Method for efficiently preparing chiral alpha-nitroalcohol

Abstract

The invention provides a method for efficiently preparing chiral alpha-nitroalcohol, and relates to the technical field of chemical synthesis. The invention provides a method for converting nitroketone into nitroalcohol, and the obtained alpha-nitroalcohol compound can be used as an intermediate for synthesizing a plurality of important drugs (such as noradrenaline) and has very high economic value. The asymmetric catalytic hydrogenation method provided by the invention is high in efficiency, quantitative in yield and excellent in enantioselectivity, and greatly reduces the difficulty and cost of synthesis of various drugs. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for efficiently preparing chiral alpha-nitro alcohol. Background Art

[0002] Nitro alcohols are useful intermediates for various organic synthesis transformations, especially for the synthesis of 1,2-amino alcohols. Many ortho-amino alcohol compounds have been found in natural products. The structural formulas of some of the compounds are as follows. Due to their pharmacological and biological activities, they can be used as key parent core structures to derive anticancer active compounds. Ortho-nitro alcohols can be used as an important raw material for the preparation of ortho-amino alcohols.

[0003] For example, patent EP1308435 forms an optically active cyano alcohol derivative from a cyanoketone by contacting the starting material with formic acid as a hydrogen donor, a metal selected from Ru, Rh or Ir belonging to Group VIII of the periodic table, and an optically active nitrogen compound, and an optically active amino alcohol can be obtained with a high reaction yield. Patent WO2023097696 provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, and the method route is as follows: (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol is synthesized by the method and applied to the preparation of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one with a yield of 87-94%. A method for synthesizing optically active aromatic epoxides was developed in the journal (Tetrahedron (2004), 60 (34), 7411-7417). The optically active alcohols were obtained by asymmetric reduction of aromatic ketones using a formic acid / triethylamine mixture containing a chiral Rh complex Cp*RhCl[(R,R)-Tsdpen], which is particularly suitable for large-scale production of optically active styrene oxides from α-chloroketones.

[0004] Although there are many methods for reducing α-nitroketones in the prior art, there are relatively few examples of asymmetric reduction of α-nitroketones, and the substrate functional groups are also relatively limited. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing chiral α-nitro alcohols with a wide range of substrate functional groups and high efficiency, wherein a nitroketone is converted into a nitro alcohol in the presence of hydrogen and a rhodium catalyst to obtain a desired chiral compound. The α-nitro alcohol compounds obtained by the present invention can be used as intermediates for synthesizing a variety of important drugs (such as norepinephrine) and have high economic value.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] In one aspect, the present invention provides a method for efficiently preparing chiral α-nitro alcohols, comprising:

[0008]

[0009] Compound 2 is prepared by using compound 1 in the presence of hydrogen, a catalyst and a base; the carbon atom marked with * is in R configuration or S configuration;

[0010] Wherein, Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0011] The catalyst is a rhodium catalyst, and the rhodium catalyst is

[0012] Further, the Ar is substituted by one or more identical or different R, each of which is independently hydrogen, deuterium, alkyl, alkoxy, halogen, nitro, alkylsulfonyl-, hydroxyl, cyano, -NH2, -CHO, -COOH, -alkyl-COOH, -SO3H, -alkyl-SO3H, nitro, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl; optionally, two adjacent R are connected to form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring.

[0013] Furthermore, the R is independently hydrogen, deuterium, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, nitro, C 1-8 Alkylsulfonyl-, hydroxyl, cyano, -NH2, -CHO, -COOH, -C 1-8 Alkyl-COOH, -SO3H, -C 1-8 Alkyl-SO3H, nitro, C 1-8 Alkylthio, C 3-12 Cycloalkyl, C 3-12 Heterocyclic group, C 6-12 Aryl or C 1-12 Heteroaryl; optionally, two adjacent R are linked to form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring.

[0014] In the present application, the alkyl group includes C 1-8 The alkyl group specifically includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0015] In the present application, the alkoxy group includes C 1-8Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.

[0016] In the present application, the halogen includes: fluorine, chlorine, bromine, and iodine.

[0017] In the present application, the "aryl" can be a monocyclic, bicyclic or tricyclic carbon ring system, wherein at least one ring system is aromatic, wherein each ring system contains 6-14 atoms. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic rings can include phenyl, naphthyl and anthracenyl.

[0018] "Heteroaryl", "heteroaromatic ring" are used interchangeably herein and are aromatic groups containing heteroatoms, stable monocyclic, bicyclic or tricyclic rings with up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, dihydroindolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridinyl, pyrimidinyl , pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydroindole, dihydroquinolyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolyl, isoquinolyl, oxazolyl, 2,3,3a,7a-tetrahydro-1H-isoindolyl, 1,2,3,4-tetrahydroquinolyl, pteridinyl, purinyl and tetrahydroquinoline. In the case where the heteroaryl substituent is bicyclic and one ring is non-aromatic or does not contain heteroatoms, it should be clear that it is connected through an aromatic ring or through a ring containing heteroatoms, respectively. If the heteroaryl contains a nitrogen atom, it should be clear that the definition also includes its corresponding N-oxide.

