阅读说明：本技术 一种(1r,2r)-硝基醇类化合物的合成方法 (Synthesis method of (1R,2R) -nitroalcohol compound ) 是由 陈芬儿 董琳 夏应奇 唐培� 肖友财 于 2019-12-11 设计创作，主要内容包括：本发明提供了一种(1R,2R)-硝基醇类化合物(I)的合成方法。该方法按照以下反应路线,在由(1S,2R)-胺基醇类手性配体与二价铜盐原位形成的铜络合物催化下,使苯甲醛化合物(II)与硝基乙醇衍生物(III)在有机溶剂中进行缩合反应,制得(1R,2R)-硝基醇类化合物(I),其中R<Sup>1</Sup>和R<Sup>2</Sup>如说明书中定义。该方法反应条件温和,非对映选择性优良,化学收率高,具有很高的工业应用价值。<Image he="129" wi="700" file="DDA0002313328660000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a synthesis method of a (1R,2R) -nitroalcohol compound (I). According to the following reaction route, under the catalysis of a copper complex formed by a (1S,2R) -amino alcohol chiral ligand and a cupric salt in situ, a benzaldehyde compound (II) and a nitroethanol derivative (III) are subjected to condensation reaction in an organic solvent to prepare a (1R,2R) -nitroalcohol compound (I), wherein R is 1 And R 2 As defined in the specification. The method has the advantages of mild reaction conditions, excellent diastereoselectivity, high chemical yield and high industrial application value.)

1. A synthesis method of (1R,2R) -nitroalcohol compounds of formula (I) is characterized in that under the catalysis of copper complexes formed by (1S,2R) -aminoalcohol chiral ligands and divalent copper salt in situ, a condensation reaction is carried out between a compound of formula (II) and a compound of formula (III) in the presence of an organic solvent to prepare the (1R,2R) -nitroalcohol compounds of formula (I),

wherein:

R¹is H or the following monosubstituted group at any substitutable position on the benzene ring: methyl, ethyl, straight or branched C₃-C₅Alkyl, cyclopropyl, phenyl, halogen, trifluoromethyl, nitro, cyano, straight or branched C₁-C₅Alkylthio, straight or branched C₁-C₅Alkyl sulfoxide group, straight chain or branched chain C₁-C₅Alkyl sulfone group, hydroxy group, methoxy group, ethoxy group, straight chain or branched chain C₃-C₅Alkoxy, straight or branched C₁-C₅An alkyl acyloxy group, a benzyloxy group;

R²is H, methyl, ethyl, straight or branched C₃-C₅Alkyl, acetyl, straight or branched C₃-C₅Alkanoyl, benzoyl, benzyl, trityl, trimethylsilyl, triethylsilyl, tris (linear or branched C)₃-C₅Alkyl) silyl, di-t-butylphenyl silyl or t-butyldimethylsilyl.

2. The process according to claim 1, wherein the chiral (1S,2R) -aminoalcohol ligand has the formula (A)

Wherein:

ar is phenyl, naphthyl or biphenyl;

R³、R⁴are identical or different and are each independently H, straight-chain or branched C₁-C₅Alkyl, or

R³、R⁴Linked together to form 1, 3-propylene, 1, 4-butylene or 1, 5-pentylene.

3. The method according to claim 2, wherein the molar ratio of the compound of formula (II), the compound of formula (III), the cupric salt, the chiral ligand of (1S,2R) -aminoalcohol is 1: 1.1-8: 0.05-0.15: 0.08-0.2.

4. The method according to claim 3, wherein the molar ratio of the compound of formula (II), the compound of formula (III), the cupric salt, the chiral ligand of (1S,2R) -aminoalcohol is 1: 2-6: 0.05-0.15: 0.08-0.2.

5. Process according to any one of claims 1 to 4, characterized in that the (1S,2R) -aminoalcohol chiral ligand is (1S,2R) -1, 2-diphenyl-2- (pyrrolidin-1-yl) ethan-1-ol, (1S,2R) -2- (dimethylamino) -1, 2-diphenylethan-1-ol or (1S,2R) -2- (diisopropylamino) -1, 2-diphenylethan-1-ol.

6. The method according to claim 5, wherein the cupric salt is a divalent inorganic cupric salt or a divalent organic cupric salt, the divalent inorganic cupric salt is cupric chloride or cupric bromide, and the divalent organic cupric salt is hydrated cupric acetate, cupric propionate or cupric trifluoromethanesulfonate.

7. The method according to claim 6, characterized in that the divalent copper salt is hydrated copper acetate or copper trifluoromethanesulfonate and the hydrated copper acetate is copper acetate monohydrate.

8. The process according to claim 7, characterized in that the organic solvent is a polar aprotic solvent.

9. The method according to claim 8, characterized in that the polar aprotic solvent is toluene, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform or ethyl acetate.

