CN115838342B

CN115838342B - Asymmetric catalytic hydrogenation method for amino ketone

Info

Publication number: CN115838342B
Application number: CN202111097411.3A
Authority: CN
Inventors: 稂琪伟; 高爽; 肖阳; 丁小兵
Original assignee: Shenzhen Catalys Technology Co Ltd
Current assignee: Shenzhen Catalys Technology Co Ltd
Priority date: 2021-09-18
Filing date: 2021-09-18
Publication date: 2024-07-26
Anticipated expiration: 2041-09-18
Also published as: CN115838342A

Abstract

The invention belongs to the technical field of chemical catalytic reaction, and discloses a practical asymmetric catalytic hydrogenation method for amino ketone. The intermediate (II) can be subjected to intramolecular cyclization under proper conditions to obtain chiral pyrrolidine or piperidine with high optical activity. The method can be used for efficiently and selectively preparing a series of chiral pyrrolidine and piperidine compounds, and has important practical value and industrialization prospect.

Description

Asymmetric catalytic hydrogenation method for amino ketone

Technical Field

The invention belongs to the technical field of chemical catalytic reaction, and particularly relates to a method for asymmetrically catalytically hydrogenating amino ketone.

Background

Chiral pyrrolidine compounds are widely found in biologically active molecules, drugs, natural product fragments, such as BMS-394136 shown below as a selective IKur inhibitor, useful in the treatment of cardiovascular disease; LY-394681 as a tachykinin receptor useful in the treatment of central and autonomic nervous system disorders; ATICAPRANT is a potent kappa-opioid receptor selective antagonist. In addition, there is a drug Larotrectinib sulfate marketed in 2018 that can be used to treat adult and pediatric patients carrying locally advanced or metastatic solid tumors of the NTRK gene fusion; and drug Osilodrostat marketed in 2020, which is the first approved human 11-beta hydroxylase inhibitor by the FDA, can directly block the synthesis of adrenocortisol, and is an orphan drug for the treatment of hypercortisolism.

Because chiral pyrrolidines have great industrial value in the pharmaceutical field, intensive research into their synthesis methods has been conducted and many synthetic routes have been developed. There are many methods for obtaining chiral pyrrolidine, but due to the economy and practicality of these methods, no simple and efficient method has yet been widely used in asymmetric synthesis of chiral pyrrolidine. Therefore, the realization of the large-scale production of chiral pyrrolidines by means of asymmetric catalytic preparation technology is of great significance.

Disclosure of Invention

The invention discloses a practical asymmetric catalytic hydrogenation method for amino ketone, which comprises the following chemical reaction equation:

Wherein R ¹ of the chemical formulas (I) and (II) represents C1-C12 alkyl, aryl or heteroatom-substituted alkyl or aryl, R ² represents an amino protecting group, n represents a saturated straight-chain or branched-chain group containing 1-5 carbon atoms, and R or S are two configurations; the transition metal catalyst is formed by mixing metal salt and chiral ligand, wherein the catalyst metal salt is selected from common transition metal compounds such as ruthenium, rhodium, iridium, palladium and the like, and the chiral ligand is selected from the following compounds:

as a preferable mode of the present invention, R ² of the chemical formulas (I) and (II) represents an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), a-hold methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylethoxycarbonyl (Teoc), a-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-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn) and the like.

As a preferred embodiment of the present invention, the solvent used for the asymmetric hydrogenation is one or a mixture of methanol, ethanol, isopropanol, tetrahydrofuran, methylene chloride, ethyl acetate, n-hexane, methylene chloride, 1, 2-dichloroethane, toluene, xylene, 1, 4-dioxane, methyl t-butyl ether in any ratio.

As a preferred embodiment of the present invention, the base used for the asymmetric hydrogenation is one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide in any ratio.

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

As a preferred embodiment of the present invention, the reaction temperature for the asymmetric hydrogenation is 20-80 ℃.

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

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

And enantiomers thereof.

The invention also discloses an asymmetric synthesis method of chiral pyrrolidine and piperidine compounds, which comprises the following synthesis routes:

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

Further, the method can be realized by the following technical scheme, which comprises the following steps:

Wherein, the alcohol hydroxyl of the chiral amino alcohol compound (II) reacts with a proper reagent to be converted into X, so as to obtain an intermediate (III), wherein X is selected from common leaving groups such as halogen, sulfonate, phosphate and the like, and the common leaving groups comprise chlorine, bromine, iodine, methanesulfonate (OMs), trifluoromethanesulfonate (OTf), p-toluenesulfonate (OTs), nitrosulfonate (ONs) and the like.

When the intermediate (III) is reacted with a suitable reagent under a suitable condition to remove the amino protecting group R ²,R² to be t-butoxycarbonyl (Boc), the reagent to remove the amino protecting group is hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, methanesulfonic acid or the like, preferably trifluoroacetic acid, methanesulfonic acid or the like.

