CN112358379B - Preparation method of optically pure S-shaped 1,1-bis- (4-fluorophenyl) -2-propanol - Google Patents

Abstract

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 method for preparing optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol. The molecular structural formula 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 new type of pyridine amide fungicide, florypicoxamid, and has high economic value.

Chemical reaction equation of the present invention is:

In the reaction formula, the compound (I) can obtain the optically pure compound (II) efficiently and selectively 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 in situ. The catalyst conversion number (TON, turnover number) of the present invention is as high as 100,000, and the optical purity is as high as 97% ee. Compared with the prior art, it has the characteristics of high atom economy, green and pollution-free, and easy industrialization.

Description

A kind of preparation method of optically pure S configuration 1,1-bis-(4-fluorophenyl)-2-propanol

technical field

The invention relates to the field of organic synthesis, in particular to a preparation method of optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol.

Background technique

Florylpicoxamid (trade name: Adavelt) is a new second-generation picolinamide fungicide developed by Corteva. Its mechanism of action is the same as that of the first-generation product fenpicoxamid, and it also acts on cytochromes in the mitochondrial respiratory system of pathogenic bacteria. The Qi site of the bc1 complex, namely Qi inhibitors (QiIs), has a wider spectrum of prevention and treatment. This product is expected to be the first to be registered in the Asia-Pacific region in 2023, and its sales peak is expected to exceed US$200 million. The company plans to market the product globally for a variety of crops. According to Corteva, fenpicoxamid mainly targets grains and bananas. In addition to these markets, florylpicoxamid will become a compound with a new mechanism of action targeting pathogenic bacteria.

Florylpicoxamid is mainly used in grains, grapes, fruit trees, nut trees, vegetables, etc. to prevent and control powdery mildews, anthracnose, scab, and diseases caused by Septorias pp., Botrytis ( Botrytis spp.), Alternaria spp., Monilinias pp. and other pathogenic bacteria. Corteva pointed out that florylpicoxamid can be used in multiple growth stages of crops and can improve crop yield and quality.

The development code of Florylpicoxamid is: X12485659, XDE-659, XR-659; the IUPAC name is: (1S)-2,2-bis(4-fluorophenyl)-1-methylethyl N-{[3-( Acetyloxy)-4-methoxy-2-pyridyl]carbonyl}-L-alanine ester; its core intermediate is S configuration 1,1-bis-(4-fluorophenyl)-2- propanol. The published literature on the synthesis of this intermediate is mainly reported by Dow Chemical. Bravo-Altamirano Karla of Dow Agrosciences LLC and others disclosed in PCTInt.Appl., 2016109257 (CN 107205405) that they invented a kind of chiral molecule starting from protection, through Grignard reagent addition, silicon hydrogen reduction, palladium carbon hydrogenation deprotection, etc. Step, the method for synthesizing S configuration 1,1-bis-(4-fluorophenyl)-2-propanol. The first two steps of the method require column chromatography, and the reaction needs to be carried out at low temperature. Grignard reagents and silyl hydride reagents are sensitive to oxygen and moisture. At the same time, the same team has a similar public report in another patent PCT Int.Appl., 2016122802 (CN107207414).

Whiteker, Gregory T. et al. of Dow Agrosciences LLC disclosed in the patent PCT Int.Appl., 2018009618 that they invented a method to prepare the S configuration starting from chiral ethyl lactate through Grignard reaction and silane reduction acidolysis 1,1-Bis-(4-fluorophenyl)-2-propanol method. The silyl hydrogen reagent can be triethyl silyl hydride, tetramethyldisilazane (TMDS), polymethoxyhydrogen silane (PMHS) and the like. Compared with the previous patent, although the steps of this route are one step shorter, the reagents used are almost the same, the yield is somewhat reduced, and the product is partially racemized. At the same time, the same team has similar public reports in another patent PCT Int.Appl., 2018009621.

Contents of the invention

The invention discloses a new method for preparing optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol. The molecular structural formula 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 new type of pyridine amide fungicide, florypicoxamid, and has high economic value.

Summary of the invention:

Chemical reaction equation of the present invention is:

In the reaction formula, the compound (I) can obtain the optically pure compound (II) efficiently and selectively 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 in situ. The solvent is methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-hexane One or a mixture in any proportion. The base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture in any proportion.