10. The method according to claim 9, wherein the condensation reaction is carried out at a temperature of-15 to 15 ℃ for 48 to 120 hours.

Technical Field

The invention relates to the field of organic synthesis, in particular to a synthesis method of a (1R,2R) -nitroalcohol compound shown in the following formula (I).

Background

The (1R,2R) -nitroalcohol compound (I) is widely existed in natural products and drug molecules due to the unique chiral structure. At present, three documents mainly report the preparation of chiral nitroalcohol compounds (I), but the obtained products are mainly trans products. At present, no report is found about a preparation method of the cis-nitro alcohol compound (I).

The trans-chiral nitroalcohol compound (I) is mainly obtained by asymmetric condensation reaction of aromatic aldehyde and nitro compound catalyzed by metal-chiral ligand complex or quinine derivative. Shibasaki et al (J.Am. chem. Soc.2009,131,13860-13869) reported asymmetric condensation of rubidium-sodium bimetallic catalyzed benzaldehyde with TBS protected nitroethanol or benzyl protected nitroethanol, but such methods have high diastereoselectivity, but the reaction temperature is low (-40 ℃), the operation is cumbersome, and large-scale production is not favored. Hong et al (Angew. chem. int. Ed.2012,51,1620-1624) reported an asymmetric condensation reaction co-catalyzed by thiourea/metallic cobalt, under the catalytic system, 2-methoxybenzaldehyde and TBS protected nitroethanol smoothly react and obtain a target compound with higher yield and enantioselectivity, but the temperature is harsh (-80 ℃), and is not beneficial to industrial production. Levacher et al (chemistry select2016,1, 3184-one 3188) reported asymmetric condensation of benzaldehyde with nitroethanol using a quinine derivative as a catalyst. This reaction gives the target compound only in moderate yields and is less diastereoselective and enantioselective (anti/syn: 83:17, 63% ee of anti, 32% ee of syn).

The above methods all mainly use trans-products, and the preparation method of the cis-product compound (I) is not reported, which is not beneficial to the research and development and production of related drugs. Under the condition of rubidium-sodium bimetallic catalytic system, one metal is used as Lewis acid to activate aromatic aldehyde, and the other metal is used as aromatic aldehyde

Alkali-activated nitroethanol derivatives. In this catalytic mode, the condensation products are predominantly trans products. In the same way, under the co-catalysis system of thiourea/metallic cobalt, thiourea activates the nitroethanol derivative, metallic cobalt activates the aromatic aldehyde, and the condensation product mainly takes a trans product. However, substrates of this type have not been reported to date to produce cis-products by condensation reactions.

In summary, a synthetic method for preparing the (1R,2R) -nitroalcohol compound (I) with simple process, low cost and less pollution needs to be researched.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide an asymmetric synthesis method for preparing the (1R,2R) -nitroalcohol compound (I), which has the advantages of simple process, low cost and less pollution.

Specifically, the invention provides a synthesis method of (1R,2R) -nitroalcohol compounds of formula (I), which is characterized in that under the catalysis of a copper complex formed by in-situ (1S,2R) -aminoalcohol chiral ligand and divalent copper salt, a compound of formula (II) and a compound of formula (III) are subjected to condensation reaction in the presence of an organic solvent to prepare the (1R,2R) -nitroalcohol compounds of formula (I),

wherein:

R¹is H or the following monosubstituted group at any substitutable position on the benzene ring: methyl, ethyl, straight or branched C₃-C₅Alkyl, cyclopropyl, phenyl, halogen, trifluoromethyl, nitro, cyano, straight or branched C₁-C₅Alkylthio, straight or branched C₁-C₅Alkyl sulfoxide group, straight chain or branched chain C₁-C₅Alkyl sulfone group, hydroxy group, methoxy group, ethoxy group, straight chain or branched chain C₃-C₅Alkoxy, straight or branched C₁-C₅An alkyl acyloxy group, a benzyloxy group;

R²is H, methyl, ethyl, straight or branched C₃-C₅Alkyl, acetyl, straight or branched C₃-C₅Alkanoyl, benzoyl, benzyl, trityl, trimethylsilyl, triethylsilyl, tris (linear or branched C)₃-C₅Alkyl) silyl, di-t-butylphenyl silyl or t-butyldimethylsilyl.

Preferably, R¹Is H, methyl, ethyl, straight or branched C₃-C₅Alkyl, phenyl, halogen, trifluoromethyl, nitro, cyano, straight or branched C₁-C₅Alkylthio, straight or branched C₁-C₅Alkyl sulfoxide group, straight chain or branched chain C₁-C₅Alkyl sulfone group, methoxy group, ethoxy group, straight chain or branched chain C₃-C₅Alkoxy or straight or branched C₁-C₅An alkanoyloxy group, which may be substituted at any substitutable position of the benzene ring, such as the 2-, 3-, 4-, 5-or 6-position, or at the ortho-, meta-or para-position of the aldehyde group on the benzene ring.

