WO2023082465A1 - Method for preparing amino alcohol by asymmetric hydrogenation and application thereof - Google Patents

Abstract

The present invention relates to the technical field of chemical catalytic reaction. Disclosed are a method for preparing an amino alcohol by asymmetric hydrogenation and an application thereof. A starting raw material of the chemical reaction is an amino ketone compound (I); the amino ketone compound (I) is subjected to asymmetric catalytic hydrogenation reduction to obtain a chiral amino alcohol intermediate (II), the yield of the intermediate (II) being almost quantitative, and the enantioselectivity being up to 99%ee; the intermediate (II) undergoes intramolecular cyclization under suitable conditions to obtain chiral pyrrolidine or piperidine having high optical activity. By utilizing the present method, a series of chiral pyrrolidine and piperidine compounds can be efficiently and highly selectively prepared, and the method has an important practical value and industrial prospect.

Description

A kind of method and its application of asymmetric hydrogenation preparation aminoalcohol technical field

The invention belongs to the technical field of chemical catalytic reaction, and in particular relates to a method for preparing amino alcohol by asymmetric hydrogenation and its application.

Background technique

Chiral pyrrolidine compounds widely exist in bioactive molecules, drugs, and natural product fragments. For example, the drug Larotrectinib sulfate, which was launched in 2018, can be used to treat adult and pediatric patients with locally advanced or metastatic solid tumors carrying NTRK gene fusions ; The drug Osilodrostat, which will be launched in 2020, is the first FDA-approved human 11-β hydroxylase inhibitor, which can directly block the synthesis of adrenal cortisol, and is an orphan drug for the treatment of hypercortisolism; and the natural product nicotine.

Due to the great industrial value of chiral pyrrolidine and piperidine compounds in the field of pharmacy, people have conducted in-depth research on their synthetic methods and developed many synthetic routes. At present, there are many ways to obtain chiral pyrrolidine, but because these methods still have certain limitations, especially the high cost and the practicability still need to be improved, there is no simple and efficient method that can be widely used in hand In the asymmetric synthesis of sexual pyrrolidines. Therefore, it is of great significance to realize the large-scale production of chiral pyrrolidines by means of asymmetric catalytic preparation technology.

Contents of the invention

The invention discloses a method for preparing amino alcohol by asymmetric hydrogenation and its application. The chemical reaction equation is as follows:

Among them, the R ¹ of the general chemical formula (I) and (II) represents a C1-C12 alkyl, aryl or a heteroatom-substituted alkyl or aryl, R ² represents an amino protecting group, and n represents a group containing 1-5 A saturated linear or branched group of carbon atoms, said * means that there are two configurations of R or S; the transition metal catalyst used is formed by mixing a metal salt and a chiral ligand, and the catalyst metal salt is selected from ruthenium, rhodium , iridium, palladium and other common transition metal compounds, chiral ligands are selected from:

As a preferred version of the present invention, the ^R of general chemical formula (I) and (II) Represent amino protecting group, be selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Watt methoxycarbonyl ( Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl or isopropyl)oxycarbonyl (COOMe, COOEt, COO ⁱ Pr), phthaloyl (Pht) , p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, trityl (Trt), 2,4-dimethoxy Benzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), etc.

As a preferred version of the present invention, the solvent used for asymmetric hydrogenation is methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, ethyl acetate, n-hexane, dichloromethane, 1,2-dichloroethane , toluene, xylene, 1,4-dioxane, methyl tert-butyl ether or a mixture of any proportion.

As a preferred version of the present invention, the base used in the asymmetric hydrogenation is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide , Potassium methylate or a mixture of any proportion.

As a preferred solution of the present invention, the molar ratio of the intermediate (I) to the catalyst is 5 mmol: 0.01-1 nmol.

As a preferred solution of the present invention, the reaction temperature of the asymmetric hydrogenation is 20-80 degrees Celsius.

As a preferred solution of the present invention, the pressure of the asymmetric hydrogenation is 1-10Mpa.

As a preferred solution of the present invention, the transition metal catalyst is preferably [Ir(COD)Cl] ₂ , and the chiral ligand is preferably:

and its enantiomer L10.

The invention also discloses an asymmetric synthesis method of chiral pyrrolidine and piperidine compounds, the synthesis route of which is as follows:

Wherein, when n in the compounds (I) and (II)=3 or 4, the chiral aminoalcohol compound (II) is prepared by the above-mentioned asymmetric catalytic hydrogenation method.

Further, it can be realized through the following technical solutions, including:

Wherein, the alcoholic hydroxyl group of the chiral aminoalcohol compound (II) is converted into X with a suitable reagent to obtain the intermediate (III), and X is selected from common leaving groups such as halogen, sulfonate, phosphate, including chlorine, Bromine, iodine, mesylate (OMs), triflate (OTf), p-toluenesulfonate (OTs), nitrosulfonate (ONs), etc.

