CN107216241B - Optically active 1, 5-pentanediol derivative and synthetic method and application thereof - Google Patents

Optically active 1, 5-pentanediol derivative and synthetic method and application thereof Download PDF

Info

Publication number
CN107216241B
CN107216241B CN201710079316.8A CN201710079316A CN107216241B CN 107216241 B CN107216241 B CN 107216241B CN 201710079316 A CN201710079316 A CN 201710079316A CN 107216241 B CN107216241 B CN 107216241B
Authority
CN
China
Prior art keywords
formula
product
pentanediol
phenyl
optically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710079316.8A
Other languages
Chinese (zh)
Other versions
CN107216241A (en
Inventor
刘顺英
李明凤
贾凯莉
胡文浩
董素珍
储睿
郑庆
郭鑫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN201710079316.8A priority Critical patent/CN107216241B/en
Publication of CN107216241A publication Critical patent/CN107216241A/en
Application granted granted Critical
Publication of CN107216241B publication Critical patent/CN107216241B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1782—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses an optically active 1, 5-pentanediol derivative and a synthesis method thereof, wherein the optically active 1, 5-pentanediol derivative has a structure shown as a formula (Ia) and a formula (Ib); the preparation method of the derivative comprises the following steps: diazo compounds, benzyl alcohol derivatives and alpha, beta-unsaturated aldehyde are taken as raw materials, and
Figure DDA0001225422830000012
the molecular sieve is a water absorbent, a metal catalyst, chiral diaryl prolinol silicon ether and substituted benzoic acid are used as a catalytic system, a metal negative hydrogen reagent is used as a reducing agent, and the optically active 1, 5-pentanediol derivative is obtained through reaction. The synthetic method has the advantages of high atom economy, high selectivity and high yield, and is mild in reaction conditions, simple and safe to operate. The pair of optically active 1, 5-pentanediol derivatives obtained by the invention has high enantioselectivity and bioactivity, and is suitable for preparation and application of antitumor drugs.
Figure DDA0001225422830000011

Description

Optically active 1, 5-pentanediol derivative and synthetic method and application thereof
Technical Field
The invention belongs to the field of synthetic medicine chemical industry, and mainly relates to an optically active 1, 5-pentanediol derivative, a chemical synthesis method and application thereof.
Background
The 1, 5-pentanediol derivative is an important chemical intermediate and is widely used for products such as polyester, polyurethane, plasticizer, coating, spice, adhesive, ink, fiber, medicine intermediate, sealant, lead printing and the like. Recently, chinese patent CN101316508A reported that a combination of 1, 5-pentanediol could be used to reduce and/or eliminate odour from mammals, such as odour from urine, faeces, liquids from leg ulcers, decubital ulcers, blood and perspiration, which could be used to make absorbent products or disposable hygiene products. Therefore, the synthesis of the 1, 5-pentanediol derivative is of great significance.
In recent years, a large number of methods for synthesizing 1, 5-pentanediol derivatives have been reported in the literature. Chinese patent CN1072168A reports that substituted vinyl ethyl ether and substituted acrolein are reacted to produce substituted 3, 4-dihydropyran, substituted 3, 4-dihydropyran acid is catalyzed and hydrolyzed to produce substituted glutaraldehyde, and nickel is loaded on alumina as catalyst and hydrogenated to produce substituted pentanediol. Chinese patent CN101225022A reports that glutaraldehyde is obtained by glutaraldehyde hydrogenation reaction catalyzed by nickel-A/X supported catalyst, wherein, the component A is Co, Mn, Cu, Cr and the like, the carrier X is molecular sieve and Al2O3、SiO2And the like. However, the above-mentioned processes for preparing 1, 5-pentanediol derivative have the common problem that the pressure of catalytic hydrogenation reaction is generally high, which will result in higher pressure requirement for the reaction equipment, and accordingly, the one-time investment of the generating device will be increased, the production cost will be increased, and the operation difficulty in production will also be increased. Meanwhile, it is difficult to asymmetrically synthesize the optically active 1, 5-pentanediol derivative by the above catalytic hydrogenation method. Is not favorable for the application of the optically active 1, 5-pentanediol derivative in industrial and organic synthesis and the industrial synthesis thereof.
Disclosure of Invention
The invention overcomes the defects of the prior art for synthesizing the optically active 1, 5-pentanediol derivative and provides the optically active 1, 5-pentanediol derivative and a preparation method thereof. In the preparation method, the three-component method is used for constructing the 1, 5-pentanediol derivative with optical activity which is more complicated than that of the existing two-component method; the raw material chiral diaryl prolinol silicon ether used in the preparation method is a naturally-existing chiral amino acid derivative, and the chemical synthesis is cheap and easy to obtain; the preparation method has the advantages of high atom economy, high enantioselectivity, high yield, wide substrate application range, simple and safe operation and the like. The optically active 1, 5-pentanediol derivative prepared by the invention has high enantioselectivity, has an obvious inhibiting effect on HCT116 (human colon cancer cells), and is suitable for preparation and application of antitumor drugs.
The structure of the optically active 1, 5-pentanediol derivative provided by the invention is shown as formula (Ia) and formula (Ib),
Figure BDA0001225422810000021
wherein Ar is1Is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl, nitro substituted phenyl;
Ar2is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl;
Ar3is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl.
Preferably, Ar is1Is aryl selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, 3-methylphenyl, 2-methylphenyl, or 3-methoxyphenyl;
Ar2is aryl selected from phenyl, 2-methylphenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, or 4-methoxyphenyl;
Ar3aryl is selected from phenyl, 2-methylphenyl, 2-bromophenyl, 3-methylphenyl, 3-bromophenyl, 3-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, or 4-methoxyphenyl.
Further preferably, the optically active 1, 5-pentanediol derivative is selected from:
(2S,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol (1a)
(2R,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol (1b)
(2S,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol (2a)
(2R,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol (2b)
(2S,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol (3a)
(2R,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol (3b)
(2S,3S) -2-p-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (4a)
(2R,3S) -2-p-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (4b)
(2S,3S) -2-m-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (5a)
(2R,3S) -2-m-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (5b)
(2S,3S) -2-p-methoxybenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (6a)
(2R,3S) -2-p-methoxybenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (6b)
(2S,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol (7a)
(2R,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol (7b)
(2S,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol (8a)
(2R,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol (8b)
(2S,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol (9a)
(2R,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol (9b)
(2S,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (10a)
(2R,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (10b)
Figure BDA0001225422810000031
Figure BDA0001225422810000041
The optically active 1, 5-pentanediol derivative provided by the invention has two chiral centers and comprises a pair of optically active 1, 5-pentanediol derivatives shown as a formula (Ia) and a formula (Ib).
The invention also provides a synthesis method of the optically active 1, 5-pentanediol derivative shown in the formula (Ia) and the formula (Ib), which comprises the steps of taking alpha, beta-unsaturated aldehyde shown in the formula (1), diazo compound shown in the formula (2) and benzyl alcohol derivative shown in the formula (3) as raw materials in an organic solvent, and taking
Figure BDA0001225422810000042
Taking a molecular sieve as a water absorbent, taking a metal catalyst, chiral diaryl prolinol silicon ether and substituted benzoic acid as a catalytic system, and taking a metal negative hydrogen reagent as a reducing agent to carry out reaction to obtain the high enantioselectivity 1, 5-pentanediol derivative shown as the formula (Ia) and the formula (Ib);
specifically, the method comprises the following steps: in an organic solvent, alpha, beta-unsaturated aldehyde shown in formula (1), diazo compound shown in formula (2) and benzyl alcohol derivative shown in formula (3) are used as raw materials
Figure BDA0001225422810000052
The molecular sieve is a water absorbent, a metal catalyst, chiral diaryl prolinol silicon ether and substituted benzoic acid are used as a catalytic system to carry out three-component reaction, and then a metal negative hydrogen reagent is used as a reducing agent to carry out reduction reaction, so that the high enantioselectivity optically active 1, 5-pentanediol derivative shown as a formula (Ia) and a formula (Ib) is obtained. The reaction process is as followsFormula (II):
Figure BDA0001225422810000051
wherein Ar is1Is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl, nitro substituted phenyl;
Ar2is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl;
Ar3is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl.