The intermediate with the removed protecting group is not separated and purified, and nucleophilic ring-closing reaction in the molecule occurs under alkaline condition, thus obtaining the optically pure chiral pyrrolidine and piperidine compound.

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

(1) The invention successfully develops a synthesis method of chiral pyrrolidine, and the compound (I) is subjected to catalytic hydrogenation reaction under the action of chiral ligand, so that chiral alcohol intermediate (II) can be efficiently obtained. The reaction has high stability and reactivity, realizes excellent three-dimensional control, and can obtain chiral alcohol intermediates with enantioselectivity of more than 99%.

(2) Through extensive experimental studies, it was found that the asymmetric hydrogenation reaction has very high reactivity with the preferred catalyst system [ Ir (COD) Cl ] ₂/f-amphox-^t Bu, and the catalyst conversion number (TON, turnovernumber) is as high as 500000.

(3) The invention has stable operation, low cost and environment protection, and has extremely high industrialization value.

Detailed Description

The invention is further illustrated by, but not limited to, the following non-limiting examples. The experimental methods for which specific conditions are not specified in the examples are generally as described in conventional conditions and handbooks, or as suggested by the manufacturer; the materials, reagents and the like used, unless otherwise specified, are all commercially available.

Example 1: in the compound (I), R ¹ is phenyl, and R ² is tert-butoxycarbonyl (Boc).

Under argon atmosphere, [ Ir (COD) Cl ] ₂ (3.4 mg,0.005 mol) and chiral ligand (S, S, R) -f-amphox- ^t Bu-L3 (5.8 mg,0.0105 mmol) were dissolved in 5mL isopropanol and stirred at room temperature for 3 hours to give an orange clear solution. 10uL of this orange solution was taken with a microsyringe and added to a mixture of intermediate (II-a) (52.6 mg,0.2 mmol), isopropanol (1 mL) and potassium tert-butoxide (1.1 mg,0.01 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced three times with hydrogen, and finally 50atm of hydrogen was charged, and reacted at 25℃for 2 hours. After the reaction was completed, the gas in the autoclave was slowly released, 50mL of methylene chloride, water washing, saturated brine washing, anhydrous sodium sulfate drying, and concentration under reduced pressure gave 53mg of a colorless oily liquid, namely, hydrogenated product (II-a), yield was 99%, and an ee value was 99% by HPLC analysis.

Examples 2 to 11

The present invention is to examine the effect of the kind of catalyst used in the asymmetric hydrogenation reaction on the conversion (conv.) and the enantioselectivity (ee). Based on example 1, the catalyst ligand L3 was replaced with L1, L2, L4, L5, L6, L8, L13, L15, L20, L22 in this order.

The results of the effect of the different catalysts in examples 1-10 on the conversion of the reduction of compound (I-a) and the ee value are shown in Table 1 below; wherein the conversion (conv.) and the enantioselectivity (ee) are determined by HPLC.

TABLE 1

Numbering device	Catalyst	Reaction time	conv.(％)	ee(％)
					Example 1	L3	2h	99	>99
Example 2	L1	2h	95	74
					Example 3	L2	2h	96	79
Example 4	L4	2h	90	86
					Example 5	L5	2h	99	93
Example 6	L6	2h	99	>99
					Example 7	L8	2h	99	95
Example 8	L13	2h	93	96
					Example 9	L15	2h	99	97
Example 10	L20	2h	95	>99
					Example 11	L22	2h	99	>99

Examples 12 to 18

To examine the effect of the reaction system solvent on the reaction, the solvents were replaced with MeOH, etOH, etOAc, DCM, THF, hexane and Toluene in this order on the basis of example 1. The reaction time was 2h, s/c=10000, and the effect of different solvents on the conversion of the reduction of compound (I-a) and the ee value is shown in table 2 below. It is worth mentioning that when the chiral ligand used in isopropanol is its enantiomer (R, R, S) -f-amphox- ^t Bu-L3, the product II-a of opposite configuration can be obtained with good stereoselectivity, and the result can facilitate the selection of the catalyst of corresponding configuration according to the chirality of the substrate in practical application. Wherein the conversion (conv.) and the enantioselectivity (ee) are determined by HPLC.

TABLE 2

Examples 20 to 27

To examine the effect of the alkali added to the reaction system on the reaction, isopropyl alcohol was used as a solvent, and based on example 1, potassium tert-butoxide was replaced with potassium carbonate, cesium carbonate, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide in this order. The reaction times 2h, s/c=10000, were carried out as shown in the following examples 19 to 16, the synthetic routes of which are shown below, and the results of which are shown in table 3 below.