Under appropriate conditions, the intermediate (III) reacts with a suitable reagent to remove the amino protecting group R ² , and when R ² is tert-butoxycarbonyl (Boc), the reagent for removing the amino protecting group is hydrochloric acid, trifluoroacetic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, etc., preferably trifluoroacetic acid, methanesulfonic acid, etc.

The intermediates from which the protective groups have been removed do not undergo separation and purification, and undergo an intramolecular nucleophilic ring-closing reaction under alkaline conditions to obtain optically pure chiral pyrrolidine and piperidine compounds. In particular, this method can be applied to the asymmetric synthesis of intermediates of nicotine and larotrectinib, and the synthetic route is as follows:

Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention successfully develops a synthesis method of chiral pyrrolidine. The compound (I) undergoes a catalytic hydrogenation reaction under the action of a chiral ligand, and the chiral alcohol intermediate (II) can be obtained efficiently. The reaction has high stability and reactivity, realizes excellent stereo control, and can obtain chiral alcohol intermediates with enantioselectivity greater than 99%.

(2) Through a large number of experimental studies, it was found that using the preferred catalyst system [Ir(COD)Cl] ₂ /f-phamidol, the asymmetric hydrogenation reaction has very high reactivity, and the catalyst turnover number (TON, turnover number) is as high as 500,000.

(3) The present invention is stable in operation, low in cost, friendly to the environment, and has extremely high industrialization value.

Detailed ways

Some non-limiting examples are further disclosed below to further illustrate the present invention, but the present invention is not limited thereto. For the experimental methods that do not indicate the specific conditions in the examples, usually follow the conventional conditions and the conditions described in the manual, or according to the conditions suggested by the manufacturer; the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified. .

Embodiment 1: In compound (I), R ¹ is phenyl, and R ² is tert-butoxycarbonyl (Boc).

[Ir(COD)Cl] ₂ (3.4 mg, 0.005 mol) and chiral ligand (S,S,R)-f-phamidol-L3 (6.0 mg, 0.0105 mmol) were dissolved in 5 mL under argon atmosphere in isopropanol and stirred at room temperature for 3 hours to obtain a clear orange solution. Take 10uL of the orange solution with a micro syringe and add it to the mixture of intermediate (II-a) (52.6mg, 0.2mmol), isopropanol (1mL) and potassium tert-butoxide (1.1mg, 0.01mmol). The reaction system was placed in an autoclave, and the gas in the autoclave was replaced with hydrogen three times, and finally filled with 50 atm of hydrogen, and reacted at 25° C. for 2 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 53 mg of a colorless oily liquid, i.e. the hydrogenated product (II-a). The rate is 99%. Through HPLC analysis, the measured ee value is 99%.

Example 2-10

The present invention is to investigate the effect of the type of catalyst used in the asymmetric hydrogenation reaction on the conversion rate (conv.) and enantioselectivity (ee). On the basis of Example 1, the catalyst ligand L3 was replaced by L1, L2, L4, L5, L6, L7, L8, L9, and L10 in sequence.

The impact results of different catalysts on the conversion rate and ee value of compound (I-a) reduction in Examples 1-10 are shown in the following table 1; wherein, conversion rate (conv.) and enantioselectivity (ee) are measured by HPLC have to.

Table 1

Examples 11-18

In order to investigate the influence of the reaction system solvent on the reaction, on the basis of Example 1, the solvent was replaced by MeOH, EtOH, EtOAc, DCM, THF, Hexane and Toluene in sequence. The reaction time is 2 h, S/C=10000, the effect of different solvents on the reduction conversion rate and ee value of compound (I-a) is shown in Table 2 below. It is worth mentioning that in isopropanol, when the chiral ligand used is its enantiomer (R,R,S)-f-phamidol-L3, the reverse configuration can be obtained with good stereoselectivity The product II-a, this result can be convenient for us to select the corresponding catalyst according to the chirality of the substrate in practical application. Wherein, conversion (conv.) and enantioselectivity (ee) were measured by HPLC.

Table 2

serial number	catalyst	Reaction solvent	conv.(%)	ee(%)
Example 1	(S,S,R)-f-phamidol-L3	i PrOH	>99	>99
Example 11	(S,S,R)-f-phamidol-L3	MeOH	NR	-
Example 12	(S,S,R)-f-phamidol-L3	EtOH	twenty one	>99
Example 13	(S,S,R)-f-phamidol-L3	EtOAc	40	>99
Example 14	(S,S,R)-f-phamidol-L3	DCM	>99	>99
Example 15	(S,S,R)-f-phamidol-L3	THF	8	>99
Example 16	(S,S,R)-f-phamidol-L3	Hexane	74	>99
Example 17	(S,S,R)-f-phamidol-L3	Toluene	99	>99
Example 18	(S,S,R)-f-phamidol-L3	DCE	97	>99