Preferably, Ar is1Is aryl selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, 3-methylphenyl, 2-methylphenyl, or 3-methoxyphenyl;
Ar2is aryl selected from phenyl, 2-methylphenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, or 4-methoxyphenyl;
Ar3aryl is selected from phenyl, 2-methylphenyl, 2-bromophenyl, 3-methylphenyl, 3-bromophenyl, 3-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, or 4-methoxyphenyl.
Further preferably, the optically active 1, 5-pentanediol derivative is selected from:
(2S,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol (1a)
(2R,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol (1b)
(2S,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol (2a)
(2R,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol (2b)
(2S,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol (3a)
(2R,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol (3b)
(2S,3S) -2-p-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (4a)
(2R,3S) -2-p-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (4b)
(2S,3S) -2-m-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (5a)
(2R,3S) -2-m-bromobenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (5b)
(2S,3S) -2-p-methoxybenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (6a)
(2R,3S) -2-p-methoxybenzyloxy-2, 3-bisphenyl-1, 5-pentanediol (6b)
(2S,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol (7a)
(2R,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol (7b)
(2S,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol (8a)
(2R,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol (8b)
(2S,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol (9a)
(2R,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol (9b)
(2S,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (10a)
(2R,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (10b)
Figure BDA0001225422810000061
Figure BDA0001225422810000071
Figure BDA0001225422810000081
Specifically, the method comprises the following steps: (1) in an organic solvent, alpha of formula (1)Beta-unsaturated aldehyde, diazo compound of formula (2) and benzyl alcohol derivative of formula (3) as raw materials
Figure BDA0001225422810000082
Taking a molecular sieve as a water absorbent, taking a metal catalyst, chiral diaryl prolinol silyl ether and substituted benzoic acid as a catalytic system, and carrying out three-component reaction at the temperature of 0-40 ℃ to obtain an intermediate 2-benzyloxy-5-oxo-2, 3-diaryl valerate derivative; (2) in an organic solvent, a metal negative hydrogen reagent is used as a reducing agent, and reduction reaction is carried out at the temperature of 20-50 ℃ to obtain the target product, namely the optically active 1, 5-pentanediol derivative.
More specifically, the method comprises: alpha, beta-unsaturated aldehyde, metal catalyst, chiral diaryl prolinol silicon ether, substituted benzoic acid and
Figure BDA0001225422810000083
dissolving a molecular sieve in an organic solvent to prepare a mixed solution A; dissolving diazo compound and benzyl alcohol derivative in organic solvent to prepare B; adding the mixed solution B into the mixed solution A for reaction; after the diazo is completely decomposed, an intermediate is obtained after purification; the second step of reaction, dissolving the intermediate in an organic solvent, adding a metal negative hydrogen reagent, and purifying after the reaction to obtain the optically active 1, 5-pentanediol derivative with high enantioselectivity shown in the formula (Ia) and the formula (Ib); the structures of the pair of optically active 1, 5-pentanediol derivatives are shown as a formula (Ia) and a formula (Ib).
In the method, the reaction temperature for synthesizing the optically active 1, 5-pentanediol derivative is 0-50 ℃; preferably, it is 25 ℃ and 40 ℃. Further preferably, the reaction temperature of the two steps in the reaction is different, the reaction temperature of the step (1) is 0-40 ℃, and the reaction temperature of the step (2) is 20-50 ℃; preferably, the temperature for the step (1) reaction is 25 ℃ and the temperature for the step (2) reaction is 40 ℃.
In the process of the invention, the diazo compound of formula (2): a benzyl alcohol derivative of formula (3): an α, β -unsaturated aldehyde of formula (1): metal catalyst: chiral diaryl prolinol silyl ether: substituted benzoic acid: the molar ratio of the metal negative hydrogen reagent is 1.0-3.0:1.0-2.5:1.0:0.05-0.2:0.15-0.2:0.15-0.5:10. Preferably, the diazo compound: benzyl alcohol derivatives: α, β -unsaturated aldehyde: metal catalyst: chiral diaryl prolinol silyl ether: substituted benzoic acid: the molar ratio of the metal negative hydrogen reagent is 3.0:2.5:1.0:0.2:0.2:0.5:10, 1.0:1.0:1.0:0.05:0.15: 10, 2.0:2.0:1.0:0.1:0.2:0.4: 10.
Figure BDA0001225422810000084
The feeding amount of the molecular sieve is 50-100 mg/mmol based on alpha, beta-unsaturated aldehyde. Preferably, the first and second electrodes are formed of a metal,
Figure BDA0001225422810000085
the feeding amount of the molecular sieve is 90 mg/mmol. The proportion of the dosage of the organic solvent to the dosage of the alpha, beta-unsaturated aldehyde is 8-20 mL: 0.8-1.2 mmol; preferably, it is 10mL:1 mmol.
The method of the invention can also comprise a step of separating and purifying the optically active 1, 5-pentanediol derivative obtained by the reaction, wherein the separation and purification of the first step reaction are carried out by using ethyl acetate: and (3) carrying out column chromatography by using an eluent with the petroleum ether ratio of 1: 500-1: 80, and separating and purifying by using ethyl acetate: and (4) carrying out column chromatography by using an eluent with the ratio of petroleum ether being 1: 50-1: 8. Preferably, the separation and purification of the first reaction step is carried out by using ethyl acetate: and (3) carrying out column chromatography by using an eluent with the petroleum ether ratio of 1:100, and separating and purifying the reaction in the second step by using ethyl acetate: and (4) carrying out column chromatography by using an eluent with the ratio of petroleum ether to 1: 10.
In the method of the present invention, the organic solvent comprises dichloromethane, tetrahydrofuran, toluene or chloroform; preferably, dichloromethane.
In the method of the invention, the metal catalyst is an iridium compound, a rhodium compound or a palladium compound; preferably, the metal catalyst is an iridium complex; further preferably, it is bis (1, 5-cyclooctadiene) iridium tetrafluoroborate.
In the method, the chiral diaryl prolinol silicon ether has a structure shown in a formula (III),
Figure BDA0001225422810000091
wherein R is1Is trimethylsilyl, triethylsilyl or dimethyl tert-butyl silyl; ar (Ar)4Is phenyl or 3, 5-bis (trifluoromethyl) phenyl. Preferably, R1Is dimethyl tert-butyl silicon base, Ar4Is phenyl.
In the method, the structure of the substituted benzoic acid is shown as a formula (IV),
Figure BDA0001225422810000092
wherein R comprises hydrogen, 3, 5-bis (trifluoromethyl), nitro, methoxy and halogen. Preferably, R is 4-nitro.
In the method, the metal negative hydrogen reagent is lithium aluminum hydride or sodium borohydride; preferably, it is sodium borohydride.
In one embodiment, the method for synthesizing the optically active 1, 5-pentanediol derivative of the present invention comprises: in the first step of reaction, raw materials are weighed according to the mol ratio of the diazo compound, the benzyl alcohol derivative, the alpha, beta-unsaturated aldehyde, the iridium compound, the chiral diaryl prolinol silicon ether and the substituted benzoic acid of 2.0:2.0:1.0:0.1:0.2:0.4, and the dosage of the alpha, beta-unsaturated aldehyde is taken as the reference
Figure BDA0001225422810000093
Molecular sieve, organic solvent, alpha, beta-unsaturated aldehyde, iridium compound, chiral diaryl prolinol silicon ether, substituted benzoic acid and
Figure BDA0001225422810000094
dissolving a molecular sieve in an organic solvent to prepare a mixed solution A; dissolving diazo compound and benzyl alcohol derivative in organic solvent at 25 deg.c to prepare mixed solution B; adding the mixed solution B into the mixed solution A by using an injection pump, and reacting; after diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether 1:100 is used as an eluant) to obtain an intermediate; and a second step of reaction, dissolving the intermediate in an organic solvent, and taking the dosage of the alpha, beta-unsaturated aldehyde as a reference, and adding the alpha, beta-unsaturated aldehyde: adding metal negative hydrogen reagent 1.0:10.0Hydrogen reagent, and performing column chromatography (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) on the crude product after reaction to obtain a pair of optically active 1, 5-pentanediol derivatives with high enantioselectivity shown in formula (Ia) and formula (Ib).
