, mixing organic phases, washing with 50kg of saturated saline solution, adding 5kg of sodium sulfate, drying, adding 1kg of silica gel, filtering, and concentrating the filtrate at 45-50 ℃ under reduced pressure to dryness; 25kg of n-heptane is added, the temperature is reduced to-5 to 0 ℃ for crystallization, filtration and drying are carried out, and 1.91kg of solid 4-methanesulfonyl phenol is obtained, the HPLC purity is 98.4%, and the yield is 39%.
HNMR(400M,CDCl 3 ):δ＝7.12-7.15(dt,1H),7.45-7.48(t,1H),7.45-7.48
(m,2H),3.08(s,3H).
Step 2:
as in example 1.
In summary, the present invention provides a process for preparing (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] oxirane. The method has the advantages of easily obtained raw materials, mild reaction conditions, simple steps, low cost, safety, no toxicity and easy mass production, can obviously improve the yield and purity of the target product (2S) -2- [ [3- (methylsulfonyl L) phenoxy ] methyl ] ethylene oxide, and has wide application prospect.
Claims (10)
1. A process for preparing compound 2, characterized by: the method comprises the following steps: taking the compound 1 and sodium methylsulfinate as raw materials for reaction to obtain a compound 2;
2. the method according to claim 1, characterized in that: the reaction is carried out in the presence of a cuprous catalyst, a catalyst ligand and an inorganic base.
3. The method according to claim 2, characterized in that: the cuprous catalyst is one or a mixture of more than two of cuprous iodide, cuprous chloride and cuprous bromide;
the catalyst ligand is L proline;
the inorganic base is one or more of cesium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
4. The method according to claim 2, characterized in that: the equivalent ratio of the compound 1 to the sodium methylsulfinate is 1: (1.5-6.0), preferably 1: (3.9-4.9);
the equivalent ratio of the compound 1 to the cuprous catalyst, the catalyst ligand and the inorganic base is 1: (0.3-0.9): (0.9-1.5): (0.2-0.8), preferably 1:0.6:1.2:0.5.
5. the method according to claim 1, characterized in that: the temperature of the reaction is 75-100 ℃, preferably 80-95 ℃; the reaction time is 10 to 30 hours, preferably 16 to 24 hours; the solvent for the reaction is an organic solvent, preferably dimethylsulfoxide.
6. The method according to any one of claims 1-5, wherein: after the reaction is finished, the method further comprises the following purification steps: pouring the system after the reaction is finished into ice water, adding ethyl acetate, filtering with diatomite, separating liquid, extracting the water phase with ethyl acetate, mixing organic phases, washing with saturated saline water, drying with sodium sulfate, filtering with silica gel, concentrating the filtrate to dryness, adding n-heptane, cooling, crystallizing, filtering, and drying the solid to obtain a compound 2; preferably, the temperature of the cooling crystallization is-5-0 ℃.
7. A process for preparing compound 3, characterized by: the method comprises the following steps:
(1) Compound 2 obtained according to the process of any one of claims 1-6;
(2) Taking the compound 2 and (S) - (+) -m-nitrobenzenesulfonic acid glycidyl ester as raw materials to react to obtain a compound 3;
8. the method according to claim 7, wherein: in the step (2), the reaction is carried out in the presence of an inorganic base, preferably one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
9. The method according to claim 7, wherein: in step (2), the equivalent ratio of compound 2 to glycidyl (S) - (+) -m-nitrobenzenesulfonate is 1: (0.85-1.05), preferably 1:0.95;
the equivalent ratio of the compound 2 to the inorganic base is 1: (1.0-2.0), preferably 1:1.5;
the temperature of the reaction is 40-70 ℃, preferably 50-60 ℃; the reaction time is 20 to 30 hours, preferably 24 hours; the solvent for the reaction is an organic solvent, preferably acetone.
10. The method according to any one of claims 7-9, wherein: in the step (2), after the reaction is finished, the method further comprises the following purification steps: filtering the system after the reaction is finished, stirring and washing a filter cake with acetone, taking filtrate, concentrating to be dry, adding ethyl acetate, methyl tertiary butyl ether and water, stirring, separating liquid, extracting the water phase once again with the methyl tertiary butyl ether, combining organic phases, washing with saturated saline water, drying with sodium sulfate, decoloring with active carbon, filtering with silica gel, concentrating the filtrate to be dry, adding ethanol, heating, dissolving, clarifying, cooling to room temperature, filtering, taking solid, and drying to obtain the compound 3.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651408A (en) * | 2004-11-26 | 2005-08-10 | 中国科学院上海有机化学研究所 | Amino acid accelerated CuI catalyzed aryl halide and coupling reaction of alkyl sulfonate |
| CN109563103A (en) * | 2016-06-06 | 2019-04-02 | 艾尼纳制药公司 | modulators of beta-3 adrenergic receptors for the treatment or prevention of disorders related thereto |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651408A (en) * | 2004-11-26 | 2005-08-10 | 中国科学院上海有机化学研究所 | Amino acid accelerated CuI catalyzed aryl halide and coupling reaction of alkyl sulfonate |
| CN109563103A (en) * | 2016-06-06 | 2019-04-02 | 艾尼纳制药公司 | modulators of beta-3 adrenergic receptors for the treatment or prevention of disorders related thereto |
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| THUY-ANH TRAN 等: "Design of a new series of potent and selective beta-3 adrenergic receptor (β3-AdrR) antagonists for the treatment of acute decompensated heart failure", RESULTS IN CHEMISTRY, vol. 4, 13 September 2022 (2022-09-13), pages 1 - 7 * |
| WEI ZHU 等: "Synthesis of Aryl Sulfones via L-Proline-Promoted CuI-Catalyzed Coupling Reaction of Aryl Halides with Sulfinic Acid Salts", J. ORG. CHEM, vol. 70, 3 March 2005 (2005-03-03), pages 2696 - 2700, XP008149403, DOI: 10.1021/jo047758b * |
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