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

Preparation method of optically pure S-shaped 1,1-bis- (4-fluorophenyl) -2-propanol Download PDF

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CN112358379B
CN112358379B CN202011242433.XA CN202011242433A CN112358379B CN 112358379 B CN112358379 B CN 112358379B CN 202011242433 A CN202011242433 A CN 202011242433A CN 112358379 B CN112358379 B CN 112358379B
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吴超
马保德
张绪穆
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Southern University of Science and Technology
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    • 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
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Abstract

The invention disclosesA preparation method of optical pure S configuration 1,1-bi- (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-shaped 1,1-bis- (4-fluorophenyl) -2-propanol is an important intermediate of a novel pyridine amide bactericide pyridine carboxamide (florypoxamid), and has high economic value.
Figure DDA0002768865500000011
The chemical reaction equation of the invention is as follows:

Description

Preparation method of optically pure S-shaped 1,1-bis- (4-fluorophenyl) -2-propanol
Technical Field
The invention relates to the field of organic synthesis, and in particular relates to a preparation method of optical 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 Qi sites of 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 rate of 2023, 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 Kedithua name, fenpicoxicamid mainly targets cereals, bananas and the like, florylpicoxamid is a compound of a new action mechanism of target pathogenic bacteria.
Florylpicoxamid 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 published literature for the synthesis of this intermediate is reported mainly by the dow chemistry. Bravo-Altamirano Karla et al, dow Agrosciences LLC, PCT int.appl.,2016109257 (CN 107205405) discloses a method for synthesizing S configuration 1,1-bis- (4-fluorophenyl) -2-propanol from protected chiral molecules through 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. The Grignard 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).
Figure BDA0002768865490000011
Whiteker, gregory T. et al of Dow Agrosciences LLC in patent PCT int.appl.,2018009618 discloses a method for preparing S-configuration 1,1-bis- (4-fluorophenyl) -2-propanol from chiral ethyl lactate through Grignard reaction and hydrosilation reduction acidolysis. 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. Meanwhile, the same team has similar public reports in another patent PCT int.appl., 2018009621.
Figure BDA0002768865490000021
Disclosure of Invention
The invention discloses a novel preparation method of optically pure S-shaped 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-shaped 1,1-bis- (4-fluorophenyl) -2-propanol is an important intermediate of a novel pyridine amide bactericide pyridine carboxamide (florypoxamid), and has high economic value.
Figure BDA0002768865490000022
Summary of the invention:
the chemical reaction equation of the invention is as follows:
Figure BDA0002768865490000023
in the reaction formula, the compound (I) is subjected to homogeneous asymmetric hydrogenation reaction, and the optically pure compound (II) is obtained 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-alpha, 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.
Detailed Description
The invention provides a preparation method of optical pure S configuration 1,1-bi- (4-fluorophenyl) -2-propanol (II), which comprises the step of carrying out asymmetric hydrogenation reaction on a compound shown in a formula (I) in an organic solvent under the conditions of a catalyst and alkali
Figure BDA0002768865490000031
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:
Figure BDA0002768865490000032
in some embodiments, the molar ratio of chiral ligand to metal precursor is 1.0 to 1.5.
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 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 to 100,000, preferably 1:5,000 to 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 1-50.
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 6MPa.
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 to the maximum, the conversion number of the catalyst can reach 100 000 to the maximum, and the product can meet the requirements 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 vial was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere] 2 (6.71mg,1.0×10 - 2 mmol,1 eq), ligand (f-amphox) (2.4X 10) -2 mmol,2.4 eq) and anhydrous isopropanol (I: (II) ((III)) i PrOH,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.
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 11.2mg of potassium tert-butoxide were added to a glass tube with a magneton, 2 ml of isopropanol were added under nitrogen protection, 10. Mu.l of 0.01M catalyst (S/C =10,000) was added, and a reaction was carried out at 40 ℃ for 24 hours by introducing 4MPa of hydrogen. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 241mg of the product, which was 97% in yield and 80% in enantioselectivity.
A colorless and transparent liquid, and a preparation method thereof, 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＝12.0Hz,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
A4.0 mL bottle was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere] 2 (6.71mg,1.0×10 - 2 mmol,1 eq), ligand (O-spiro-PNN) (2.4X 10 -2 mmol,2.4 eq) and anhydrous isopropanol: ( i PrOH,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.
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 11.2mg of potassium tert-butoxide are added to a glass tube with a magneton, 2 ml of tetrahydrofuran are added under nitrogen protection, 10. Mu.l of 0.01M catalyst (S/C =10,000) are added, 6MPa of hydrogen is introduced, and the reaction is carried out at 30 ℃ for 20 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 241mg of the product, which was 97% in yield and 93% in enantioselectivity.
Example 3
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 9.6mg of sodium tert-butoxide in a glass tube with a magnet, 2 ml of tetrahydrofuran are added under nitrogen, and 0.2mg of RuCl are added 2 [(R)-binap][(S,S)-dpen](S/C =5,000), and the reaction was carried out at 20 ℃ for 25 hours with hydrogen gas pressure of 10 MPa. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 240mg of the product, the yield was 96%, and the enantioselectivity was 85% ee.
Example 4