In the invention, the optically active 1, 5-pentanediol derivatives shown as the formula (Ia) and the formula (Ib) are a pair of compounds with high enantioselectivity.
The invention also provides optically active 1, 5-pentanediol derivatives shown as formula (Ia) and formula (Ib) prepared by the synthesis method; the optically active 1, 5-pentanediol derivatives represented by formula (Ia) and formula (Ib) have two chiral centers.
The invention also provides optically active 1, 5-pentanediol derivatives as shown in formula (Ia) and formula (Ib); the optically active 1, 5-pentanediol derivatives represented by formula (Ia) and formula (Ib) have two chiral centers.
The invention also provides application of the optically active 1, 5-pentanediol derivative shown as the formula (Ia) and the formula (Ib) in preparation of a medical intermediate.
The invention also provides application of the optically active 1, 5-pentanediol derivative shown as the formula (Ia) and the formula (Ib) in preparation of antitumor drugs. Wherein, the tumor diseases comprise colon cancer and the like.
The invention also provides application of the pair of optically active 1, 5-pentanediol derivatives with high enantioselectivity shown in the formula (Ia) and the formula (Ib) in preparation of anti-colon cancer drugs.
The pair of optically active 1, 5-pentanediol derivatives with two chiral centers, shown as formula (Ia) and formula (Ib), provided by the invention is an important chemical and pharmaceutical intermediate, is widely applied to the field of pharmaceutical chemicals, and has a great application prospect. The preparation method of the invention takes cheap and easily available compounds as raw materials, and has the advantages of mild reaction conditions, few reaction steps, fast reaction, low cost, less generated waste, simple and safe operation, high atom economy, high selectivity, high yield and the like.
Drawings
FIG. 1 shows the product (1a) obtained in example 11H NMR scheme.
FIG. 2 shows the product (1a) obtained in example 113Schematic C NMR.
FIG. 3 is a liquid phase diagram of a racemic product of the product (1a) obtained in example 1.
FIG. 4 is a liquid phase diagram of the chiral product of the product (1a) obtained in example 1.
FIG. 5 shows the product (1b) obtained in example 11H NMR scheme.
FIG. 6 shows the product (1b) obtained in example 113Schematic C NMR.
FIG. 7 is a liquid phase diagram of a racemic product of the product (1b) obtained in example 1.
FIG. 8 is a liquid phase diagram of the chiral product of the product (1b) obtained in example 1.
FIG. 9 shows the product (2a) obtained in example 21H NMR scheme.
FIG. 10 shows the product (2a) obtained in example 213Schematic C NMR.
FIG. 11 is a liquid phase diagram of a racemic product of the product (2a) obtained in example 2.
FIG. 12 is a liquid phase diagram of the chiral product of the product (2a) obtained in example 2.
FIG. 13 shows the product (2b) obtained in example 21H NMR scheme.
FIG. 14 shows the product (2b) obtained in example 213Schematic C NMR.
FIG. 15 is a liquid phase diagram of a racemic product of the product (2b) obtained in example 2.
FIG. 16 is a liquid phase diagram of a chiral product of the product (2b) obtained in example 1.
FIG. 17 shows the product (3a) obtained in example 31H NMR scheme.
FIG. 18 shows the product (3a) obtained in example 313Schematic C NMR.
FIG. 19 is a liquid phase diagram of a racemic product of the product (3a) obtained in example 3.
FIG. 20 is a liquid phase diagram of a chiral product of the product (3a) obtained in example 3.
FIG. 21 shows the product (3b) obtained in example 31H NMR scheme.
FIG. 22 shows a sample of the product (3b) obtained in example 313Schematic C NMR.
FIG. 23 is a liquid phase diagram of a racemic product of the product (3b) obtained in example 3.
FIG. 24 is a liquid phase diagram of a chiral product of the product (3b) obtained in example 3.
FIG. 25 shows a sample of the product (4a) obtained in example 41H NMR scheme.
FIG. 26 shows a schematic representation of the product (4a) obtained in example 413Schematic C NMR.
FIG. 27 is a liquid phase diagram of a racemic product of the product (4a) obtained in example 4.
FIG. 28 is a liquid phase diagram of a chiral product of the product (4a) obtained in example 4.
FIG. 29 shows the product (4b) obtained in example 41H NMR scheme.
FIG. 30 shows a sample of the product (4b) obtained in example 413Schematic C NMR.
FIG. 31 is a liquid phase diagram of a racemic product of the product (4b) obtained in example 4.
FIG. 32 is a liquid phase diagram of a chiral product of the product (4b) obtained in example 4.
FIG. 33 is a photograph of the product (5a) obtained in example 51H NMR scheme.
FIG. 34 shows a sample of the product (5a) obtained in example 513Schematic C NMR.
FIG. 35 is a liquid phase diagram of a racemic product of the product (5a) obtained in example 5.
FIG. 36 is a liquid phase diagram of a chiral product of the product (5a) obtained in example 5.
FIG. 37 shows a sample of a product (5b) obtained in example 51H NMR scheme.
FIG. 38 shows a sample of a product (5b) obtained in example 513Schematic C NMR.
FIG. 39 is a liquid phase diagram of a racemic product of the product (5b) obtained in example 5.
FIG. 40 is a liquid phase diagram of a chiral product of the product (5b) obtained in example 5.
FIG. 41 shows a sample of a product (6a) obtained in example 61H NMR scheme.
FIG. 42 is a photograph of the product (6a) obtained in example 613Schematic C NMR.
FIG. 43 is a liquid phase diagram of a racemic product of the product (6a) obtained in example 6.
FIG. 44 is a liquid phase diagram of a chiral product of the product (6a) obtained in example 6.
FIG. 45 is a photograph of the product (6b) obtained in example 61H NMR scheme.
FIG. 46 shows a sample of a product (6b) obtained in example 613Schematic C NMR.
FIG. 47 is a liquid phase diagram of a racemic product of the product (6b) obtained in example 6.
FIG. 48 is a liquid phase diagram of a chiral product of the product (6b) obtained in example 6.
FIG. 49 is a photograph of the product (7a) obtained in example 71H NMR scheme.
FIG. 50 is a photograph of the product (7a) obtained in example 713Schematic C NMR.
FIG. 51 is a liquid phase diagram of a racemic product of the product (7a) obtained in example 7.
FIG. 52 is a liquid phase diagram of a chiral product of the product (7a) obtained in example 7.
FIG. 53 is a photograph of the product (7b) obtained in example 71H NMR scheme.
FIG. 54 is a photograph of the product (7b) obtained in example 713Schematic C NMR.
FIG. 55 is a liquid phase diagram of a racemic product of the product (7b) obtained in example 7.
FIG. 56 is a liquid phase diagram of a chiral product of the product (7b) obtained in example 7.
FIG. 57 is a photograph of the product (8a) obtained in example 81H NMR scheme.
FIG. 58 is a photograph of the product (8a) obtained in example 813Schematic C NMR.
FIG. 59 is a liquid phase diagram of a racemic product of the product (8a) obtained in example 8.
FIG. 60 is a liquid phase diagram of a chiral product of the product (8a) obtained in example 8.
FIG. 61 is a drawing showing a reaction scheme for producing a product (8b) obtained in example 81H NMR scheme.
FIG. 62 is a photograph of the product (8b) obtained in example 813Schematic C NMR.
FIG. 63 is a liquid phase diagram of a racemic product of the product (8b) obtained in example 8.
FIG. 64 is a liquid phase diagram of a chiral product of the product (8b) obtained in example 8.
FIG. 65 is a photograph of the product (9a) obtained in example 81H NMR scheme.
FIG. 66 shows a schematic representation of the product (9a) obtained in example 813Schematic C NMR.
FIG. 67 is a liquid phase diagram of a racemic product of the product (9a) obtained in example 8.
FIG. 68 is a liquid phase diagram of a chiral product of the product (9a) obtained in example 8.
FIG. 69 is a photograph of the product (9b) obtained in example 81H NMR scheme.
FIG. 70 is a photograph of the product (9b) obtained in example 813Schematic C NMR.