The catalyst is a chiral ligand and metal precursor complex. Complexes can be prepared in advance or in situ. Preferred chiral ligands include tridentate ligands f-amphox, f-amphol, f-ampha, O-spiroPNN; axial chiral bisphosphine ligands BINAP, SegPhos, MeO-Biphep, P-Phos. Preferred metal precursors are ruthenium, rhodium, iridium salts, and the molar ratio of ligand to metal is 1.0-1.5:1.

Detailed description of the invention

The present invention provides a method for preparing optically pure S-configuration 1,1-bis-(4-fluorophenyl)-2-propanol (II), which comprises, in an organic solvent, a compound represented by formula (I) in a catalyst and Asymmetric hydrogenation under alkaline conditions

In some embodiments, the catalyst is a complex of a chiral ligand and a metal precursor, and the chiral ligand includes a tridentate ligand f-amphox, f-amphol, f-ampha, O-spiroPNN, Axial chiral bisphosphine ligands BINAP, SegPhos, MeO-Biphep, P-Phos, the metal precursors are ruthenium, rhodium, iridium salts, the structural formula of the chiral ligands is as follows:

In some embodiments, the molar ratio of the chiral ligand to the metal precursor is 1.0-1.5:1.

In some embodiments, the organic solvent is methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane Alkanes, ethyl acetate, n-hexane or a mixture of any proportion.

In some embodiments, the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture 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 1:5-100, preferably 1:10-50.

In some embodiments, the temperature of the asymmetric hydrogenation reaction is 20-80 degrees Celsius, more preferably 40-60 degrees Celsius.

In some embodiments, the hydrogen pressure of the asymmetric hydrogenation reaction is 1-10 MPa, preferably 2-6 MPa.

In some embodiments, the time for the asymmetric hydrogenation reaction is 10-30 hours, preferably 20-25 hours.

Compared with the prior art, the invention adopts the asymmetric hydrogenation technology creatively, and carefully selects the catalyst, solvent, alkali and other conditions, and the developed process is simple, efficient, green and easy to industrialize. Specifically, the yield of the present invention can reach 95%-98%, the enantioselectivity can reach up to 95% ee, the catalyst conversion number can reach up to 100,000, and the product can be obtained without column chromatography to meet the requirements for the preparation of raw materials. demand. Compared with the existing technology, it has obvious economic advantages and operational advantages.

The above content of the present invention will be further described in detail below through specific examples, but the present invention is not limited to the examples.

Detailed ways

The reagents and raw materials used in the present invention are all available on the market.

The enantioselectivity of the present invention adopts following method to measure:

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

Add catalyst precursor [Ir(COD)Cl] ₂ (6.71mg, 1.0×10 ^{- 2} mmol, 1eq), ligand (f-amphox) (2.4×10 ^-2 mmol, 2.4eq) and anhydrous isopropanol ( ^iPrOH , 2.0mL). The mixture was stirred at 25° C. for 12.0 h in an argon-filled glove box to obtain an orange-red solution, which can be directly used for catalytic reactions.

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 11.2mg potassium tert-butoxide to a glass test tube with a magnet, add 2ml of isopropanol under nitrogen protection, and add 10 μl 0.01M catalyst (S/C=10,000), filled with 4MPa hydrogen, reacted at 40°C for 24 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 241 mg of the product, with a yield of 97% and an enantioselectivity of 80% ee.

Colorless transparent liquid, ¹ H NMR (400MHz, CDCl ₃ ) δ7.36–7.23(m,4H),7.07–6.89(m,4H),4.52–4.46(m,1H),3.82(d,J＝12.0 Hz,1H),1.72(s,1H),1.21(d,J=8.0Hz,3H); ¹³ C NMR(101MHz,CDCl ₃ )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

Add catalyst precursor [Ir(COD)Cl] ₂ (6.71mg, 1.0×10 ^{- 2} mmol, 1eq), ligand (O-spiro-PNN) (2.4×10 ^-2 mmol, 2.4eq) and anhydrous isopropanol ( ⁱ PrOH, 2.0mL). The mixture was stirred at 25° C. for 12.0 h in an argon-filled glove box to obtain an orange-red solution, which can be directly used for catalytic reactions.

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 11.2mg of potassium tert-butoxide to a glass test tube with a magnet, add 2ml of tetrahydrofuran under nitrogen protection, and add 10 microliters of 0.01M catalyst (S/C=10,000), filled with 6MPa hydrogen, and reacted at 30°C for 20 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 241 mg of the product, with a yield of 97% and an enantioselectivity of 93% ee.