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol), 11.2mg of potassium tert-butoxide, nitrogen gas were added to a glass tube with a magnetonAdding 2 ml of isopropanol under protection, adding 0.2mg of RuCl 2 [(R)-Segphos][(S,S)-dpen](S/C =5,000), 2MPa of hydrogen was introduced, and the reaction was carried out at 20 ℃ for 25 hours. After the reaction was completed, the reaction mixture was naturally cooled to room temperature, hydrogen was carefully discharged, the reaction mixture was filtered through celite, and the organic solvent was removed from the filtrate to obtain 235mg of the product, the yield was 95%, and the enantioselectivity was 84% ee.
Example 5
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 4mg of sodium hydroxide are added into a glass test tube with a magneton, 2 ml of ethyl acetate is added under the protection of nitrogen, and 0.2mg of RuCl is added 2 [(R)-MeO-Biphep][(S,S)-dpen](S/C =5,000), and hydrogen gas of 4MPa was introduced to react at 20 ℃ for 25 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 240mg of the product, the yield was 96%, and the enantioselectivity was 86% ee.
Example 6
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 8mg of lithium tert-butoxide are added to a glass tube with a magneton, 2 ml of n-hexane are added under nitrogen protection, and 0.2mg of RuCl is added 2 [(R)-P-Phos][(S,S)-dpen](S/C =5,000), and the reaction was carried out at 30 ℃ for 21 hours while introducing 3MPa of hydrogen gas. After the reaction, it was cooled to room temperature, followed by careful removal of hydrogen, filtration through celite, and removal of the organic solvent from the filtrate, 240mg of the product was obtained, with a yield of 96%, and an enantioselectivity of 88% ee.
Example 7
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 10.6mg of sodium carbonate are added to a glass tube with a magnetizer, 2 ml of dichloromethane are added under nitrogen protection, and 0.2mg of RuCl is added 2 [(R)-binap][(S)-daipen](S/C =5,000), 5MPa hydrogen gas was introduced, and the reaction was carried out at 40 ℃ for 20 hours. After the reaction, the reaction mixture was cooled to room temperature, and then hydrogen was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to give 237mg of the product, the yield was 96%, and the enantioselectivity was 87% ee.
Example 8
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 5.6mg of potassium hydroxide are added to a glass tube with a magnet, 2 ml of 1,2-dichloroethane are added under nitrogen protection, and 0.2mg of RuCl is added 2 [(R)-Segphos][(S)-daipen](S/C =5,000), 6MPa of hydrogen was charged, and the reaction was carried out at 50 ℃ for 22 hours. After the reaction, it was naturally cooled to room temperature, followed by careful removal of hydrogen, filtration through celite, and removal of the organic solvent from the filtrate, to give 237mg of product, yield 96%, enantioselectivity 89% ee.
Example 9
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 13.8mg of potassium carbonate are added into a glass test tube with a magneton, 2 ml of methanol and 0.2mg of RuCl are added under the protection of nitrogen 2 [(R)-MeO-Biphep][(S)-daipen](S/C =5,000), and hydrogen gas of 5MPa was introduced and the reaction was carried out at 70 ℃ for 20 hours. After the reaction, it was cooled to room temperature, followed by careful removal of hydrogen, filtration through celite, and removal of the organic solvent from the filtrate, 240mg of the product was obtained, with a yield of 97%, and an enantioselectivity of 88% ee.
Example 10
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 5.6mg of potassium hydroxide are added into a glass test tube with a magnet, 2 ml of 1,2-dichloroethane and 0.2mg of RuCl are added under the protection of nitrogen 2 [(R)-P-Phos][(S)-daipen](S/C =5,000), 7MPa of hydrogen was introduced, and the reaction was carried out at 50 ℃ for 23 hours. After the reaction, the reaction mixture was cooled to room temperature, and then hydrogen was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to give 237mg of the product, the yield was 96%, and the enantioselectivity was 89% ee.
Example 11
A4.0 mL vial was charged with the catalyst precursor [ Ir (COD) Cl ] under an argon atmosphere] 2 (6.71mg,1.0×10 - 2 mmol,1 eq), ligand (f-amphol) (2.1X 10 -2 mmol,2.1 eq) and anhydrous isopropanol: ( i PrOH,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.
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 11.2mg of potassium tert-butoxide are added to a glass tube with a magneton, 2 ml of methyl tert-butyl ether are added under nitrogen protection, 10. Mu.l of 0.01M catalyst (S/C =10,000) are added, 5MPa of hydrogen is introduced, and the reaction is carried out at 40 ℃ for 28 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 242mg of the product, which was 98% in yield and 82% in enantioselectivity.
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 - 2 mmol,1 eq), ligand (f-alpha) (2.2X 10 -2 mmol,2.2 eq) and anhydrous isopropanol: ( i PrOH,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.
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 9.6mg of sodium tert-butoxide are added to a glass tube with a magneton, 2 ml of ethanol are added under nitrogen protection, 10. Mu.l of 0.01M catalyst (S/C =10,000) are added, 3MPa hydrogen is introduced, and the reaction is carried out at 50 ℃ for 20 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 240mg of the product, which was 97% in yield and 84% in enantioselectivity.
Example 13
2.46g of 1, 1-bis- (4-fluorophenyl) -acetone (10 mmol) and 11.2mg of potassium tert-butoxide were placed in a glass tube with a magneton, 2 ml of isopropanol were added under nitrogen protection, 10. Mu.l of 0.01M catalyst (O-spiro-PNN/Ir, S/C =100,000) were added, 10MPa of hydrogen was introduced, and the reaction was carried out at 80 ℃ for 30 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 241mg of the product, which was 97% in yield and 96% in enantioselectivity.
Example 14
246mg of 1, 1-bis- (4-fluorophenyl) -acetone (1 mmol) and 32.5mg of cesium carbonate were put into a glass tube with a magneton, 2 ml of toluene was added under nitrogen protection, 200. Mu.l of 0.01M catalyst (O-spiro-PNN/Ir, S/C = 500) was added, 1MPa of hydrogen was introduced, and the reaction was carried out at 40 ℃ for 30 hours. After the reaction, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 242mg of the product, which was 98% in yield and 97% enantioselectivity.
Example 15
A glass tube with a magneton was charged with 2.46g of 1, 1-bis- (4-fluorophenyl) -acetone (10 mmol), 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, the reaction mixture was cooled to room temperature, and then the hydrogen gas was carefully discharged, followed by filtration through celite, and the organic solvent was removed from the filtrate to obtain 240mg of the product, which was 97% in yield and 96% in enantioselectivity.