FIG. 71 is a liquid-phase diagram of a racemic product of the product (9b) obtained in example 8.
FIG. 72 is a liquid phase diagram of a chiral product of the product (9b) obtained in example 8.
FIG. 73 is a photograph of the product (10a) obtained in example 81H NMR scheme.
FIG. 74 is a photograph of the product (10a) obtained in example 813Schematic C NMR.
FIG. 75 is a liquid phase diagram of a racemic product of the product (10a) obtained in example 8.
FIG. 76 is a liquid phase diagram of a chiral product of the product (10a) obtained in example 8.
FIG. 77 shows a schematic representation of the product (10b) obtained in example 81H NMR scheme.
FIG. 78 shows a sample of a product (10b) obtained in example 813Schematic C NMR.
FIG. 79 is a liquid-phase diagram of a racemic product of the product (10b) obtained in example 8.
FIG. 80 is a liquid phase diagram of a chiral product of the product (10b) obtained in example 8.
FIG. 81 is a graph of concentration-survival for different concentrations of two compounds of the invention (FB1-3-S, FB1-3-X) versus HCT116 (human colon cancer cells).
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The preparation method of the optically active 1, 5-pentanediol derivative comprises the first step of reaction, wherein alpha, beta-unsaturated aldehyde, a metal catalyst, chiral diaryl prolinol silyl ether, substituted benzoic acid and
Figure BDA0001225422810000133
dissolving a molecular sieve in an organic solvent to prepare a mixed solution A; dissolving diazo compound and benzyl alcohol derivative in organic solvent to prepare B; adding the mixed solution B into the mixed solution A for reaction; after the diazo is completely decomposed, an intermediate is obtained after purification; the second step of reaction, dissolving the intermediate in an organic solvent, adding a metal negative hydrogen reagent, and purifying after the reaction to obtain the optically active 1, 5-pentanediol derivative with high enantioselectivity shown in the formula (Ia) and the formula (Ib); the synthesis reaction is shown as a formula (II):
Figure BDA0001225422810000131
wherein Ar is1Is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl, nitro substituted phenyl;
Ar2is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl;
Ar3is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl.
Example 1
Figure BDA0001225422810000132
In the first reaction step, 3-methyl cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000141
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving methyl phenyl diazoacetate (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formula (1a) and (1b), (1a) is (2S,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol, (1b) is (2R,3S) -2-benzyloxy-2-phenyl-3-m-methylphenyl-1, 5-pentanediol, (the total yield of the 1a) and the 1b is 75%, and the dr value is (1 a): (1b) equal to 50: 50. (1a) ee of (1b) is equal to 99% and ee of (1b) is equal to 95%.
Of the optically active product (1a)1The H NMR is shown in FIG. 1, which13The schematic diagram of C NMR is shown in FIG. 2, the liquid phase diagram of its racemic product is shown in FIG. 3, and the liquid phase diagram of its chiral product is shown in FIG. 4.
1H NMR(400MHz,CDCl3)7.34(dt,J＝14.8,7.2Hz,4H),7.23(td,J＝5.6,3.8Hz,3H),7.19(s,1H),6.96(d,J＝3.7Hz,2H),6.87(d,J＝8.0Hz,2H),6.57(d,J＝6.8Hz,2H),4.37(s,2H),3.86(s,2H),3.46(dd,J＝11.6,3.2Hz,1H),3.34(ddd,J＝20.6,12.5,6.5Hz,2H),2.45(ddd,J＝10.1,6.7,3.9Hz,1H),2.21(s,3H),1.93(s,1H),1.70–1.57(m,1H).
13C NMR(100MHz,CDCl3)138.59,137.29,136.48,136.07,129.92,128.58,128.40,127.96,127.66,127.58,127.14,84.08,77.32,77.01,76.69,64.85,62.00,61.83,47.60,31.69,21.03.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor33.13 min, tminor8.15 min.
Of the optically active product (1b)1The H NMR is shown in FIG. 5, which13The schematic diagram of C NMR is shown in FIG. 6, the liquid phase diagram of its racemic product is shown in FIG. 7, and the liquid phase diagram of its chiral product is shown in FIG. 8.
1H NMR(400MHz,CDCl3)7.39–7.25(m,6H),7.20(dd,J＝12.4,4.5Hz,4H),7.06(d,J＝7.7Hz,2H),6.99(d,J＝7.6Hz,2H),4.51(q,J＝12.1Hz,2H),4.08–3.91(m,2H),3.33–3.22(m,1H),3.11(dd,J＝15.6,9.2Hz,1H),2.99(dd,J＝11.4,2.7Hz,1H),2.23(d,J＝14.4Hz,3H),2.05–1.93(m,1H),1.86(s,1H),1.55–1.48(m,2H).
13C NMR(100MHz,CDCl3)140.51,139.39,136.62,136.55,129.91,128.80,128.44,128.41,127.34,127.17,126.88,126.75,84.15,77.34,77.02,76.71,65.71,65.66,61.18,52.10,32.81,21.06.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor7.39 min, tminor12.91 min.
Example 2
Figure BDA0001225422810000151
In the first reaction step, 4-methyl cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000152
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; methyl phenyl diazoacetate (2.0mmol) and benzyl alcohol (2.0mmol)) Dissolving the mixture in 5mL of dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formula (2a) and (2b), (2a) is (2S,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol, (2b) is (2R,3S) -2-benzyloxy-2-phenyl-3-p-methylphenyl-1, 5-pentanediol, (the total yield of the 2a) and the (2b) is 80%, and the dr value is (2 a): (2b) equal to 50: 50. (2a) ee of (2b) equals 53% and ee of (2b) equals 98%.
Of the optically active product (2a)1The H NMR is shown in FIG. 9, which13The schematic diagram of C NMR is shown in FIG. 10, the liquid phase diagram of its racemic product is shown in FIG. 11, and the liquid phase diagram of its chiral product is shown in FIG. 12.
1H NMR(400MHz,CDCl3).7.39–7.27(m,4H),7.27–7.16(m,4H),6.99–6.84(m,4H),6.44(s,2H),4.37(s,2H),3.86(s,2H),3.44(dd,J＝11.6,3.2Hz,1H),3.36(ddd,J＝11.8,7.5,4.7Hz,1H),3.28(dd,J＝16.3,8.7Hz,1H),2.52–2.38(m,1H),2.11(s,3H),1.98(d,J＝24.6Hz,1H),1.71–1.61(m,1H),1.38–1.36(m,1H).
13C NMR(100MHz,CDCl3)139.15,138.62,137.38,137.05,130.88,128.58,127.99,127.67,127.61,127.59,127.49,127.16,84.04,77.35,77.04,76.72,64.86,62.03,61.79,47.95,31.66,21.34.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor17.58 min, tminor6.54 min.
Of the optically active product (2b)1The H NMR is shown in FIG. 13, which13The schematic diagram of C NMR is shown in FIG. 14, the liquid phase diagram of its racemic product is shown in FIG. 15, and the liquid phase diagram of its chiral product is shown in FIG. 16.
1H NMR(400MHz,CDCl3)7.44–7.26(m,9H),7.25–7.23(m,1H),7.14(t,J＝7.7Hz,1H),7.04(t,J＝8.1Hz,3H),4.59(dd,J＝27.1,12.0Hz,2H),4.08(s,2H),3.36(ddd,J＝11.1,6.9,4.5Hz,1H),3.20(dd,J＝15.8,9.4Hz,1H),3.08(dd,J＝11.6,3.3Hz,1H),2.29(s,3H),2.13–2.01(m,1H),1.93(ddd,J＝8.9,6.9,3.4Hz,1H),1.36–1.34(m,1H),1.09–1.07(m,1H).
13C NMR(100MHz,CDCl3)140.37,139.62,139.34,137.43,131.02,128.39,127.87,127.73,127.37,127.19,126.99,126.91,126.83,84.16,77.33,77.21,77.01,76.69,65.67,65.59,61.23,52.29,32.75,21.43.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor7.46 min, tminor9.88 min.