[0019] Further, Ar is phenyl, 4-methylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 2,5-difluorophenyl, 2-chloro-4-methoxyphenyl, 4-nitrophenyl, 4-methylsulfonylphenyl, naphthalene-2-yl, furan-2-yl, 3-cyanophenyl or benzo[d][1,3]dioxol-5-yl.

[0020] Further, the base is selected from at least one of NaOH, KOH, KHCO3, Na2CO3, K2CO3, PhONa, PhCOONa, AcONa, KH2PO4, K2HPO4, Py, TEA, NaHCO3 or (PhO)2POONa.

[0021] Further, the method is carried out in a solvent, and the solvent is selected from at least one of i-PrOH, EtOH, MeOH, TFE, HFIP, DCM, hexane, THF, toluene or benzene. In the present application, a compound with high yield, high ee value and high conversion rate is obtained by selecting a suitable solvent.

[0022] Furthermore, the method is carried out at 20-40° C., preferably 25, 30, 35, 40° C. In order to reduce the formation of by-products and achieve a reasonable yield, the method is carried out under mild temperature conditions.

[0023] Furthermore, the method is carried out under atmospheric pressure, specifically 30 to 50 atmospheres of hydrogen, preferably 30, 35, 40, 45, 50 atmospheres. In order to increase the efficiency of the reaction, a suitable atmospheric pressure is used.

[0024] Furthermore, the reaction time of the method is 8 to 30 hours, preferably 8, 10, 12, 14, 15, 16, 18, 20, 24 hours. In order to achieve a reasonable yield and conversion rate, the reaction time is controlled.

[0025] Furthermore, the amount of the rhodium catalyst is 0.0001-0.01 mol%, preferably 0.002 mol%. The amount of the catalyst can not only achieve the preparation of nitro alcohol, but also maximize the catalytic performance of the catalyst.

[0026] Furthermore, the amount of the base is 0.1 to 0.2 eq. The amount of the base is controlled based on the amount of compound 1.

[0027] Furthermore, the concentration of the compound 1 is 0.1-0.4 M, preferably 0.2 M. A suitable concentration of the compound 1 can maximize the efficiency of the asymmetric reaction.

[0028] Furthermore, the R is further optionally and independently substituted by the same or different substituents; the substituents are hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, alkyl-COOH, alkyl-SO3H, -B(OH)2, hydroxyl, -SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

[0029] Furthermore, in the method, 0.002 mol% rhodium catalyst, NaHCO3 as base, toluene as solvent, react at 20-30°C for 15-30 hours to obtain the product, preferably at 25°C for 24 hours to obtain the product.

[0030] Furthermore, the compound 1 is selected from one of the following structures:

[0031]

[0032] Further, the compound 2 is preferably

[0033] Furthermore, the compound 2 is selected from one of the following structures:

[0034]

[0035] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0036] The present application has demonstrated the high catalytic efficiency of the developed [Rh] complex in the asymmetric hydrogenation of α-nitroketones which is simple and practical to operate. The preparation of the catalyst [Rh] complex is based on the records in the journal literature (Angew. Chem. Int. Ed. 2024, 63, e202319662.).

[0037] The reaction conditions of the present application are applicable to a series of differently substituted 2,5-difluoroα-nitroacetophenone derivatives, piperonyl α-nitroacetophenone derivatives, 3-methoxy α-nitroacetophenone derivatives and 4-methylsulfonyl α-nitroacetophenone derivatives.

[0038] The reaction of the present invention can directly obtain the corresponding enantiomer-enriched o-nitro alcohol through asymmetric catalytic hydrogenation, with excellent enantioselectivity (up to 99.9% ee) and a conversion rate of 99%. The reaction of the present invention is carried out under mild indoor conditions and has good application value. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0040] Preparation Example 1

[0041] The following routes were used to investigate different solvents, and the results are as follows:

[0042]

[0043] Examples 1-1 to 1-8: Compound 1a was used as a template substrate, and 1.5 mmol thereof was dissolved in 7.5 ml of different solvents under an inert gas atmosphere, and [Rh] catalyst solution (0.2 mol%), a molar ratio of compound 1a to catalyst of 1000 / 1, (PhO)2POONa (20 mol%, 0.3 mmol) were taken, and the reaction was carried out at 25°C and 50 atmospheres of H2 for 16 hours. The reaction solution was analyzed by hydrogen spectrum nuclear magnetic resonance to determine the conversion rate, and its optical purity was determined by chiral HPLC.

[0044] Table 1

[0045] Example Solvents Conversion rate (%) Ee(%) 1-1 MeOH 99 0 1-2 EtOH 99 99 1-3 i-PrOH 99 99 1-4 EA 99 99 1-5 THF 99 99 1-6 Toluene 99 99 1-7 DCM 99 99 1-8 MTBE 99 99

[0046] The results are shown in Table 1. Except for the racemic product obtained when methanol was used as the solvent, complete conversion was obtained for all solutions. The other solvents all had good enantioselectivity, and the ee value reached >99:1.