TABLE 3 Table 3

Numbering device	Alkali	Reaction solvent	conv.(％)	ee(％)
					Example 1	^tBuOK	ⁱPrOH	>99	>99
Example 20	K₂CO₃	ⁱPrOH	92	>99
					Example 21	Cs₂CO₃	ⁱPrOH	>99	>99
Example 22	KOH	ⁱPrOH	>99	>99
					Example 23	NaOH	ⁱPrOH	>99	>99
Example 24	NaOMe	ⁱPrOH	>99	>99
					Example 25	KOMe	ⁱPrOH	>99	>99
Example 26	^tBuONa	ⁱPrOH	>99	>99
					Example 27	^tBuOLi	ⁱPrOH	>99	>99

Examples 28 to 31

Further, the catalyst (S, S, R) -f-amphox- ^t Bu-L3 was used as a catalyst and isopropyl alcohol as a green solvent was used as a solvent, and the catalyst amount, the reaction time, etc. were changed, respectively, and the results are shown in Table 4 below.

TABLE 4 Table 4

Numbering device	S/C	Reaction temperature (. Degree. C.)	Reaction time	conv.(％)	ee(％)
						Example 1	10000	25	2h	>99	>99
Example 28	20000	25	2h	>99	>99
						Example 29	50000	25	4h	>99	>99
Example 30	100000	25	8h	>99	>99
						Example 31	500000	25	16h	>99	>99

Examples 32 to 56

Further, in order to examine the universality of the reaction on different substrates, a catalyst (S, S, R) -f-amphox- ^t Bu-L3 is used as a catalyst, potassium tert-butoxide is used as a base, green solvent isopropanol is used as a solvent, the reaction temperature is 25 ℃, the gas pressure is 50bar, the reaction time is 2h, and S/C=10000. Asymmetric catalytic hydrogenation experiments were performed on different substrates, respectively, and the results of the obtained products are shown in table 5 below.

TABLE 5

Example 57 (amplified, S/c=500000)

[ Ir (COD) Cl ] ₂ (1.4 mg, 0.002mol) and chiral ligand (S, S, R) -f-amphox- ^t Bu-L3 (2.4 mg,0.0042 mmol) were dissolved in 10mL of isopropanol under argon atmosphere and stirred at room temperature for 2 hours to give an orange clear solution. The orange solution, 20uL, was taken with a microsyringe and added to a mixture of intermediate (I-a) (1.05 g,4 mmol), isopropanol (2 mL) and potassium methoxide (14 mg,0.2 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced three times with hydrogen, and finally 50atm of hydrogen was charged, and reacted at 25℃for 16 hours. After the reaction was completed, the gas in the autoclave was slowly released, the base was filtered off with silica gel, washed with DCM, and concentrated under reduced pressure to give 1.05g of a white solid, i.e., hydrogenated product (II-a), in 99% yield, which was analyzed by HPLC to give an ee value of >99%.

Example 58

1.06G of chiral alcohol intermediate (II-a, 4 mmol) was weighed, 20mL of methylene chloride was added to dissolve, 0.84mL of triethylamine (6 mmol) was added dropwise, the reaction system was placed in a cold bath at a low temperature of 0 ℃ and 0.40mL of methanesulfonyl chloride (5.2 mmol) was slowly added dropwise with stirring, the reaction was continued at 0 ℃ for 3 hours after the dropwise addition, 80mL of ethyl acetate was added to dilute after the reaction was completed, washed twice with water, washed twice with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, to the yellow oily liquid obtained above was added dropwise a mixture of 1.04mL of methanesulfonic acid (16 mmol) and 16mL of methylene chloride, and the mixture was stirred at room temperature for 2 hours, and after the completion of the reaction, the reaction mixture was placed in a low-temperature cold bath at 0 ℃, and then 20mL of water was added thereto, and sodium hydroxide solution (1M) was added dropwise while stirring until ph=11. The reaction mixture was extracted three times with 150mL of methylene chloride, the organic phase was retained, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 476mg of colorless oily liquid (IV-a) was obtained by column purification, the reaction yield was 81%, and the ee value was 97% by HPLC analysis.

Example 59 (amplification, S/c=200000)

[ Ir (COD) Cl ] ₂ (1.4 mg, 0.002mol) and chiral ligand (S, S, R) -f-amphox- ^t Bu-L3 (2.4 mg,0.0042 mmol) were dissolved in 10mL of isopropanol under argon atmosphere and stirred at room temperature for 2 hours to give an orange clear solution. The orange solution, 50uL, was taken with a microsyringe and added to a mixture of intermediate (I-d) (1.10 g,4 mmol), isopropanol (2 mL) and potassium methoxide (14 mg,0.2 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced three times with hydrogen, and finally 50atm of hydrogen was charged, and reacted at 25℃for 16 hours. After the reaction was completed, the gas in the autoclave was slowly released, the base was filtered off with silica gel, washed with DCM, and concentrated under reduced pressure to give 1.11g of a pale yellow oily liquid, namely a hydrogenated product (II-d) in 99% yield, which was analyzed by HPLC and found to have an ee value of >99%.