Example 3
Figure BDA0001225422810000161
In the first reaction step, 4-methoxycinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000162
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving methyl phenyl diazoacetate (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (ethyl acetate: petroleum ether: 1:10 is used as an eluent) to obtain a pure product with the structure shown in formula (3)a) And (3b) shows that (3a) is (2S,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol, (3b) is (2R,3S) -2-benzyloxy-2-phenyl-3-p-methoxyphenyl-1, 5-pentanediol, the total yield of (3a) and (3b) is 84%, and the dr value (3 a): (3b) equal to 50: 50. (3a) ee of (3b) is equal to 97% and ee of (3b) is equal to 98%.
Of the optically active product (3a)1The H NMR is shown in FIG. 17, which13The C NMR is shown in FIG. 18, the liquid phase diagram of the racemic product is shown in FIG. 19, and the liquid phase diagram of the chiral product is shown in FIG. 20.
1H NMR(400MHz,CDCl3)7.47–7.35(m,4H),7.29(t,J＝14.9Hz,4H),7.02(s,2H),6.67(s,4H),4.43(s,2H),3.93(s,2H),3.76(s,3H),3.52(dd,J＝11.5,2.6Hz,1H),3.44(dd,J＝13.0,8.8Hz,1H),3.40–3.29(m,1H),2.63–2.45(m,1H),2.07(s,1H),1.67(dd,J＝15.0,9.0Hz,2H).
13C NMR(100MHz,CDCl3)158.47,138.59,137.27,131.15,131.01,128.59,127.92,127.69,127.67,127.59,127.15,113.04,84.16,77.35,77.03,76.71,64.88,61.94,61.76,55.14,47.06,31.69.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor22.97 min, tminor8.82 minutes.
Of the optically active product (3b)1The H NMR is shown in FIG. 21, which13The C NMR is shown in FIG. 22, the liquid phase diagram of the racemic product is shown in FIG. 23, and the liquid phase diagram of the chiral product is shown in FIG. 24.
1H NMR(400MHz,CDCl3)7.33(ddd,J＝19.0,13.4,7.1Hz,8H),7.24(d,J＝7.6Hz,2H),7.13(d,J＝8.3Hz,2H),6.79(d,J＝8.4Hz,2H),4.57(q,J＝12.1Hz,2H),4.07(s,2H),3.79(s,3H),3.46–3.29(m,1H),3.27–3.13(m,1H),3.08(dd,J＝11.4,2.9Hz,1H),1.99(dd,J＝20.5,14.8Hz,2H),1.66(s,2H).
13C NMR(100MHz,CDCl3)158.59,140.34,139.36,131.57,131.00,128.42,127.36,127.19,126.90,126.72,113.41,84.22,77.36,77.04,76.72,65.58,65.47,61.13,55.20,51.38,32.83.
HPLC (hand)Linear IC column, wavelength equal to 220 nm, n-hexane: isopropyl alcohol 4.5: 1 flow rate 1.0 ml/min), tmajor7.97 min, tminor12.59 min.
Example 4
Figure BDA0001225422810000171
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000172
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving methyl phenyl diazoacetate (2.0mmol) and 4-bromobenzyl alcohol (2.0mmol) in 5mL of dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formula (4a) and (4b), (4a) is (2S,3S) -2-p-bromobenzyloxy-2, 3-diphenyl-1, 5-pentanediol, (4b) is (2R,3S) -2-p-bromobenzyloxy-2, 3-diphenyl-1, 5-pentanediol, (the total yield of 4a) and (4b) is 75%, and the dr value is (4 a): (4b) equal to 50: 50. (4a) ee of (4b) is equal to 98% and ee of (4b) is equal to 99%.
Of the optically active product (4a)1The H NMR is shown in FIG. 25, which13The C NMR is shown in FIG. 26, the liquid phase diagram of the racemic product is shown in FIG. 27, and the liquid phase diagram of the chiral product is shown in FIG. 28.
1H NMR(400MHz,CDCl3)7.50(d,J＝7.7Hz,2H),7.32(d,J＝22.0Hz,5H),7.21–7.07(m,3H),6.99(s,2H),6.76(s,2H),4.39(dd,J＝25.7,11.8Hz,2H),3.95(s,2H),3.55(d,J＝10.6Hz,1H),3.43(s,1H),3.33(d,J＝6.6Hz,1H),2.56–2.40(m,1H),2.12(s,1H),1.73(dd,J＝18.4,13.0Hz,2H).
13C NMR(100MHz,CDCl3)139.10,137.62,137.23,131.65,130.07,128.77,128.54,127.99,127.79,127.71,126.99,126.07,121.36,84.09,77.35,77.04,76.72,64.22,62.22,61.53,48.03,31.59.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol 10: 1, flow rate 1.0 ml/min), tmajor26.81 min, tminor13.34 min.
Of the optically active product (4b)1The H NMR is shown in FIG. 29, which13The C NMR is shown in FIG. 30, the liquid phase diagram of the racemic product is shown in FIG. 31, and the liquid phase diagram of the chiral product is shown in FIG. 32.
1H NMR(400MHz,CDCl3)7.50(d,J＝7.9Hz,2H),7.43–7.14(m,12H),4.53(dd,J＝33.1,12.3Hz,2H),4.06(q,J＝12.5Hz,2H),3.35(d,J＝3.7Hz,1H),3.25–3.07(m,2H),2.00(dd,J＝23.2,17.4Hz,2H),1.64(s,2H).
13C NMR(100MHz,CDCl3)139.94,139.59,138.33,131.49,130.08,128.52,128.36,128.02,127.51,127.07,126.82,120.94,84.33,77.35,77.03,76.71,65.58,65.03,60.97,51.97,32.71.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol-8.0: 1, flow rate 1.0 ml/min), tmajor19.29 min, tminor14.99 min.
Example 5
Figure BDA0001225422810000191
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000192
molecular sieve (90mg)Dissolving in 5mL of dichloromethane to prepare a mixed solution A, and stirring for 1 hour at 25 ℃; dissolving methyl phenyl diazoacetate (2.0mmol) and 3-bromobenzyl alcohol (2.0mmol) in 5mL of dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formula (5a) and (5b), (5a) is (2S,3S) -2-m-bromobenzyloxy-2, 3-diphenyl-1, 5-pentanediol, (5b) is (2R,3S) -2-m-bromobenzyloxy-2, 3-diphenyl-1, 5-pentanediol, (5a) and (5b) have the total yield of 75% and the dr value (5 a): (5b) equal to 50: 50. (5a) ee of (5b) is equal to 87% and ee of (5b) is equal to 99%.
Of the optically active product (5a)1The H NMR is shown in FIG. 33, which13The C NMR is shown in FIG. 34, the liquid phase diagram of the racemic product is shown in FIG. 35, and the liquid phase diagram of the chiral product is shown in FIG. 36.
1H NMR(400MHz,CDCl3)7.56(s,1H),7.43(d,J＝7.7Hz,1H),7.34(d,J＝5.0Hz,2H),7.29(s,3H),7.14(dd,J＝15.2,7.5Hz,3H),6.99(d,J＝4.6Hz,2H),6.76(d,J＝5.7Hz,2H),4.41(dd,J＝24.6,11.9Hz,2H),3.96(s,2H),3.55(d,J＝10.3Hz,1H),3.43(d,J＝3.6Hz,1H),3.38–3.22(m,1H),2.56–2.40(m,1H),2.19(s,1H),1.76(s,2H).
13C NMR(100MHz,CDCl3)140.99,139.08,137.29,130.59,130.12,130.10,128.53,127.82,127.77,127.71,126.99,126.08,125.61,122.61,84.10,77.37,77.05,76.73,64.15,62.29,61.47,48.09,31.57.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol 4.5: 1, flow rate 1 ml/min), tmajor6.15 min, tminor9.43 min.
Of the optically active product (5b)1The schematic diagram of H NMR is shown in FIG. 37,it is composed of13The C NMR is shown in FIG. 38, the liquid phase diagram of the racemic product is shown in FIG. 39, and the liquid phase diagram of the chiral product is shown in FIG. 40.