Examples 19-26

In order to investigate the influence of the alkali added on the reaction system on the reaction, using isopropanol as a solvent, on the basis of Example 1, potassium tert-butoxide was replaced successively by potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, methanol Sodium, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide. The reaction time was 2 hours, S/C=10000, and the following examples 19-26 were carried out. The synthesis routes are shown below, and the results are shown in Table 3 below.

table 3

serial number	alkali	Reaction solvent	conv.(%)	ee(%)
Example 1	t BuOK	i PrOH	>99	>99
Example 19	K 2 CO 3	i PrOH	92	>99
Example 20	Cs 2 CO 3	i PrOH	>99	>99
Example 21	KOH	i PrOH	>99	>99
Example 22	NaOH	i PrOH	>99	>99
Example 23	NaOMe	i PrOH	>99	>99
Example 24	KOM	i PrOH	>99	>99
Example 25	t BuONa	i PrOH	>99	>99
Example 26	t BuOLi	i PrOH	>99	>99

Examples 27-30

Further, the catalyst (S,S,R)-f-phamidol-L3 was used as the catalyst, and the green solvent isopropanol was used as the solvent, and the catalyst dosage, reaction time, etc. were changed respectively, and the results are shown in Table 4 below.

Table 4

serial number	S/C	Reaction temperature (°C)	Reaction time	conv.(%)	ee(%)
Example 1	10000	25	2 hours	>99	>99
Example 27	20000	25	2 hours	>99	>99

Example 28	50000	25	4 hours	>99	>99
Example 29	100000	25	8 hours	>99	>99
Example 30	500000	25	16h	>99	>99

Example 31

Further, in order to investigate the universality of the reaction to different substrates, the catalyst (S,S,R)-f-phamidol-L3 was used as the catalyst, potassium methylate was used as the base, and the green solvent isopropanol was used as the solvent, and the reaction temperature was 25 degrees Celsius, gas pressure 50bar, reaction time 4h, S/C=10000. The asymmetric catalytic hydrogenation experiments were carried out on different substrates, and the results of the obtained products are shown in Table 5 below.

Table 5 Substrate expansion of asymmetric hydrogenation of aminoketones

Embodiment 32 (enlargement, S/C=500000)

Under argon atmosphere, [Ir(COD)Cl] ₂ (1.4 mg, 0.002 mol) and chiral ligand (S,S,R)-f-phamidol-L3 (2.4 mg, 0.0042 mmol) were dissolved in 10 mL in isopropanol and stirred at room temperature for 2 hours to obtain a clear orange solution. 20uL of the orange solution was taken with a micro syringe, and added to the mixed system of intermediate (Ia) (1.05g, 4mmol), isopropanol (2mL) and potassium methoxide (14mg, 0.2mmol). The reaction system was placed in an autoclave, and the gas in the autoclave was replaced with hydrogen three times, and finally filled with 50 atm hydrogen, and reacted at 25° C. for 16 hours. After the reaction, the gas in the autoclave was slowly released, the alkali was filtered out with silica gel, rinsed with DCM, and concentrated under reduced pressure to obtain 1.05 g of a white solid, namely the hydrogenated product (II-a), with a yield of 99%, which was analyzed by HPLC Analysis, the measured ee value> 99%. [α] _D ²⁵ ＝+22.1(c＝1.00in CHCl ₃ ).The enantiomeric excess was determined by HPLC on Chiralcel IA column, 210nm, 30℃, n-hexane:i-PrOH＝92:8; flow rate 1.0mL /min; t _R (minor) = 15.0min, t _R (major) = 19.1min. ¹ H NMR (600MHz, CDCl ₃ ) δ7.26–7.26 (m, 4H), 7.18–7.17 (m, 1H), 4.60–4.35(m,2H),3.05–3.05(m,2H),2.40(br,1H),1.73–1.67(m,1H),1.65–1.60(m,1H),1.51–1.49(m,1H ),1.44–1.42(m,1H),1.34(s,9H). ¹³ C NMR(151MHz,CDCl ₃ )δ156.07,144.69,128.37,127.43,125.75,79.10,74.00,40.24,35.98,28.35,26.39.