Example 3

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 9.6mg sodium tert-butoxide to a glass test tube with a magnet, add 2ml tetrahydrofuran under nitrogen protection, add 0.2mg RuCl ₂ [ (R)-binap][(S,S)-dpen](S/C=5,000), filled with 10MPa hydrogen, reacted at 20°C for 25 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 240 mg of the product, with a yield of 96% and an enantioselectivity of 85% ee.

Example 4

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 11.2mg of potassium tert-butoxide to a glass test tube with a magnet, add 2ml of isopropanol under nitrogen protection, add 0.2mg of RuCl ₂ [(R)-Segphos][(S,S)-dpen] (S/C=5,000), filled with 2MPa hydrogen, reacted at 20°C for 25 hours. After the reaction, it was naturally cooled to room temperature, the hydrogen gas was released carefully, filtered with diatomaceous earth, and the filtrate was stripped of the organic solvent to obtain 235 mg of the product with a yield of 95% and an enantioselectivity of 84% ee.

Example 5

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 4mg of sodium hydroxide to a glass test tube with a magnet, add 2ml of ethyl acetate under nitrogen protection, add 0.2mg of RuCl ₂ [ (R)-MeO-Biphep][(S,S)-dpen](S/C=5,000), filled with 4MPa hydrogen, reacted at 20°C for 25 hours. After the reaction, it was naturally cooled to room temperature, the hydrogen gas was released carefully, filtered with diatomaceous earth, and the filtrate was stripped of the organic solvent to obtain 240 mg of the product with a yield of 96% and an enantioselectivity of 86% ee.

Example 6

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 8mg lithium tert-butoxide to a glass test tube with a magnet, add 2ml of n-hexane under nitrogen protection, add 0.2mg RuCl ₂ [ (R)-P-Phos][(S,S)-dpen](S/C=5,000), filled with 3MPa hydrogen, reacted at 30°C for 21 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 240 mg of the product, with a yield of 96% and an enantioselectivity of 88% ee.

Example 7

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 10.6mg of sodium carbonate to a glass test tube with a magnet, add 2ml of dichloromethane under nitrogen protection, add 0.2mg of RuCl ₂ [ (R)-binap][(S)-daipen] (S/C=5,000), filled with 5MPa hydrogen, reacted at 40°C for 20 hours. After the reaction, cool to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 237 mg of the product, with a yield of 96% and an enantioselectivity of 87% ee.

Example 8

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 5.6mg potassium hydroxide to a glass test tube with a magnet, and add 2 milliliters of 1,2-dichloroethane under nitrogen protection, Add 0.2mg RuCl ₂ [(R)-Segphos][(S)-daipen] (S/C=5,000), fill with 6MPa hydrogen, and react at 50°C for 22 hours. After the reaction, it was naturally cooled to room temperature, and the hydrogen gas was released carefully, filtered through celite, and the filtrate was stripped of the organic solvent to obtain 237 mg of the product, with a yield of 96% and an enantioselectivity of 89% ee.

Example 9

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 13.8mg of potassium carbonate to a glass test tube with a magnet, add 2ml of methanol under nitrogen protection, add 0.2mg of RuCl ₂ [(R )-MeO-Biphep][(S)-daipen](S/C=5,000), filled with 5MPa hydrogen, and reacted at 70°C for 20 hours. After the reaction, it was naturally cooled to room temperature, and the hydrogen gas was released carefully, filtered through diatomaceous earth, and the organic solvent was removed from the filtrate to obtain 240 mg of the product with a yield of 97% and an enantioselectivity of 88% ee.

Example 10

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 5.6mg potassium hydroxide to a glass test tube with a magnet, and add 2 milliliters of 1,2-dichloroethane under nitrogen protection, Add 0.2 mg RuCl ₂ [(R)-P-Phos][(S)-daipen] (S/C=5,000), fill with 7 MPa hydrogen, and react at 50°C for 23 hours. After the reaction, it was naturally cooled to room temperature, and the hydrogen gas was released carefully, filtered through celite, and the filtrate was stripped of the organic solvent to obtain 237 mg of the product, with a yield of 96% and an enantioselectivity of 89% ee.

Example 11

Add catalyst precursor [Ir(COD)Cl] ₂ (6.71mg, 1.0×10 ^{- 2} mmol, 1eq), ligand (f-amphol) (2.1×10 ^-2 mmol, 2.1eq) and anhydrous isopropanol ( ^iPrOH , 2.0mL). The mixture was stirred at 25° C. for 12.0 h in an argon-filled glove box to obtain an orange-red solution, which can be directly used for catalytic reactions.