Example 60

1.11G of chiral alcohol intermediate (II-d, 4 mmol) was weighed, 20mL of methylene chloride was added to dissolve, 0.84mL of triethylamine (6 mmol) was added dropwise, the reaction system was placed in a cold bath at a low temperature of 0 ℃ and 0.40mL of methanesulfonyl chloride (5.2 mmol) was slowly added dropwise with stirring, the reaction was continued at 0 ℃ for 3 hours after the dropwise addition, 80mL of ethyl acetate was added to dilute after the reaction was completed, washed twice with water, washed twice with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, to the yellow oily liquid obtained above was added dropwise a mixture of 1.04mL of methanesulfonic acid (16 mmol) and 16mL of methylene chloride, and the mixture was stirred at room temperature for 2 hours, and after the completion of the reaction, the reaction mixture was placed in a low-temperature cold bath at 0 ℃, and then 20mL of water was added thereto, and sodium hydroxide solution (1M) was added dropwise while stirring until ph=11. The reaction mixture was extracted three times with 150mL of methylene chloride, the organic phase was retained, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 509mg of colorless oily liquid (IV-d) was obtained by column purification, the reaction yield was 79%, and the ee value was 98% by HPLC analysis.

Example 61 (amplification, S/c=200000)

[ Ir (COD) Cl ] ₂ (1.4 mg, 0.002mol) and chiral ligand (S, S, R) -f-amphox- ^t Bu-L3 (2.4 mg,0.0042 mmol) were dissolved in 10mL of isopropanol under argon atmosphere and stirred at room temperature for 2 hours to give an orange clear solution. The orange solution, 50uL, was taken with a microsyringe and added to a mixture of intermediate (I-h) (1.12 g,4 mmol), isopropanol (2 mL) and potassium methoxide (14 mg,0.2 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced three times with hydrogen, and finally 50atm of hydrogen was charged, and reacted at 25℃for 16 hours. After the reaction was completed, the gas in the autoclave was slowly released, the base was filtered off with silica gel, washed with DCM, and concentrated under reduced pressure to give 1.13g of a colorless oily liquid, i.e., a hydrogenated product (II-h) in 99% yield, and an ee value of >99% was measured by HPLC analysis.

Example 62

1.13G of chiral alcohol intermediate (II-h, 4 mmol) was weighed, 20mL of methylene chloride was added to dissolve, 0.84mL of triethylamine (6 mmol) was added dropwise, the reaction system was placed in a cold bath at low temperature of 0 ℃ and 0.40mL of methanesulfonyl chloride (5.2 mmol) was slowly added dropwise with stirring, the reaction was continued at 0 ℃ for 3 hours after the dropwise addition, 80mL of ethyl acetate was added to dilute after the reaction was completed, washed twice with water and twice with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid. Then, to the yellow oily liquid obtained above was added dropwise a mixture of 1.04mL of methanesulfonic acid (16 mmol) and 16mL of methylene chloride, and the mixture was stirred at room temperature for 2 hours, and after the completion of the reaction, the reaction mixture was placed in a low-temperature cold bath at 0 ℃, and then 20mL of water was added thereto, and sodium hydroxide solution (1M) was added dropwise while stirring until ph=11. The reaction mixture was extracted three times with 150mL of methylene chloride, the organic phase was retained, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, 561mg of a colorless oily liquid (IV-h) was obtained by column purification, the reaction yield was 85%, and the ee value was 99% by HPLC analysis.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. A method for asymmetrically catalytically hydrogenating an aminoketone, characterized in that the chemical reaction equation is as follows:

the transition metal catalyst is formed by mixing metal salt and chiral ligand, wherein the metal salt is selected from transition metal compounds of ruthenium, rhodium, iridium and palladium, and the chiral ligand is selected from the following compounds:

The solvent used for asymmetric hydrogenation is isopropanol, n-hexane or dichloromethane;

The base used for asymmetric hydrogenation is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium methoxide or potassium methoxide;

The molar ratio of intermediate (I-a) to catalyst was 5mmol:0.01-1nmol.

2. The process according to claim 1, wherein the reaction temperature of the asymmetric hydrogenation is 20-80 degrees celsius and the pressure of the asymmetric hydrogenation is 1-10MPa.

3. The method according to claim 1, wherein the transition metal compound is [ Ir (COD) Cl ] ₂.

4. An asymmetric synthesis method of chiral pyrrolidine is characterized by comprising the following synthesis routes:

Wherein the chiral amino alcohol compound (II-a) is produced by the method of any one of claims 1 to 3.