Example 33

Weigh 1.06g of the chiral alcohol intermediate (II-a, 4mmol), add 20mL of dichloromethane to dissolve, then add 0.84mL of triethylamine (6mmol) dropwise, and place the reaction system in a low-temperature cooling bath at 0°C while stirring Slowly add 0.40mL methanesulfonyl chloride (5.2mmol) dropwise, continue to react at 0°C for 3h after the dropwise addition, add 80mL ethyl acetate to dilute, wash twice with water, wash twice with saturated sodium bicarbonate, organic The phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, a mixture of 1.04mL methanesulfonic acid (16mmol) and 16mL dichloromethane was added dropwise to the yellow oily liquid obtained above, stirred at room temperature for 2h, and the reaction was completed. Water, while stirring, add sodium hydroxide solution (1M) dropwise to about PH=11. The reaction mixture was extracted three times with 150 mL of dichloromethane, the organic phase was retained, dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 476 mg of colorless oily liquid (IV-a) was obtained through column purification. The reaction yield was 81%. After HPLC analysis, the measured ee value was 95%. [α] _D ²⁵ ＝-31.3(c＝1.00in CHCl ₃ ).The enantiomeric excess was determined by HPLC on Chiralcel OD-3column, 254nm, 30℃, n-hexane(0.1%DEA):i-PrOH＝95: 5; flow rate 1.0mL/min; t _R (minor) = 5.8min, t _R (major) = 6.6min. ¹ H NMR (600MHz, CDCl ₃ ) δ7.36 (d, J = 7.5Hz, 2H), 7.32(t, J＝7.6Hz, 2H), 7.23(t, J＝7.2Hz, 1H), 4.12(t, J＝7.8Hz, 1H), 3.22–3.18(M, 1H), 3.03–2.97(M ,2H),2.22–2.17(M,1H),1.97–1.82(m,2H),1.73–1.66(M,1H). ¹³ C NMR(151MHz,CDCl ₃ )δ144.25,128.27,126.77,126.47,62.47, 46.75, 34.11, 25.42.

Example 34

Weigh 1.06g of chiral alcohol intermediate (II-b, 4mmol), add 20mL of dichloromethane to dissolve, then add 0.84mL of triethylamine (6mmol) dropwise, and place the reaction system in a low-temperature cooling bath at 0°C while stirring Slowly add 0.40mL methanesulfonyl chloride (5.2mmol) dropwise, continue to react at 0°C for 3h after the dropwise addition, add 80mL ethyl acetate to dilute, wash twice with water, wash twice with saturated sodium bicarbonate, organic The phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, a mixture of 1.04mL methanesulfonic acid (16mmol) and 16mL dichloromethane was added dropwise to the yellow oily liquid obtained above, stirred at room temperature for 2h, and the reaction was completed. Water, while stirring, add sodium hydroxide solution (1M) dropwise to about PH=11. The reaction mixture was extracted three times with 150 mL of dichloromethane, the organic phase was retained, dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 476 mg of colorless oily liquid (IV-b) was obtained through column purification. The reaction yield was 80%. After HPLC analysis, the measured ee value was >99%. [α] _D ²⁵ = -30.6 (c = 0.25, MeOH), ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.60 (d, J = 2.0Hz, 1H), 8.49 (dd, J = 1.6, 4.8Hz 1H ),7.71-7.73(m,1H),7.25-7.28(m,1H),4.19(t,J＝7.6Hz，1H),3.21-3.22(m,1H),3.07-3.11(m,1H), 2.30-2.40(m,2H),1.87-2.04(m,2H),1.66(m,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ:148.5,148.1,140.0,134.0,123.2,59.9,46.8, 34.2, 25.4.

Synthesis of Example 35 Nicotine

Intermediate IV-b (1.48g, 10mmol) was added with a mixed solution of 18mL 88% formic acid and 9.2mL 37% formaldehyde. The mixture was reacted at 80°C for 5 h, then cooled to room temperature, solid potassium carbonate was added until the reaction solution was alkaline (pH=10-11), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Distilled under reduced pressure to obtain 1.3 g of the target product nicotine. Nicotine, colorless to pale yellow oily liquid, 82% yield, 99% ee, [α] ²⁵ _D =-98.2 (c = 1, CHCl ₃ ), ¹ H NMR (400MHz, CDCl ₃ ): δ8.56-8.47 (m,2H),7.75-7.67(m,1H),7.27-7.23(m,1H),3.32-3.21(m,1H),3.10(t,J＝8.3Hz,1H),2.39-2.28(m ^13C NMR (101MHz, CDCl ₃ ): δ149.5, 148.6, 138.6, 134.9, 123.6, 68.9, 57.0, 40.3, 35.1, 22.6.

