CN112358379A - Preparation method of optically pure S-configuration 1, 1-bis- (4-fluorophenyl) -2-propanol - Google Patents
Preparation method of optically pure S-configuration 1, 1-bis- (4-fluorophenyl) -2-propanol Download PDFInfo
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- YJVQZQLORSIHLL-UHFFFAOYSA-N CC(O)C(C1=CC=C(F)C=C1)C1=CC=C(F)C=C1 Chemical compound CC(O)C(C1=CC=C(F)C=C1)C1=CC=C(F)C=C1 YJVQZQLORSIHLL-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- JZOSBBLJKXSBBN-UHFFFAOYSA-N [3-(4-diphenylphosphanyl-2,6-dimethoxypyridin-3-yl)-2,6-dimethoxypyridin-4-yl]-diphenylphosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 JZOSBBLJKXSBBN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 3
- 150000002503 iridium Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 34
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 230000007306 turnover Effects 0.000 abstract 2
- 230000000855 fungicidal effect Effects 0.000 abstract 1
- 239000000417 fungicide Substances 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- 239000000047 product Substances 0.000 description 21
- ZIYSZWKTXDQXRA-UHFFFAOYSA-N 1,1-bis(4-fluorophenyl)propan-2-one Chemical compound C=1C=C(F)C=CC=1C(C(=O)C)C1=CC=C(F)C=C1 ZIYSZWKTXDQXRA-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000011521 glass Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 7
- ATZHVIVDMUCBEY-HOTGVXAUSA-N florylpicoxamid Chemical compound C(C)(=O)OC=1C(=NC=CC=1OC)C(=O)N[C@H](C(=O)O[C@H](C(C1=CC=C(C=C1)F)C1=CC=C(C=C1)F)C)C ATZHVIVDMUCBEY-HOTGVXAUSA-N 0.000 description 5
- WDYGPMAMBXJESZ-SFHVURJKSA-N (2s)-1,1-bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1C(N)([C@@H](N)C(C)C)C1=CC=C(OC)C=C1 WDYGPMAMBXJESZ-SFHVURJKSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000003899 bactericide agent Substances 0.000 description 4
- 239000012018 catalyst precursor Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 4
- 238000006459 hydrosilylation reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- 206010039509 Scab Diseases 0.000 description 2
- GJWAPAVRQYYSTK-UHFFFAOYSA-N [(dimethyl-$l^{3}-silanyl)amino]-dimethylsilicon Chemical compound C[Si](C)N[Si](C)C GJWAPAVRQYYSTK-UHFFFAOYSA-N 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- -1 (4-fluorophenyl) -1-methylethyl Chemical group 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000223600 Alternaria Species 0.000 description 1
- 241001465180 Botrytis Species 0.000 description 1
- 102000015782 Electron Transport Complex III Human genes 0.000 description 1
- 108010024882 Electron Transport Complex III Proteins 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 240000005561 Musa balbisiana Species 0.000 description 1
- 241000221662 Sclerotinia Species 0.000 description 1
- 241001533598 Septoria Species 0.000 description 1
- 241000219094 Vitaceae Species 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000021015 bananas Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 235000021021 grapes Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MVILWLLYYQVYNH-UHFFFAOYSA-N pyridine-2-carboxamide Chemical compound NC(=O)C1=CC=CC=N1.NC(=O)C1=CC=CC=N1 MVILWLLYYQVYNH-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
- C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
-
- 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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- 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
本发明公开了一种光学纯S构型1,1‑双‑(4‑氟苯基)‑2‑丙醇制备方法。光学纯S构型1,1‑双‑(4‑氟苯基)‑2‑丙醇化学分子结构式如(II)所示。S构型1,1‑双‑(4‑氟苯基)‑2‑丙醇是新型吡啶酰胺类杀菌剂吡啶菌酰胺(florypicoxamid)的重要中间体，具有很高的经济价值。本发明的化学反应方程式为：
反应式中，化合物(I)通过均相不对称氢化反应，高效高选择性得到光学纯化合物(II)。反应中，催化剂为手性配体与过渡金属的络合物，络合物可以预先制备，也可以原位配合。本发明的催化剂转化数(TON，turnover number)高达100,000，光学纯度最高达97％ee，与现有技术相比具有原子经济性高、绿色无污染、易于工业化等特点。The invention discloses a preparation method of optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol. The chemical molecular structure of optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol is shown in (II). S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol is an important intermediate of a novel pyridine amide fungicide, florypicoxamid, with high economic value. 