1H NMR(400MHz,CDCl3)7.54(s,1H),7.42(d,J＝7.7Hz,1H),7.36(t,J＝7.3Hz,2H),7.29(dd,J＝14.8,7.2Hz,5H),7.22(t,J＝5.5Hz,5H),4.55(dd,J＝33.2,12.5Hz,2H),4.15–3.99(m,2H),3.37(dd,J＝9.5,5.2Hz,1H),3.25–3.11(m,2H),2.03(dt,J＝10.9,7.0Hz,1H),1.95(dd,J＝13.4,5.3Hz,1H),1.62(s,1H),1.14(d,J＝8.2Hz,1H).
13C NMR(100MHz,CDCl3)141.67,139.76,139.46,130.22,130.12,129.93,129.68,128.53,128.06,127.53,127.12,126.83,125.12,122.58,84.37,77.34,77.02,76.70,65.50,64.89,60.99,51.80,32.67.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol-20: 1, flow rate 1.0 ml/min), tmajor5.76 min, tminor9.71 min.
Example 6
Figure BDA0001225422810000201
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000202
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving methyl phenyl diazoacetate (2.0mmol) and 4-methoxybenzyl alcohol (2.0mmol) in 5mL of dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. The second step, dissolving the intermediate in 5mL dichloromethane, stirring at 40 deg.C, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finishedAnd performing column chromatography on the crude product (by using ethyl acetate: petroleum ether as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formulas (6a) and (6b), (6a) is (2S,3S) -2-p-methoxybenzyloxy-2, 3-diphenyl-1, 5-pentanediol, (6b) is (2R,3S) -2-p-methoxybenzyloxy-2, 3-diphenyl-1, 5-pentanediol, the total yield of (6a) and (6b) is 74%, and the dr value is (6 a): (6b) equal to 50: 50. (6a) ee of (6b) equals 98% and ee of (6b) equals 99%.
Of the optically active product (6a)1The H NMR is shown in FIG. 41, which13The C NMR is shown in FIG. 42, the liquid phase diagram of the racemic product is shown in FIG. 43, and the liquid phase diagram of the chiral product is shown in FIG. 44.
1H NMR(400MHz,CDCl3)7.36–7.28(m,5H),7.20–7.08(m,3H),7.02(d,J＝4.2Hz,2H),6.93(d,J＝8.6Hz,2H),6.74(d,J＝5.7Hz,2H),4.44–4.28(m,2H),3.92(s,2H),3.83(s,3H),3.55(dd,J＝11.3,3.4Hz,1H),3.43(ddd,J＝11.7,7.4,4.7Hz,1H),3.36(dd,J＝15.9,9.1Hz,1H),2.59–2.46(m,1H),2.07(s,1H),1.78–1.67(m,1H).
13C NMR(100MHz,CDCl3)159.20,139.38,137.29,130.56,130.07,128.81,127.98,127.67,127.31,126.90,114.04,84.00,77.34,77.02,76.70,64.64,61.94,61.80,55.32,48.02,31.71.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor38.04 min, tminor20.48 minutes.
Of the optically active product (6b)1The H NMR is shown in FIG. 45, which13The C NMR is shown in FIG. 46, the liquid phase diagram of the racemic product is shown in FIG. 47, and the liquid phase diagram of the chiral product is shown in FIG. 48.
1H NMR(400MHz,CDCl3)7.47–7.28(m,6H),7.27–7.13(m,6H),6.93(d,J＝8.5Hz,2H),4.50(q,J＝11.5Hz,2H),4.19–3.98(m,2H),3.83(s,3H),3.45–3.28(m,1H),3.24–3.14(m,1H),3.11(dd,J＝11.4,3.3Hz,1H),2.13–1.86(m,2H).
13C NMR(100MHz,CDCl3)158.91,140.35,139.82,131.36,130.10,128.40,128.30,127.96,127.38,126.94,113.88,84.13,77.34,77.02,76.71,65.42,61.15,55.32,52.31,32.81.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor22.18 min, tminor38.56 minutes.
Example 7
Figure BDA0001225422810000211
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000212
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving 3-methoxy phenyl diazoacetic acid methyl ester (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, in which the intermediate is dissolved in 5mL of dichloromethane, stirred at 40 ℃, sodium borohydride (10.0mmol) is added in batches, after the reaction is finished, the crude product is subjected to column chromatography (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, the structure of which is shown in the formulas (7a) and (7b), (7a) is (2S,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol, (7b) is (2R,3S) -2-benzyloxy-2-m-methoxyphenyl-3-phenyl-1, 5-pentanediol, (7a) and (7b) have a total yield of 81% and a dr value (7 a): (7b) equal to 50: 50. (7a) ee of (7b) is equal to 96% and ee of (7b) is equal to 97%.
Of the optically active product (7a)1The H NMR is shown in FIG. 49, which13The C NMR is shown in FIG. 50, the liquid phase diagram of the racemic product is shown in FIG. 51, and the liquid phase diagram of the chiral product is shown in FIG. 52.
1H NMR(400MHz,CDCl3)7.46–7.27(m,4H),7.26–7.19(m,1H),7.16–6.96(m,4H),6.81–6.62(m,3H),6.58–6.39(m,2H),4.38(s,2H),3.93–3.76(m,2H),3.59(s,3H),3.48(dd,J＝11.6,3.1Hz,1H),3.41–3.30(m,1H),3.30–3.17(m,1H),2.52–2.35(m,1H),2.11(brs,1H),1.79–1.65(m,1H),1.53(brs,1H).
13C NMR(100MHz,CDCl3)158.05,138.23,138.07,137.60,129.12,127.63,127.54,126.60,126.53,126.07,125.89,119.23,112.67,112.16,83.02,63.94,61.17,60.62,54.10,47.01,30.56.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor9.22 min, tminor8.06 min.
Of the optically active product (7b)1The H NMR is shown in FIG. 53, which13The C NMR is shown in FIG. 54, the liquid phase diagram of the racemic product is shown in FIG. 55, and the liquid phase diagram of the chiral product is shown in FIG. 56.
1H NMR(400MHz,CDCl3)7.40–7.34(m,4H),7.31–7.19(m,7H),6.86–6.79(m,2H),6.77(s,1H),4.58(q,J＝12.2Hz,2H),4.04(q,J＝12.7Hz,2H),3.64(s,3H),3.40–3.27(m,1H),3.24–3.08(m,2H),2.13–1.98(m,1H),1.99–1.86(m,1H),1.79(brs,1H),1.42(brs,1H).
13C NMR(100MHz,CDCl3)159.67,141.84,139.67,139.36,130.21,129.49,128.41,127.93,127.16,126.97,126.65,118.98,112.99,112.86,84.34,65.70,65.43,61.06,55.09,51.81,32.74.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor6.61 min, tminor10.59 min.
Example 8
Figure BDA0001225422810000221
In the first step, cinnamyl aldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol) and chiral diphenyl prolinol dimethyl tert-butyl silyl ether(0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000222
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving 2-bromophenyl diazoacetic acid methyl ester (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. The second step, dissolving the intermediate in 5mL dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, the structure of which is shown in formula (8a) and (8b), (8a) is (2S,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol, (8b) is (2R,3S) -2-benzyloxy-2-o-bromophenyl-3-phenyl-1, 5-pentanediol, (8a) and (8b) have the total yield of 68% and the dr value (8 a): (8b) equal to 37: 63. (8a) ee of (8b) equals 92% and ee of (8b) equals 98%.
Of the optically active product (8a)1The H NMR is shown in FIG. 57, which13The C NMR is shown in FIG. 58, the liquid phase diagram of the racemic product is shown in FIG. 59, and the liquid phase diagram of the chiral product is shown in FIG. 60.
1H NMR(400MHz,CDCl3)7.54–7.36(m,4H),7.34–7.27(m,3H),7.22–7.08(m,3H),7.06–6.97(m,2H),6.88–6.60(m,2H),4.56–4.29(m,2H),3.94(d,J＝4.8Hz,2H),3.57(dd,J＝11.6,3.2Hz,1H),3.49–3.26(m,2H),2.63–2.46(m,1H),2.15–2.00(m,1H),1.82–1.67(m,1H),1.36(s,1H).
13C NMR(100MHz,CDCl3)139.27,138.57,137.27,130.10,128.59,127.92,127.71,127.67,127.60,127.15,126.93,84.04,64.88,62.05,61.73,48.02,31.66.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor15.82 min, tminor5.99 min.