Add 246mg 1,1-bis-(4-fluorophenyl)-acetone (1mmol) and 11.2mg potassium tert-butoxide to a glass test tube with a magnet, add 2ml methyl tert-butyl ether under nitrogen protection, add 10 microliters of 0.01M catalyst (S/C=10,000), filled with 5MPa hydrogen, reacted at 40°C for 28 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 242 mg of the product with a yield of 98% and an enantioselectivity of 82% ee.

Example 12

Add catalyst precursor [Ir(COD)Cl] ₂ (6.71mg, 1.0×10 ^{- 2} mmol, 1eq), ligand (f-ampha) (2.2×10 ^-2 mmol, 2.2eq) and anhydrous isopropanol ( ^iPrOH , 2.0mL). The mixture was stirred at 25° C. for 12.0 h in an argon-filled glove box to obtain an orange-red solution, which can be directly used for catalytic reactions.

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 9.6mg of sodium tert-butoxide to a glass test tube with a magnet, add 2ml of ethanol under nitrogen protection, and add 10 microliters of 0.01M catalyst (S/C=10,000), filled with 3MPa hydrogen, and reacted at 50°C for 20 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 240 mg of the product with a yield of 97% and an enantioselectivity of 84% ee.

Example 13

Add 2.46g 1,1-bis-(4-fluorophenyl)-acetone (10mmol) and 11.2mg potassium tert-butoxide to a glass test tube with a magnet, add 2ml isopropanol under nitrogen protection, add 10 μg Liter 0.01M catalyst (O-spiro-PNN/Ir, S/C=100,000), fill with 10MPa hydrogen, and react at 80°C for 30 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 241 mg of the product, with a yield of 97% and an enantioselectivity of 96% ee.

Example 14

Add 246mg of 1,1-bis-(4-fluorophenyl)-acetone (1mmol), 32.5mg of cesium carbonate to a glass test tube with a magnet, add 2ml of toluene under nitrogen protection, and add 200 microliters of 0.01M catalyst (O-spiro-PNN/Ir, S/C=500), filled with 1MPa hydrogen, and reacted at 40°C for 30 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 242 mg of the product with a yield of 98% and an enantioselectivity of 97% ee.

Example 15

Add 2.46g of 1,1-bis-(4-fluorophenyl)-acetone (10mmol), 11.2mg of potassium tert-butoxide to a glass test tube with a magnet, add 2ml of isopropanol under nitrogen protection, add 20 μg Add 0.01M catalyst (O-spiro-PNN/Ir, S/C=50000), fill with 1MPa hydrogen, and react at 60°C for 28 hours. After the reaction, cool down to room temperature naturally, release the hydrogen carefully, filter with diatomaceous earth, and remove the organic solvent from the filtrate to obtain 240 mg of the product, with a yield of 97% and an enantioselectivity of 96% ee.

Claims (9)

1. A method for preparing optically pure S- configuration 1,1-bis-(4-fluorophenyl)-2-propanol (II), which comprises, in an organic solvent, the compound shown in formula (I) in a catalyst and a base asymmetric hydrogenation reaction

The catalyst is a complex of a chiral ligand and a metal precursor, and the chiral ligand is a tridentate ligand f-amphox, f-amphol, f-ampha or O-spiroPNN or an axial chiral bisphosphine ligand Body BINAP, SegPhos, MeO-Biphep or P-Phos, the metal precursor is ruthenium, rhodium or iridium salt; the molar ratio of the chiral ligand to the metal precursor is 1.0-1.5:1. 2. the preparation method according to claim 1, described organic solvent is methanol, ethanol, Virahol, THF, toluene, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1 , One of 2-dichloroethane, ethyl acetate, n-hexane or a mixture of any proportion. 3. preparation method according to claim 1, described alkali is a kind of of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate Or a mixture of any proportion. 4. The preparation method according to claim 1, wherein the molar ratio of the catalyst to the compound (I) is 1:5,000-50,000. 5. preparation method according to claim 3, described organic solvent is Virahol, THF or toluene. 6. The preparation method according to claim 1 or 4, wherein the base is potassium tert-butoxide or potassium carbonate, and the molar ratio of the base to compound (I) is 1:10-50. 7. The preparation method according to claim 1, wherein the temperature of the asymmetric hydrogenation reaction is 40-60 degrees Celsius. 8. The preparation method according to claim 1, wherein the hydrogen pressure of the asymmetric hydrogenation reaction is 2-6 MPa. 9. The preparation method according to claim 1, the time of the asymmetric hydrogenation reaction is 20-25 hours.