Preferably, R²Is H, methyl, ethyl, straight or branched C₃-C₅Alkyl, trimethylsilyl, triethylsilyl, tri (linear or branched C)₃-C₅Alkyl) silyl, di-t-butylphenyl silyl or t-butyldimethylsilyl.

The condensation reaction is asymmetric condensation reaction, and the yield of the (1R,2R) -nitroalcohol compound obtained by the method is more than 95%, dr is more than 10:1, ee is more than 97%.

The (1S,2R) -amino alcohol chiral ligand has high diastereoselectivity and enantioselectivity catalytic effect, mild reaction condition, simple and convenient operation, and high yield and optical purity of the obtained product.

The (1S,2R) -amino alcohol chiral ligand used in the invention has a structural formula of the following formula (A)

Wherein: ar is phenyl, naphthyl or biphenyl;

R³、R⁴are identical or different and are each independently H, straight-chain or branched C₁-C₅Alkyl, or

R³、R⁴Linked together to form 1, 3-propylene, 1, 4-butylene or 1, 5-pentylene.

In the (1S,2R) -aminoalcohol chiral ligands of formula (A), Ar is preferably phenyl.

In the asymmetric condensation reaction of the invention, (1S,2R) -1, 2-diphenyl-2- (pyrrolidine-1-yl) ethane-1-alcohol, (1S,2R) -2- (dimethylamino) -1, 2-diphenylethane-1-alcohol or (1S,2R) -2- (diisopropylamine) -1, 2-diphenylethane-1-alcohol is preferably adopted as the chiral ligand of (1S,2R) -amino alcohol, the chiral ligand is easy to prepare, convenient to recover and reasonable in economy, and the complex formed by the chiral ligand and divalent copper salt can catalyze the condensation reaction with high selectivity to obtain a cis-product.

The metallic copper salt can form a stable complex with the amino alcohol compound. In the present invention, the copper complex is formed in situ from (1S,2R) -aminoalcohol chiral ligand and a divalent copper salt. The cupric salt is a divalent inorganic cupric salt or a divalent organic cupric salt, wherein the divalent inorganic cupric salt is cupric chloride or cupric bromide, the divalent organic cupric salt is hydrated cupric acetate, cupric propionate or cupric trifluoromethanesulfonate, preferably hydrated cupric acetate or cupric trifluoromethanesulfonate, and more preferably the hydrated cupric acetate is cupric acetate monohydrate. Although cuprous salts can adapt to the reaction system, compared with cupric salts, the cuprous salts are easy to oxidize and have poor stability, so the cupric salts are selected in the invention.

In the embodiment of the invention, the cupric acetate monohydrate or the copper trifluoromethanesulfonate is adopted as the cupric salt, so that the catalytic effect is better, the dr value and the ee value are higher, the effect is better and the source is wide.

In the present invention, the compound of formula (II) used is a substituted or unsubstituted benzaldehyde compound, and the compound of formula (III) used is nitroethanol or a derivative thereof. The molar ratio of the compound of formula (II), the compound of formula (III), a divalent copper salt, and a (1S,2R) -aminoalcohol chiral ligand is preferably 1: 1.1-8: 0.05-0.15: 0.08-0.2, and the molar ratio of the compound of formula (II), the compound of formula (III), a divalent copper salt, and a (1S,2R) -aminoalcohol chiral ligand is more preferably 1: 2-6: 0.05-0.15: 0.08-0.2. The dosage of the nitroethanol or the derivative (III) thereof is too small, and the reaction of the benzaldehyde compound (II) may be incomplete; the dr and ee values of the product may be reduced by using an excessive amount of nitroethanol or the derivative (III).

In the asymmetric condensation reaction of the present invention, the organic solvent used is generally a polar aprotic solvent, preferably toluene, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform or ethyl acetate. The solvents are wide in source, cheap and easy to obtain, and convenient to recover.

In the asymmetric condensation reaction of the invention, the reaction temperature of the condensation reaction is preferably controlled to be-15 ℃. The yield may be reduced due to the low temperature, the enantioselectivity and diastereoselectivity may be reduced due to the high temperature, and the condensation reaction has a reaction time of 48-120h, so that the effect is better.

In the asymmetric condensation reaction of the present invention, the concentration of the final product of the (1R,2R) -nitroalcohols of formula (I) is preferably controlled to be 0.5M to 0.7M after completion of the condensation reaction. The yield may be reduced if the concentration is too low; at too high a concentration, enantioselectivity and diastereoselectivity may decrease.

The invention has the beneficial effects that:

the method has the characteristics of easily obtained raw materials, mild reaction conditions, simple and convenient operation, easy recovery of the catalyst, high product purity and the like, and is suitable for industrial production.

Detailed Description

In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

The following examples are provided to further illustrate the present invention in detail, but the scope of the present invention is not limited to the following.