Of the optically active product (8b)1The H NMR is shown in FIG. 61, which13The C NMR is shown in FIG. 62, the liquid phase diagram of the racemic product is shown in FIG. 63, and the liquid phase diagram of the chiral product is shown in FIG. 64.
1H NMR(400MHz,CDCl3)7.45–7.35(m,5H),7.34–7.26(m,4H),7.25–7.18(m,5H),4.59(q,J＝12.2Hz,2H),4.17–3.98(m,2H),3.44–3.31(m,1H),3.25–3.16(m,1H),3.13(dd,J＝11.6,3.3Hz,1H),2.14–2.03(m,1H),2.01–1.90(m,1H),1.09(brs,1H).
13C NMR(100MHz,CDCl3)140.23,139.77,139.32,130.10,128.46,128.43,128.01,127.42,127.20,126.99,126.90,126.72,84.21,65.68,65.55,61.13,52.30,32.81.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor5.77 min, tminor8.11 min.
Example 9
Figure BDA0001225422810000241
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000242
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving 4-methyl phenyl diazoacetic acid methyl ester (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. In the second reaction step, this intermediate was dissolved in 5mL of dichloromethane, stirred at 40 ℃ and added portionwise with sodium borohydride (10.0 mmo)l), after the reaction is finished, the crude product is subjected to column chromatography (with ethyl acetate: petroleum ether 1:10 as eluent) to give a pure product of the formula (9a) and (9b), (9a) being (2S,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol, (9b) being (2R,3S) -2-benzyloxy-2-p-methylphenyl-3-phenyl-1, 5-pentanediol, (9a) and (9b) having a total yield of 66%, dr value (9 a): (9b) equal to 50: 50. (9a) ee of (9b) equals 96% and ee of (9b) equals 98%.
Of the optically active product (9a)1The H NMR is shown in FIG. 65, which13The C NMR is shown in FIG. 66, the liquid phase diagram of the racemic product is shown in FIG. 67, and the liquid phase diagram of the chiral product is shown in FIG. 68.
1H NMR(400MHz,CDCl3)7.53–7.32(m,4H),7.32–7.25(m,1H),7.21–7.01(m,5H),6.88(d,J＝7.4Hz,2H),6.83–6.52(m,2H),4.40(s,2H),3.88(s,2H),3.54(dd,J＝11.3,2.5Hz,1H),3.48–3.35(m,1H),3.35–3.21(m,1H),2.64–2.44(m,1H),2.34(s,3H),2.31–2.10(m,1H),1.91–1.49(m,2H).
13C NMR(100MHz,CDCl3)139.48,138.70,137.35,134.18,130.16,128.58,128.43,127.88,127.66,127.55,127.18,126.86,83.94,64.74,62.07,61.66,47.95,31.75,21.12.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor18.20 min, tminor6.11 min.
Of the optically active product (9b)1The H NMR is shown in FIG. 69, which13The C NMR is shown in FIG. 70, the liquid phase diagram of the racemic product is shown in FIG. 71, and the liquid phase diagram of the chiral product is shown in FIG. 72.
1H NMR(400MHz,CDCl3)7.47–7.32(m,4H),7.30–7.26(m,1H),7.25–7.17(m,5H),7.15–7.01(m,4H),4.56(d,J＝12.2Hz,1H),4.50(d,J＝12.2Hz,1H),4.02(s,2H),3.46–3.26(m,1H),3.12(d,J＝7.8Hz,2H),2.32(s,3H),2.10–1.84(m,3H),1.69(brs,1H).
13C NMR(100MHz,CDCl3)139.81,139.48,137.03,136.88,130.28,129.10,128.41,127.88,127.14,126.96,126.88,126.69,84.13,65.46,65.26,60.96,51.71,32.77,21.08.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor5.91 min, tminor8.33 min.
Example 10
Figure BDA0001225422810000251
In the first reaction step, cinnamaldehyde (1.0mmol), bis (1, 5-cyclooctadiene) iridium tetrafluoroborate (0.1mmol), chiral diphenyl prolinol dimethyl tert-butyl silyl ether (0.2mmol), 4-nitrobenzoic acid (0.4mmol) and
Figure BDA0001225422810000252
dissolving a molecular sieve (90mg) in 5mL of dichloromethane to prepare a mixed solution A, and stirring at 25 ℃ for 1 hour; dissolving 4-bromophenyl diazoacetic acid methyl ester (2.0mmol) and benzyl alcohol (2.0mmol) in 5mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 25 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:100 is used as an eluent) to obtain an intermediate. And a second step of reaction, dissolving the intermediate in 5mL of dichloromethane, stirring at 40 ℃, adding sodium borohydride (10.0mmol) in batches, and after the reaction is finished, performing column chromatography on the crude product (using ethyl acetate: petroleum ether ═ 1:10 as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as formula (10a) and (10b), (10a) is (2S,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol, (10b) is (2R,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol, (10a) and (10b) have a total yield of 62% and a dr value (10 a): (10b) equal to 50: 50. (10a) ee of (10b) is equal to 97%.
Of the optically active product (10a)1The H NMR is shown in FIG. 73, which13The C NMR is shown in FIG. 74, the liquid phase diagram of the racemic product is shown in FIG. 75, and the liquid phase diagram of the chiral product is shown in FIG. 76.
1H NMR(400MHz,CDCl3)7.55–7.36(m,6H),7.35–7.30(m,1H),7.22–7.07(m,3H),6.89(d,J＝8.2Hz,2H),6.83–6.62(m,2H),4.42(dd,J＝27.1,11.7Hz,2H),3.90(s,2H),3.56(dd,J＝11.7,3.0Hz,1H),3.51–3.39(m,1H),3.39–3.25(m,1H),2.58–2.40(m,1H),2.11(brs,1H),1.78–1.65(m,1H),1.42(brs,1H).
13C NMR(100MHz,CDCl3)138.88,138.29,136.69,130.84,130.05,129.67,128.65,127.85,127.71,127.10,121.89,83.83,64.90,62.07,61.46,47.69,31.48.
HPLC (chiral IA column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor9.38 min, tminor6.88 min.
Of the optically active product (10b)1The H NMR is shown in FIG. 77, which13The C NMR is shown in FIG. 78, the liquid phase diagram of the racemic product is shown in FIG. 79, and the liquid phase diagram of the chiral product is shown in FIG. 80.
1H NMR(400MHz,CDCl3)7.52–7.43(m,2H),7.42–7.34(m,4H),7.34–7.28(m,1H),7.27–7.19(m,5H),7.13(d,J＝8.5Hz,2H),4.54(dd,J＝43.5,12.1Hz,2H),4.05(s,2H),3.38(ddd,J＝10.9,6.9,4.3Hz,1H),3.27–3.16(m,1H),3.13(dd,J＝11.7,3.3Hz,1H),2.13–2.00(m,1H),1.98–1.86(m,1H),1.61(s,2H).
13C NMR(100MHz,CDCl3)139.50,139.39,138.97,131.50,130.09,128.79,128.49,128.10,127.34,127.13,126.67,121.50,83.96,65.65,65.20,60.94,51.84,32.62.
HPLC (chiral IC column, wavelength equal to 220 nm, n-hexane: isopropanol ═ 4.5: 1, flow rate ═ 1.0 ml/min), tmajor5.37 min, tminor4.66 minutes.
Example 11
In this example, the biological activity of the compound of the present invention was tested by the CCK8 method, and the compound of the present invention (10a), (2S,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (accession number FB1-3-S) prepared in example 10 and the compound of the present invention (10b), (2R,3S) -2-benzyloxy-2-p-bromophenyl-3-phenyl-1, 5-pentanediol (accession number FB1-3-X) prepared in example 10 were used to investigate the inhibitory effect on tumor cells. The cell lines specifically used in this example are: HCT116 (human colon cancer cells).
1. Inoculating cells: single cell suspensions were prepared in McCoy'5A medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seeded into 96 well cell culture plates in 3000 cells per well, 100. mu.l per well.