The chemical reaction equation of the present invention is: In the reaction formula, compound (I) obtains optically pure compound (II) with high efficiency and high selectivity through a homogeneous asymmetric hydrogenation reaction. In the reaction, the catalyst is a complex of a chiral ligand and a transition metal, and the complex can be prepared in advance or coordinated in situ. The catalyst of the present invention has a turnover number (TON, turnover number) of up to 100,000 and an optical purity of up to 97% ee. Compared with the prior art, the catalyst has the characteristics of high atom economy, green and pollution-free, and easy industrialization.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of optically pure S configuration 1, 1-bis- (4-fluorophenyl) -2-propanol.
Background
Pyridine carboxamide (Florilpicoxamide, trade name: Adavelt) is a second generation novel pyridine carboxamide (picolinamide) bactericide developed by Keditawa, the action mechanism of the bactericide is the same as that of a first generation product fenpicoamid, and the bactericide also acts on the Qi site of a cytochrome bc1 complex of a mitochondrial respiratory system of pathogenic bacteria, namely Qi inhibitors (QiaIs), but the control spectrum is wider, the product is expected to be registered in Asia Pacific region at the time of 2023 years, and the sale peak value of the product is expected to exceed $ 2 billion. Companies plan to market the product globally for a variety of crops. In addition to the Keditawa's name, fenpicoamid, which is the main target of cereals and bananas, florylpicoxamid will be the compound of the new mechanism of action of the target pathogenic bacteria.
Florilpicoxamid is mainly used for grains, grapes, fruit trees, nut trees, vegetables and the like, and is used for preventing and treating powdery mildew (powdery milews), anthracnose (anthracnose), Scab (Scab) and diseases caused by pathogenic bacteria such as Septoria spp, Botrytis spp, Alternaria spp and sclerotinia spp. Keditawa points out that florylpicoxamid can be used in crops at multiple growth stages and can improve crop yield and quality.
The development code of Florilpicoxamid is: x12485659, XDE-659, XR-659; IUPAC names: (1S) -2, 2-bis (4-fluorophenyl) -1-methylethyl N- { [3- (acetyloxy) -4-methoxy-2-pyridinyl ] carbonyl } -L-alanine ester; the core intermediate is S configuration 1, 1-bis- (4-fluorophenyl) -2-propanol. The literature on the synthesis of this intermediate is reported mainly by the dow chemistry. Bravo-Altamirano Karlla et al, Dow Agrosciences LLC, PCT int.appl.,2016109257(CN 107205405), discloses a method for synthesizing 1, 1-bis- (4-fluorophenyl) -2-propanol with S-configuration from protected chiral molecules by the steps of Grignard reagent addition, hydrosilylation, palladium-carbon hydrogenation deprotection and the like. The first two steps of the method require column chromatography, and the reaction needs to be carried out at low temperature. Grignard reagents and hydrosilation reagents are sensitive to oxygen and moisture. Meanwhile, the same team has similar public reports in another patent PCT int.appl.,2016122802(CN 107207414).
Whiteker, Gregory T. et al of Dow Agrosciences LLC in patent PCT Int.appl. 2018009618 discloses a method for preparing 1, 1-bis- (4-fluorophenyl) -2-propanol with S-configuration by Grignard reaction and hydrosilation reduction acidolysis starting from chiral ethyl lactate. The hydrosilation agent can be triethylhydrosilazane, Tetramethyldisilazane (TMDS), Polymethoxyhydrosilane (PMHS), etc. In comparison with the previous patent, although the procedure is a short step, the reagents used are almost identical, the yield is somewhat reduced and the product is partially racemic. Also, the same team has similar published reports in another patent, PCT int.appl., 2018009621.
Disclosure of Invention
The invention discloses a novel preparation method of optically pure S-configuration 1, 1-bis- (4-fluorophenyl) -2-propanol. The chemical molecular structural formula of the optically pure S configuration 1, 1-bis- (4-fluorophenyl) -2-propanol is shown as (II). The S-configuration 1, 1-bis- (4-fluorophenyl) -2-propanol is an important intermediate of novel pyridine amide bactericide pyridine carboxamide (florypicamid), and has high economic value.
Summary of the invention:
the chemical reaction equation of the invention is as follows:
in the reaction formula, the optically pure compound (II) is obtained by the compound (I) through homogeneous asymmetric hydrogenation reaction with high efficiency and high selectivity.
In the reaction, the catalyst is a complex of a chiral ligand and a transition metal, and the complex can be prepared in advance or can be matched in situ. The solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate and n-hexane or a mixture of any proportion. The alkali is one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate in any proportion.