Claims (9)

1. Optical puritySThe preparation method of the configuration 1,1-bis- (4-fluorophenyl) -2-propanol (II) comprises the step of carrying out asymmetric hydrogenation reaction on a compound shown as the formula (I) in an organic solvent under the conditions of a catalyst and alkali
Figure 690419DEST_PATH_IMAGE001
The catalyst is a complex of a chiral ligand and a metal precursor, the chiral ligand is a tridentate ligand f-amphox, f-amphol, f-ampho or O-spiroPNN or an axial chiral diphosphine ligand BINAP, segPhos, meO-Biphep or P-Phos, and 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.
2. The preparation method of 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, n-hexane or a mixture of any proportion.
3. 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.
4. The production method according to claim 1, wherein the molar ratio of the catalyst to the compound (I) is 1.
5. The production method according to claim 3, wherein the organic solvent is isopropanol, tetrahydrofuran or toluene.
6. 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.
7. The method of claim 1, wherein the asymmetric hydrogenation reaction is carried out at a temperature of 40 to 60 degrees Celsius.
8. The production process according to claim 1, wherein the hydrogen pressure in the asymmetric hydrogenation is 2 to 6MPa.
9. The production method according to claim 1, wherein the asymmetric hydrogenation is carried out for a period of 20 to 25 hours.
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