Embodiment 36 (enlargement, S/C=200000)

Under argon atmosphere, [Ir(COD)Cl] ₂ (1.4 mg, 0.002 mol) and chiral ligand (S,S,R)-f-phamidol-L3 (2.4 mg, 0.0042 mmol) were dissolved in 10 mL in isopropanol and stirred at room temperature for 2 hours to obtain a clear orange solution. 50uL of the orange solution was taken with a micro syringe, and added to the mixed system of intermediate (Ih) (1.12g, 4mmol), isopropanol (2mL) and potassium methoxide (14mg, 0.2mmol). The reaction system was placed in an autoclave, and the gas in the autoclave was replaced with hydrogen three times, and finally filled with 50 atm hydrogen, and reacted at 25° C. for 16 hours. After the reaction, the gas in the autoclave was slowly released, the base was filtered off with silica gel, rinsed with DCM, and concentrated under reduced pressure to obtain 1.13 g of a colorless oily liquid, namely the hydrogenated product (II-e), with a yield of 99%. After HPLC analysis, the measured ee value was >99%. [α] _D ²⁵ ＝+22.2 (c＝1.00in CHCl ₃ ).The enantiomeric excess was determined by HPLC on Chiralcel IA column, 210nm, 30℃, n-hexane:i-PrOH＝92:8; flow rate 1.0mL /min; t _R (minor)＝11.2min, t _R (major)＝12.9min. ¹ H NMR (600MHz, CDCl ₃ )δ7.29–7.27(m,2H),7.01–6.99(m,2H), 4.69–4.66(m,2H),3.12–3.12(m,2H),2.98(br,1H),1.78–1.72(m,1H),1.70–1.64(m,1H),1.59–1.56(m,1H ), 1.49–1.48 (m, 1H), 1.41 (s, 9H). ¹³ C NMR (151MHz, CDCl ₃ ) δ162.01 (d, J＝245.1Hz), 156.13, 140.52, 127.36 (d, J＝8.0 Hz), 115.09 (d, J=21.3Hz), 79.17, 73.23, 40.15, 36.04, 28.32, 26.36. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-115.26.

Example 37

Weigh 1.13g of chiral alcohol intermediate (II-h, 4mmol), add 20mL of dichloromethane to dissolve, then add 0.84mL of triethylamine (6mmol) dropwise, and place the reaction system in a low-temperature cooling bath at 0°C while stirring Slowly add 0.40mL methanesulfonyl chloride (5.2mmol) dropwise, continue to react at 0°C for 3h after the dropwise addition, add 80mL ethyl acetate to dilute, wash twice with water, wash twice with saturated sodium bicarbonate, organic The phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, a mixture of 1.04mL methanesulfonic acid (16mmol) and 16mL dichloromethane was added dropwise to the yellow oily liquid obtained above, stirred at room temperature for 2h, and the reaction was completed. Water, while stirring, add sodium hydroxide solution (1M) dropwise to about PH=11. The reaction mixture was extracted three times with 150 mL of dichloromethane, the organic phase was retained, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 561 mg of a colorless oily liquid (IV-h) was obtained through column purification. The reaction yield was 85%. After HPLC analysis, the measured ee value was 99%. [α] _D ²⁵ =-20.5 (c=1.00in CHCl ₃ ), ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.29–7.26 (m, 2H), 6.98–6.93 (m, 2H), 4.07–4.03 ( m,1H),3.16–3.12(m,1H),2.97–2.92(m,1H),2.33(br,1H),2.15–2.08(m,1H),1.90–1.87(m,2H),1.63- 1.55(m,1H). Its H NMR data is consistent with the literature (Org.Lett.2017,16,4215-4218.)

Example 38

[Ir(COD)Cl] ₂ (1.4mg, 0.002mmol) and chiral ligand (R,R,S)-f-phamidol-L10 (2.4mg, 0.0042mmol) were dissolved in 10mL under argon atmosphere in isopropanol and stirred at room temperature for 3 hours to obtain a clear orange solution. Take 2.5 mL of the orange solution with a syringe, and add it to the mixed system of intermediate (II) (29.9 g, 100 mmol), isopropanol (50 mL) and potassium methoxide (70 mg, 1 mmol). The reaction system was placed in an autoclave, and the gas in the autoclave was replaced with hydrogen three times, and finally filled with 50 atm hydrogen, and reacted at 25° C. for 24 hours. After the reaction was over, the gas in the autoclave was slowly released, the reaction solution was filtered with silica gel to remove the catalyst and the alkali, rinsed with DCM, and the filtrate was concentrated under reduced pressure to 29.5 g of a white solid, i.e. the hydrogenated product (III), with a yield of 98%. After HPLC analysis, the measured ee value was >99%. Enantiomers were determined by HPLC, chromatographic conditions were: Chiralcel AD-3 column, 210nm, 30°C, mobile phase: n-hexane:i-PrOH=90:10; flow rate 1.0mL/min; t _R (major )=10.5min, t _R (minor)=14.1min. Characterization data of compound II-1: [α] _D ²⁵ =-18.2 (c=1.00in CHCl ₃ ). ¹ H NMR (400MHz, CDCl ₃ ) δ7.20 –7.16(m,1H),6.95–6.83(m,2H),4.98(q,J＝5.7Hz,1H),4.71(br,1H),3.42(s,1H),3.18–3.07(m,2H ), 1.72(q, J＝7.3Hz, 2H), 1.65–1.50(m, 2H), 1.39(s, 9H). ¹³ C NMR (151MHz, CDCl ₃ ) δ158.92(dd, J＝242.0, 1.9 Hz), 156.29, 155.25(dd, J=240.6, 2.1Hz), 133.84(dd, J=15.6, 6.3Hz), 116.11(dd, J=25.0, 8.5Hz), 114.75(dd, J=24.2, 8.6 Hz), 113.73 (dd, J=24.9, 5.0Hz), 79.33, 67.23, 40.12, 34.71, 28.30, 26.21. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-118.46, -125.70.