The catalyst is chiral ligand and metal precursor complex. The complex may be prepared in advance or may be incorporated in situ. Preferred chiral ligands include the tridentate ligands f-amphox, f-amphol, f-alphal, O-spiroPNN; the axially chiral diphosphine ligand BINAP, SegPhos, MeO-Biphep, P-Phos. Preferred metal precursors are ruthenium, rhodium, iridium salts, and the molar ratio of ligand to metal is 1.0 to 1.5: 1.
Detailed Description
The invention provides a preparation method of optically pure S configuration 1, 1-bis- (4-fluorophenyl) -2-propanol (II), which comprises the step of carrying out asymmetric hydrogenation reaction on a compound shown as a formula (I) in an organic solvent under the conditions of a catalyst and alkali
In some embodiments, the catalyst is a complex of a chiral ligand comprising a tridentate ligand f-amphox, f-amphol, f-ampho, O-spiroPNN, an axial chiral bisphosphine ligand BINAP, SegPhos, MeO-Biphep, P-Phos, and a metal precursor of ruthenium, rhodium, iridium salts, the chiral ligand having the formula:
in some embodiments, the molar ratio of the chiral ligand to the metal precursor is 1.0 to 1.5: 1.
In some embodiments, the organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate, n-hexane or a mixture thereof in any proportion.
In some embodiments, the base is one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof in any proportion.
In some embodiments, the molar ratio of the catalyst to compound (I) is 1:5, 00-100,000, preferably 1:5, 000-50,000.
In some embodiments, the organic solvent is isopropanol, tetrahydrofuran, or toluene.
In some embodiments, the base is potassium tert-butoxide, potassium carbonate, and the molar ratio of the base to compound (I) is 1:5 to 100, preferably 1:10 to 50.
In some embodiments, the temperature of the asymmetric hydrogenation reaction is 20 to 80 degrees Celsius, more preferably 40 to 60 degrees Celsius.
In some embodiments, the hydrogen pressure of the asymmetric hydrogenation reaction is from 1 to 10MPa, preferably from 2 to 6 MPa.
In some embodiments, the asymmetric hydrogenation reaction is carried out for a period of time ranging from 10 to 30 hours, preferably from 20 to 25 hours.
Compared with the prior art, the invention creatively adopts the asymmetric hydrogenation technology, and the developed process is simple, efficient, green and easy to industrialize through meticulous screening of the catalyst, the solvent, the alkali and other conditions. Specifically, the yield of the invention can reach 95-98%, the enantioselectivity can reach 95% ee at most, the catalyst conversion number can reach 100000 at most, and the product can meet the requirement of preparing raw material medicaments without column chromatography. Compared with the prior art, the method has obvious economic advantages and operational advantages.
The present invention will be described in further detail with reference to the following examples, but the present invention is not limited to the examples.
Detailed Description
The reagents and raw materials used in the present invention are commercially available.
The enantioselectivity of the invention is determined by the following method:
Chiracel AD-H,n-hexane/IPA＝95:5,1.0mL/min,30℃,230nm UV detector,t＝11.72min for(S)isomer and t＝13.54for(R)isomer
example 1
A4.0 mL bottle was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere]2(6.71mg,1.0×10- 2mmol,1eq), ligand (f-amphox) (2.4X 10-2mmol,2.4eq) and anhydrous isopropanol: (iPrOH,2.0 mL). The mixture was stirred in a glove box filled with argon at 25 ℃ for 12.0h to give an orange-red solution, which was used directly for the catalytic reaction.
In a glass tube with a magneton, 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 11.2mg of potassium tert-butoxide were added, 2 ml of isopropanol were added under nitrogen protection, 10. mu.l of a 0.01M catalyst (S/C. RTM.10,000) was added, and hydrogen gas at 4MPa was introduced and the reaction was carried out at 40 ℃ for 24 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and 241mg of the product is obtained after the organic solvent is removed from the filtrate, the yield is 97%, and the enantioselectivity is 80% ee.
A colorless and transparent liquid, and a preparation method thereof,1H NMR(400MHz,CDCl3)δ7.36–7.23(m,4H),7.07–6.89(m,4H),4.52–4.46(m,1H),3.82(d,J＝12.0Hz,1H),1.72(s,1H),1.21(d,J＝8.0Hz,3H)；13C NMR(101MHz,CDCl3)δ163.01,162.80,160.57,160.36,138.24,138.20,137.08,137.05,130.22,130.14,129.63,129.56,115.77,115.62,115.56,115.41,70.08,58.61,21.64.
example 2
A4.0 mL bottle was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere]2(6.71mg,1.0×10- 2mmol,1eq), ligand (O-spiro-PNN) (2.4X 10-2mmol,2.4eq) and anhydrous isopropanol: (iPrOH,2.0 mL). The mixture was stirred in a glove box filled with argon at 25 ℃ for 12.0h to give an orange-red solution, which was used directly for the catalytic reaction.