[0047] Preparation Example 2

[0048] Based on the preparation example 1, Toluene was selected as the solvent, PhCOONa was selected as the base, the catalyst loading was 0.2 mol%, and the H2 pressure was 50 atmospheres. The effect of the amount of added base on the reaction was investigated. The results are shown in Table 2:

[0049] Example Equivalent of base Conversion rate (%) Ee(%) 2-1 1mol% 0 / 2-2 5mol% 32 99 2-3 20mol% 99 99

[0050] From the results in Table 2, it can be found that different alkali dosages have an impact on the reaction results of the present application. When the alkali dosage is too low (for example, 1 mol%), the conversion rate is 0. When the alkali dosage is above 20 mol%, good conversion rates and ee values ​​are obtained.

[0051] Preparation Example 3

[0052] Based on the preparation of Example 2, Toluene was selected as the solvent, the catalyst loading was 0.2 mol%, the H2 pressure was 50 atmospheres, and different bases were screened for reaction. The results are shown in Table 3:

[0053]

[0054]

[0055] From the results in Table 3, it can be found that different weak bases have little effect on the reaction results of the present application, and good conversion rates and ee values ​​are achieved.

[0056] Based on the above screening conditions, the optimized conditions were set as follows: 0.2 mol% [Rh] catalyst, (PhO)2POONa or NaHCO3 (0.2 equivalent) as base, Toluene or DCM or THF (0.2 M) as solvent at 25°C. Under the optimized conditions, a series of cyclic α-nitroketones were used to explore the substrate range of the reaction, and the results are shown in Table 3:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] In the table, (a) solvent = Toluene, base = (PhO)2POONa, (b) solvent = DCM, base = (PhO)2POONa, (c) solvent = THF, base = NaHCO3, (d) solvent = Toluene, base = NaHCO3, (e) 1 mol% catalyst, solvent = Toluene, base = NaHCO3

[0064] As can be seen from the above table, the asymmetric catalytic hydrogenation method provided by the present invention is highly efficient, has a quantitative yield, has excellent enantioselectivity, and greatly reduces the difficulty and cost of synthesizing various drugs.

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for efficiently preparing chiral α-nitro alcohols, characterized in that: include: Compound 2 is prepared by using compound 1 in the presence of hydrogen, a catalyst and a base; the carbon atom marked with * is in R configuration or S configuration; Wherein, Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; The catalyst is a rhodium catalyst, and the rhodium catalyst is 2. The method according to claim 1, characterized in that: The Ar is substituted by one or more identical or different R, each of which is independently hydrogen, deuterium, alkyl, alkoxy, halogen, nitro, alkylsulfonyl-, hydroxyl, cyano, -NH2, -CHO, -COOH, -alkyl-COOH, -SO3H, -alkyl-SO3H, nitro, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl; optionally, two adjacent R are connected to form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring.

3. The method according to claim 2, characterized in that: The R is independently hydrogen, deuterium, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, nitro, C 1-8 Alkylsulfonyl-, hydroxyl, cyano, -NH2, -CHO, -COOH, -C 1-8 Alkyl-COOH, -SO3H, -C 1-8 Alkyl-SO3H, nitro, C 1-8 Alkylthio, C 3-12 Cycloalkyl, C 3-12 Heterocyclic group, C 6-12 Aryl or C 1-12 Heteroaryl; optionally, two adjacent R are linked to form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring.

4. The method according to claim 1, characterized in that: Ar is phenyl, 4-methylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 2,5-difluorophenyl, 2-chloro-4-methoxyphenyl, 4-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl, furan-2-yl, 3-cyanophenyl or benzo[d][1,3]dioxol-5-yl.

5. The method according to claim 1, characterized in that: The base is selected from at least one of NaOH, KOH, KHCO3, Na2CO3, K2CO3, PhONa, PhCOONa, AcONa, KH2PO4, K2HPO4, Py, TEA, NaHCO3 or (PhO)2POONa.

6. The method according to claim 1, characterized in that: The method is carried out in a solvent, and the solvent is selected from at least one of i-PrOH, EtOH, MeOH, TFE, HFIP, DCM, hexane, THF, toluene or benzene.

7. The method according to claim 1, characterized in that: The method is carried out at 20-40°C, preferably 25, 30, 35, 40°C; the method is carried out at atmospheric pressure, specifically 30-50 atmospheres of hydrogen, preferably 30, 35, 40, 45, 50 atmospheres; the reaction time of the method is 8-30 hours, preferably 8, 10, 12, 14, 15, 16, 18, 20, 24 hours.

8. The method according to claim 1, characterized in that: The amount of the rhodium catalyst used is 0.0001-0.01 mol%, preferably 0.002 mol%; further, the amount of the base used is 0.1-0.2 eq; further, the concentration of the compound 1 is 0.1-0.4M.

9. The method according to claim 1, characterized in that: In the method, 0.002 mol% rhodium catalyst, NaHCO3 as base, toluene as solvent, reaction at 20-30°C for 15-30 hours are used to prepare the product.

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