Example 39

Weigh 12.0g of compound II-I (40mmol), add 40mL of dichloromethane to dissolve, then dropwise add 11.2mL of triethylamine (80mmol), place the reaction system in a low-temperature cold bath at 0°C, and slowly add 3.4 mL methanesulfonyl chloride (44mmol), continue to react at 0°C for 30min after the dropwise addition. After the reaction, wash with saturated sodium carbonate, extract three times with 120mL dichloromethane, and concentrate to obtain 14.4g of a yellow oily liquid. Then, dropwise add a mixture of 20mL of 30% sulfuric acid and 50mL of dichloromethane to the yellow oily liquid obtained above, stir at room temperature for 2h, concentrate the reaction solution after the reaction is complete, then add 100mL of water to dissolve, and place the reaction solution at 0°C for low temperature cooling. In the bath, 250 mL of sodium hydroxide solution (2M) was added dropwise while stirring. The reaction mixture was extracted three times with 200 mL of ethyl acetate, the organic phase was retained, dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 6.2 g of light yellow oily liquid (IV-1) was obtained through column purification, and the reaction yield was 84%. , analyzed by HPLC, the measured ee value was 96%. [α] _D ²⁵ ＝+35.6(c＝1.00in CHCl ₃ ), ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.28–7.11(m,1H),6.99–6.84(m,1H),6.88–6.82(m ,1H),4.39(t,J＝7.9Hz,1H),3.17–3.13(m,1H),3.07–3.01(m,1H),2.29–2.21(m,1H),2.17(s,1H), 1.93–1.80(m,2H), 1.65–1.58(m,1H), the H NMR spectrum data are consistent with the literature (J.Am.Chem.Soc.2019,141,14083-14088.).

Example 40

The compound of formula IV-1 (1.83g, 10mmol), the compound of formula Vl (1.99g, 10mmol) and 20mL of ethanol were added into a 50mL three-necked flask, stirred evenly, and the temperature of the system was kept within 30°C. Triethylamine (1.53mL, 11mmol) was added dropwise, and after the addition was completed, reacted at 50°C for 2 hours. After the reaction was completed, it was directly spin-dried and purified by column (petroleum ether:ethyl acetate=2:1) to obtain larotretinib The intermediate VI-l was 2.76g, the yield was 80%, and the measured ee value was 96% by HPLC analysis. Characterization data of compound VI-1: [α] _D ²⁵ ＝-27.0 (c＝1.00in CHCl ₃ ). The enantiomers were determined by HPLC method, and the chromatographic conditions were: Chiralcel IA column, 250nm, 30°C, mobile phase n -hexane:i-PrOH＝90:10; flow rate 1.0mL/min; t _R (minor)＝26.6min, t _R (major)＝28.9min.

Major: ¹ H NMR (600MHz,DMSO-d ₆ )δ8.71(d,J＝7.8Hz,1H),8.42(s,1H),7.16–7.08(m,1H),6.95–6.89(m,2H ),6.68(d,J=7.8Hz,1H),5.48(d,J=5.6Hz,1H),3.98–3.92(m,1H),3.58(q,J=8.1Hz,1H),2.38–2.32 (m,1H),2.01–1.83(m,3H). ¹³ C NMR (151MHz,DMSO-d ₆ )δ158.06(d,J=240.1Hz),156.16,155.76(d,J=240.8Hz), 142.85, 141.53, 136.99, 132.04 (dd, J = 15.9, 7.1 Hz), 119.34, 116.69 (dd, J = 24.6, 8.6 Hz), 114.68 (dd, J = 24.2, 8.7 Hz), 114.07 (dd, J = 25.1, 4.5 Hz), 100.49, 56.39, 48.18, 32.65, 23.13. ¹⁹ F NMR (565MHz, DMSO-d ₆ ) δ-118.93 (ddd, J＝16.9, 12.7, 8.4Hz), -123.75 (dd, J＝ 15.2,6.7Hz).