In a glass tube with a magneton, 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 11.2mg of potassium tert-butoxide were added, 2 ml of tetrahydrofuran was added under nitrogen protection, 10. mu.l of a 0.01M catalyst (S/C. RTM.10,000) was added, and a reaction was carried out under 6MPa of hydrogen at 30 ℃ for 20 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 241mg of the product, wherein the yield is 97%, and the enantioselectivity is 93% ee.
Example 3
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 9.6mg of sodium tert-butoxide are added to a glass test tube with a magnet, 2 ml of tetrahydrofuran are added under nitrogen protection, and 0.2mg of RuCl are added2[(R)-binap][(S,S)-dpen](S/C. about.5,000), hydrogen gas of 10MPa was introduced, and the reaction was carried out at 20 ℃ for 25 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 85 percent ee.
Example 4
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 11.2mg of potassium tert-butoxide are added to a glass test tube with a magnet, 2 ml of isopropanol are added under nitrogen protection, and 0.2mg of RuCl are added2[(R)-Segphos][(S,S)-dpen](S/C. about.5,000), 2MPa of hydrogen was charged, and the reaction was carried out at 20 ℃ for 25 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 235mg of the product, wherein the yield is 95 percent, and the enantioselectivity is 84 percent ee.
Example 5
A glass tube with a magnet was charged with 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 4mg of sodium hydroxide, 2 ml of ethyl acetate under nitrogen protection, 0.2mg of RuCl2[(R)-MeO-Biphep][(S,S)-dpen](S/C. about.5,000), hydrogen gas of 4MPa was introduced, and the reaction was carried out at 20 ℃ for 25 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 86 percent ee.
Example 6
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 8mg of lithium tert-butoxide are added to a glass test tube with a magneton, 2 ml of n-hexane are added under nitrogen protection, and 0.2mg of RuCl is added2[(R)-P-Phos][(S,S)-dpen](S/C. about.5,000), 3MPa of hydrogen was charged, and the reaction was carried out at 30 ℃ for 21 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 88 percent ee.
Example 7
A glass tube with a magneton was charged with 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 10.6mg of sodium carbonate, 2 ml of dichloromethane under nitrogen protection, 0.2mg of RuCl2[(R)-binap][(S)-daipen](S/C. about.5,000), 5MPa of hydrogen was charged, and the reaction was carried out at 40 ℃ for 20 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent in the filtrate is removed to obtain 237mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 87 percent ee.
Example 8
A glass tube with a magnet was charged with 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 5.6mg of potassium hydroxide, 2 ml of 1, 2-dichloroethane under nitrogen protection, 0.2mg of RuCl2[(R)-Segphos][(S)-daipen](S/C. about.5,000), 6MPa of hydrogen was charged, and the reaction was carried out at 50 ℃ for 22 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent in the filtrate is removed to obtain 237mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 89 percent ee.
Example 9
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 13.8mg of potassium carbonate are added into a glass test tube with a magnet, 2 ml of methanol and 0.2mg of RuCl are added under the protection of nitrogen2[(R)-MeO-Biphep][(S)-daipen](S/C. about.5,000), 5MPa of hydrogen was charged, and the reaction was carried out at 70 ℃ for 20 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of a product, wherein the yield is 97%, and the enantioselectivity is 88% ee.
Example 10
A glass tube with a magnet was charged with 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 5.6mg of potassium hydroxide, 2 ml of 1, 2-dichloroethane under nitrogen protection, 0.2mg of RuCl2[(R)-P-Phos][(S)-daipen](S/C. 5,000), fill 7MPa reaction for 23 hours under hydrogen at 50 ℃. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent in the filtrate is removed to obtain 237mg of a product, wherein the yield is 96 percent, and the enantioselectivity is 89 percent ee.
Example 11
A4.0 mL bottle was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere]2(6.71mg,1.0×10- 2mmol,1eq), ligand (f-amphol) (2.1X 10-2mmol,2.1eq) and anhydrous isopropanol: (iPrOH,2.0 mL). The mixture was stirred in a glove box filled with argon at 25 ℃ for 12.0h to give an orange-red solution, which was used directly for the catalytic reaction.