Minor: ¹ H NMR(600MHz,DMSO-d ₆ )δ8.54(d,J＝7.8Hz,1H),8.51(s,1H),7.26–7.22(m,1H),7.11–7.08(m,1H ),6.98–6.96(m,1H),6.12(d,J＝7.8Hz,1H),5.26(d,J＝7.4Hz,1H),3.98–3.92(m,1H),3.77–3.73(m, 1H), 2.48–2.43(m,1H), 2.01–1.83(m,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ158.30(d,J=241.5Hz),156.40,155.38(d, J=236.4Hz), 143.32, 141.79, 136.94, 130.62(dd, J=15.8, 6.8Hz), 119.60, 117.51(dd, J=24.1, 8.7Hz), 115.77(dd, J=24.1, 8.6Hz), ^- _{_} 122.75–-122.91(m).

Example 41 (enlargement, S/C=200000)

Under argon atmosphere, [Ir(COD)Cl] ₂ (1.4 mg, 0.002 mol) and chiral ligand (S,S,R)-f-phamidol-L3 (2.4 mg, 0.0042 mmol) were dissolved in 10 mL in isopropanol and stirred at room temperature for 2 hours to obtain a clear orange solution. Take 50uL of the orange solution with a microsyringe and add it to the mixed system of intermediate (It) (1.10g, 4mmol), isopropanol (2mL) and potassium methoxide (14mg, 0.2mmol). The reaction system was placed in an autoclave, and the gas in the autoclave was replaced with hydrogen three times, and finally filled with 50 atm hydrogen, and reacted at 25° C. for 16 hours. After the reaction, the gas in the autoclave was slowly released, the alkali was filtered out with silica gel, rinsed with DCM, and concentrated under reduced pressure to obtain 1.11 g of a light yellow oily liquid, namely the hydrogenated product (II-t), with a yield of 99%. After HPLC analysis, the measured ee value was >99%. [α] _D ²⁵ ＝+18.7(c＝1.00in CHCl ₃ ).The enantiomeric excess was determined by HPLC on Chiralcel OD-H column, 210nm, 30℃, n-hexane:i-PrOH＝95:5; flow rate 1.0mL/min; t _R (minor) = 20.8min, t _R (major) = 25.1min. ¹ H NMR (400MHz, CDCl ₃ ) δ7.34–7.30(m,4H), 7.27–7.23(m,1H ),4.64–4.61(m,2H),3.07–3.06(m,2H),2.53(br,1H),1.83–1.65(m,2H),1.48–1.42(m,12H),1.32–1.26(m ,1H). ¹³ C NMR (151MHz, CDCl ₃ ) δ156.00, 144.78, 128.31, 127.34, 125.77, 79.00, 74.17, 40.23, 38.55, 29.83, 28.34, 22.82.

Example 42

Weigh 1.11g of chiral alcohol intermediate (II-t, 4mmol), add 20mL of dichloromethane to dissolve, then add 0.84mL of triethylamine (6mmol) dropwise, and place the reaction system in a low-temperature cooling bath at 0°C while stirring Slowly add 0.40mL methanesulfonyl chloride (5.2mmol) dropwise, continue to react at 0°C for 3h after the dropwise addition, add 80mL ethyl acetate to dilute, wash twice with water, wash twice with saturated sodium bicarbonate, organic The phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, a mixture of 1.04mL methanesulfonic acid (16mmol) and 16mL dichloromethane was added dropwise to the yellow oily liquid obtained above, stirred at room temperature for 2h, and the reaction was completed. Water, while stirring, add sodium hydroxide solution (1M) dropwise to about PH=11. The reaction mixture was extracted three times with 150 mL of dichloromethane, the organic phase was retained, dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 509 mg of colorless oily liquid (IV-t) was obtained through column purification. The reaction yield was 79%. After HPLC analysis, the measured ee value was 98%. [α] _D ²⁵ ＝-35.0(c＝1.00in CHCl ₃ ). ¹ H NMR (400MHz, CDCl ₃ ) δ7.34–7.20(m,5H),3.55–3.53(m,1H),3.15–3.12( m,1H),2.70–2.69(m,1H),1.83–1.81(m,1H),1.76-1.74(m,1H),1.68(br,1H),1.62–1.60(m,1H),1.52– 1.45(m,3H). Its H NMR data is consistent with the literature (Org. Lett. 2017, 16, 4215-4218.).

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (10)

1. A method for preparing aminoalcohol by asymmetric hydrogenation, characterized in that the chemical reaction equation is as follows:

   

   Among them, the R ¹ of the general chemical formula (I) and (II) represents a C1-C12 alkyl, aryl or a heteroatom-substituted alkyl or aryl, R ² represents an amino protecting group, and n represents a group containing 1-5 A saturated straight-chain or branched chain group of 2 carbon atoms, said * means that there are two configurations of R or S;

   The transition metal catalyst used is formed by mixing a metal salt and a chiral ligand. The catalyst metal salt is selected from common transition metal compounds such as ruthenium, rhodium, iridium, and palladium, and the chiral ligand is selected from:

   
2. preparation method according to claim 1, is characterized in that, the ^R of general chemical formula (I) and (II) Represent amino protecting group, be selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Wat Methoxycarbonyl (Fmoc), Allyloxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Methyl (or Ethyl or Isopropyl) Oxycarbonyl (COOMe, COOEt, COO ⁱ Pr), phthalic di Formyl (Pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, trityl (Trt), 2,4 - Dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn) and the like.
3. The preparation method according to claim 1, wherein the solvent used for asymmetric hydrogenation is methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, ethyl acetate, n-hexane, dichloromethane, 1,2 - One of dichloroethane, toluene, xylene, 1,4-dioxane, methyl tert-butyl ether or a mixture in any proportion.
4. preparation method according to claim 1, is characterized in that, the alkali used for asymmetric hydrogenation is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, One or any mixture of cesium carbonate, sodium methylate, potassium methylate; the molar ratio of the intermediate (I) to the catalyst is 5mmol: 0.01-1nmol; the reaction temperature of asymmetric hydrogenation is 20-80 degrees Celsius, asymmetric The hydrogenation pressure is 1-10Mpa.
5. The preparation method according to claim 1, wherein the transition metal catalyst is [Ir(COD)Cl] ₂ , and the chiral ligand is:

   

   and its enantiomer L10.
6. A kind of asymmetric synthetic method of chiral pyrrolidine and piperidine compound, it is characterized in that, synthetic route is as follows:

   

   Wherein, the chiral aminoalcohol compound (II) is prepared by the method described in any one of claims 1-7, n=3 or 4 in the compounds (I) and (II), R ^represents C1-C12 alkyl, aryl or heteroatom-substituted alkyl, aryl, R ² represents an amino protecting group.
7. The method according to claim 6, characterized in that, the alcoholic hydroxyl group of the chiral aminoalcohol compound (II) is converted into X with a suitable reagent to obtain intermediate (III), and X is selected from the group consisting of halogen, sulfonate, phosphoric acid Common leaving groups such as esters, including chlorine, bromine, iodine, mesylate (OMs), triflate (OTf), p-toluenesulfonate (OTs), nitrosulfonate (ONs) wait.
8. The method according to claim 6, characterized in that, under suitable conditions, the intermediate (III) reacts with a suitable reagent to remove the amino protecting group R ² , and when R ² is tert-butoxycarbonyl (Boc), the removal The reagents for removing the amino protecting group are hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etc., and an intramolecular nucleophilic ring-closing reaction occurs under alkaline conditions to obtain optically pure chiral pyrrolidine and piperidine pyridine compounds.
9. According to the method according to claim 6, when R ¹ represents 3-pyridyl, the method can be applied to the asymmetric synthesis of nicotine, it is characterized in that, synthetic route is as follows:

   

   Wherein, the "*" in the formulas II-b, III-b, IV-b and V-b represents two configurations containing R and S, and the synthesis includes the following steps:

   1) Dissolve the intermediate I-b in a suitable solvent, add a chiral catalyst and a suitable base, the molar ratio of the intermediate I-b to the catalyst is 2 mmol: 0.01-1 nmol, replace the gas in the reactor with hydrogen for three times, and finally fill Add 2-8Mpa hydrogen, react at 20-80°C for 2-60 hours, slowly release the gas in the reactor, spin dry, and purify by silica gel column chromatography to obtain the chiral hydrogenation product II-b;

   2) The chiral alcohol product II-b is activated by SOCl ₂ , MsCl, TsCl and other reagents to form suitable leaving groups LG such as halogen and sulfonate;

   3) Intermediate III-b reacts with hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etc. or any mixture of them to remove the amino protecting group, and then under alkaline conditions, intramolecular nucleophilicity occurs Ring closure reaction, extraction with ethyl acetate after the reaction, collecting the organic phase and concentrating to obtain the chiral tetrahydropyrrole compound IV-b;

   4) Under heating conditions, add intermediate IV-b to formic acid and paraformaldehyde solution to react for 5 hours, cool the reaction to room temperature, add potassium carbonate until the reaction solution is alkaline, extract with ethyl acetate, and distill under reduced pressure to obtain nicotine product .
10. According to the method according to claim 6, when ^R represents 2,5-difluorophenyl, the method can be applied to the asymmetric synthesis of larotretinib intermediates, characterized in that the synthetic route is as follows:

    

    Specifically, it comprises the following steps: 1) under a chiral catalyst, the compound I-1 is subjected to asymmetric catalytic hydrogenation reduction using the preparation method described in any one of claims 1-6 to obtain a chiral alcohol compound II-1; 2) chiral The important intermediate (R)-2-(2,5-difluorophenyl)pyrrolidine with high optical activity is obtained by activation, removal of Boc protecting group and intramolecular cyclization of alcohol II-1 under the action of base IV-1; 3) A substitution reaction occurs between the compound of formula IV-1 and the compound of formula V-1 to obtain the intermediate VI-1 of larotrectinib.