A glass tube with a magneton was charged with 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol) and 11.2mg of potassium tert-butoxide, 2 ml of methyl tert-butyl ether under nitrogen protection, 10. mu.l of 0.01M catalyst (S/C. RTM.10,000) was added, and the mixture was reacted at 40 ℃ for 28 hours under hydrogen pressure of 5 MPa. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 242mg of the product, wherein the yield is 98 percent, and the enantioselectivity is 82 percent ee.
Example 12
A4.0 mL bottle was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere]2(6.71mg,1.0×10- 2mmol,1eq), ligand (f-alpha) (2.2X 10-2mmol,2.2eq) and anhydrous isopropanol: (iPrOH,2.0 mL). The mixture was stirred in a glove box filled with argon at 25 ℃ for 12.0h to give an orange-red solution, which was used directly for the catalytic reaction.
In a glass tube with a magneton, 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 9.6mg of sodium tert-butoxide, 2 ml of ethanol under nitrogen protection, 10. mu.l of a 0.01M catalyst (S/C. RTM. 10,000), 3MPa of hydrogen gas, and reaction at 50 ℃ for 20 hours were added. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of a product, wherein the yield is 97%, and the enantioselectivity is 84% ee.
Example 13
A glass tube with a magneton was charged with 2.46g of 1, 1-bis- (4-fluorophenyl) -acetone (10mmol), 11.2mg of potassium tert-butoxide, 2 ml of isopropanol under nitrogen protection, 10. mu.l of a 0.01M catalyst (O-spiro-PNN/Ir, S/C. RTM. 100,000), charged with 10MPa of hydrogen, and reacted at 80 ℃ for 30 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 241mg of the product, wherein the yield is 97%, and the enantioselectivity is 96% ee.
Example 14
In a glass tube with a magneton, 246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1mmol), 32.5mg of cesium carbonate, 2 ml of toluene under nitrogen protection, 200. mu.l of a 0.01M catalyst (O-spiro-PNN/Ir, S/C. RTM. 500) were added, and the mixture was reacted at 40 ℃ for 30 hours under 1MPa of hydrogen gas. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 242mg of the product, wherein the yield is 98 percent, and the enantioselectivity is 97 percent ee.
Example 15
A glass tube with magnetons was charged with 2.46g of 1, 1-bis- (4-fluorophenyl) -acetone (10mmol), 11.2mg of potassium tert-butoxide, 2 ml of isopropanol under nitrogen protection, 20. mu.l of 0.01M catalyst (O-spiro-PNN/Ir, S/C. 50000), charged with 1MPa of hydrogen, and reacted at 60 ℃ for 28 hours. After the reaction is finished, the reaction product is naturally cooled to room temperature, hydrogen is carefully discharged, the reaction product is filtered by diatomite, and the organic solvent is removed from the filtrate to obtain 240mg of the product, wherein the yield is 97%, and the enantioselectivity is 96% ee.
Claims (10)
1. A preparation method of optically pure S configuration 1, 1-bis- (4-fluorophenyl) -2-propanol (II) comprises the step of carrying out asymmetric hydrogenation reaction on a compound shown as a formula (I) in an organic solvent under the conditions of a catalyst and alkali
The catalyst is a complex of a chiral ligand and a metal precursor, the chiral ligand comprises a tridentate ligand f-amphox, f-amphol, f-ampho, O-spiroPNN, an axial chiral diphosphine ligand BINAP, SegPhos, MeO-Biphep and P-Phos, and the metal precursor is ruthenium, rhodium and iridium salt.
2. The method of claim 1, wherein the molar ratio of chiral ligand to metal precursor is 1.0-1.5: 1.
3. The preparation method according to claim 1, wherein the organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate and n-hexane or a mixture of the two in any proportion.
4. The preparation method of claim 1, wherein the base is one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate or a mixture of the above in any proportion.
5. The preparation method according to claim 1, wherein the molar ratio of the catalyst to the compound (I) is 1: 500 to 100,000, preferably 1:5,000 to 50,000.
6. The production method according to claim 3, wherein the organic solvent is isopropanol, tetrahydrofuran or toluene.
7. The process according to claim 1 or 4, wherein the base is potassium tert-butoxide or potassium carbonate, and the molar ratio of the base to the compound (I) is 1:5 to 100, preferably 1:10 to 50.
8. The process according to claim 1, wherein the asymmetric hydrogenation is carried out at a temperature of 20 to 80 degrees Celsius, more preferably 40 to 60 degrees Celsius.
9. The production process according to claim 1, wherein the hydrogen pressure in the asymmetric hydrogenation is 1 to 10MPa, preferably 2 to 6 MPa.
10. The production process according to claim 1, wherein the asymmetric hydrogenation is carried out for a period of 10 to 30 hours, preferably 20 to 25 hours.
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