2. The compound of the present invention was prepared as a powdery drug by a milling treatment step, and the powdery drug was prepared as a mother liquor at a final concentration of 10mM, followed by gradient dilution to 0.01mM, 0.03mM, 0.1mM, 0.3mM, 1mM, 3mM, 10mM, 30mM in this order. Three duplicate wells were set for each concentration group.
3. Administration: the gradient stock solution was diluted with complete medium to a final concentration of 0.01. mu.M, 0.03. mu.M, 0.1. mu.M, 0.3. mu.M, 1. mu.M, 3. mu.M, 10. mu.M, 30. mu.M, 200. mu.l per well acted on the cells, three duplicate wells were set for each group concentration, and the DMSO content in the culture solution was 1 ‰.
4. Culturing: 5% CO2And culturing in an incubator with saturated humidity at 37 ℃ for 72 hours.
5. Color generation: the culture was aspirated for 72 hours, 100. mu.l of complete 1640 medium and 10. mu.l of CCK8 were added to each well, and incubated at 37 ℃ for 4 hours.
6. Color comparison: the wavelengths of 620nm and 450nm were selected, and the Optical Density (OD) value of each well was measured on a microplate reader, and the results were recorded.
7. The absorbance value at 450nm to 620nm (background absorbance value) of the same well was used as the final absorbance, and the final absorbance was substituted into the following formula.
8. Cell proliferation activity (%) ([ a (dosed) -a (blank) ]/[ a (0 dosed) -a (blank) ] × 100
A (dosing): absorbance of wells with cells, CCK solution and drug solution
A (blank): absorbance of wells with medium and CCK solution without cells
A (0 dosing): absorbance of wells with cells, CCK solution and no drug solution
9. The experimental results show that: the proliferation activity of HCT116 cells was significantly inhibited by the compound of the present invention at a concentration of 10. mu.M and 30. mu.M.
FIG. 81 is a graph showing the survival rate of HCT116 (human colon cancer cells) at various concentrations of the compound of the present invention (accession number FB1-3-S, FB1-3-X), plotted as concentration on the abscissa and survival rate on the ordinate, as a concentration-survival curve. It can be seen from the curve that the compound of the present invention (FB1-3-S, FB1-3-X) has a semi-lethal concentration IC for HCT116 (human colon cancer cells)5011.87. mu.M and 21.99. mu.M, respectively.
Therefore, the FB1-3-S, FB1-3-X has an inhibiting effect on the activity of HCT116 (human colon cancer cells), and is suitable for preparation and application of antitumor drugs.

Claims (10)

1. The optically active 1, 5-pentanediol derivative is characterized in that the structure is shown as formula (Ia) and formula (Ib),
Figure FDA0002612620370000011
wherein,
Ar1is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl, nitro substituted phenyl;
Ar2is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl;
Ar3is aryl selected from phenyl, halogen substituted phenyl, methoxy substituted phenyl, C1-C3 alkyl substituted phenyl.
2. The method for synthesizing an optically active 1, 5-pentanediol derivative according to claim 1, wherein the α, β -unsaturated aldehyde of formula (1), the diazo compound of formula (2), and the benzyl alcohol derivative of formula (3) are used as raw materials in an organic solvent, and the raw materials are used as a solvent
Figure FDA0002612620370000013
Molecular sieve is water absorbent, and metal catalyst, chiral diaryl prolinol silicon ether and substituted benzoic acid are used as catalytic systemThe method comprises the following steps of (1) taking a metal negative hydrogen reagent as a reducing agent, and reacting to obtain the optically active 1, 5-pentanediol derivative with high enantioselectivity shown as a formula (Ia) and a formula (Ib), wherein the metal catalyst is bis (1, 5-cyclooctadiene) iridium tetrafluoroborate; the reaction process is shown as a formula (II):
Figure FDA0002612620370000012
3. the synthesis method according to claim 2, characterized in that it comprises in particular the following steps: (1) alpha, beta-unsaturated aldehyde shown in formula (1), diazo compound shown in formula (2) and benzyl alcohol derivative shown in formula (3) are used as raw materials
Figure FDA0002612620370000014
Taking a molecular sieve as a water absorbent, taking a metal catalyst, chiral diaryl prolinol silyl ether and substituted benzoic acid as a catalytic system, and carrying out three-component reaction in an organic solvent at the temperature of 0-40 ℃ to obtain an intermediate 2-benzyloxy-5-oxo-2, 3-diaryl valerate derivative; (2) and (2) taking a metal negative hydrogen reagent as a reducing agent, and carrying out reduction reaction in an organic solvent at the temperature of 20-50 ℃ to obtain the optically active 1, 5-pentanediol derivative.
4. The synthesis method of claim 2 or 3, wherein the molar ratio of the diazo compound of formula (2), the benzyl alcohol derivative of formula (3), the α, β -unsaturated aldehyde of formula (1), the metal catalyst, the chiral diarylprolinol silicon ether, the substituted benzoic acid, and the metal hydriding agent is 1.0-3.0:1.0-2.5:1.0:0.05-0.2:0.15-0.2:0.15-0.5: 10;
Figure FDA0002612620370000015
the feeding amount of the molecular sieve is 50-100 mg/mmol of alpha, beta-unsaturated aldehyde.
5. A synthesis process according to claim 2 or 3, characterized in that the chiral diaryl prolinol silicon ether has the structure according to formula (III),
Figure FDA0002612620370000021
wherein R is1Is trimethylsilyl, triethylsilyl or dimethyl tert-butyl silyl; ar (Ar)4Is phenyl or 3, 5-bis (trifluoromethyl) phenyl.
6. The method of claim 2 or 3, wherein the substituted benzoic acid has the structure of formula (IV),
Figure FDA0002612620370000022
wherein R is 3, 5-bis (trifluoromethyl), nitryl, methoxyl or halogen.
7. The synthetic method of claim 2 or 3 wherein the metal hydride reagent is lithium aluminum hydride or sodium borohydride.
8. The method of synthesis according to claim 2 or 3, wherein the organic solvent comprises dichloromethane, tetrahydrofuran, toluene, chloroform.
9. Use of the optically active 1, 5-pentanediol derivative of formula (Ia) and formula (Ib) as defined in claim 1 in the preparation of an antitumor medicament.
10. The use of claim 9, wherein the tumor comprises colon cancer.
CN201710079316.8A 2017-02-14 2017-02-14 Optically active 1, 5-pentanediol derivative and synthetic method and application thereof Active CN107216241B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710079316.8A CN107216241B (en) 2017-02-14 2017-02-14 Optically active 1, 5-pentanediol derivative and synthetic method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710079316.8A CN107216241B (en) 2017-02-14 2017-02-14 Optically active 1, 5-pentanediol derivative and synthetic method and application thereof

Publications (2)

Publication Number Publication Date
CN107216241A CN107216241A (en) 2017-09-29
CN107216241B true CN107216241B (en) 2020-10-30

Family

ID=59927515

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710079316.8A Active CN107216241B (en) 2017-02-14 2017-02-14 Optically active 1, 5-pentanediol derivative and synthetic method and application thereof

Country Status (1)

Country Link
CN (1) CN107216241B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108658812B (en) * 2018-04-09 2020-12-22 华东师范大学 Alpha-alkoxy-alpha-nitrogen oxyacetate derivative and synthesis method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225022A (en) * 2008-02-13 2008-07-23 上海华谊丙烯酸有限公司 Method for preparing 1,5-pentadiol by hydrogenation of 1,5-glutaraldehyde
CN104557665A (en) * 2015-01-09 2015-04-29 华东师范大学 Optically active 3-substituted indole derivatives as well as synthesis method and application thereof
CN105315167A (en) * 2014-08-01 2016-02-10 华东师范大学 2,2,3-triaryl-3-aryl amino methyl propionate derivative and synthetic method therefor and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225022A (en) * 2008-02-13 2008-07-23 上海华谊丙烯酸有限公司 Method for preparing 1,5-pentadiol by hydrogenation of 1,5-glutaraldehyde
CN105315167A (en) * 2014-08-01 2016-02-10 华东师范大学 2,2,3-triaryl-3-aryl amino methyl propionate derivative and synthetic method therefor and application thereof
CN104557665A (en) * 2015-01-09 2015-04-29 华东师范大学 Optically active 3-substituted indole derivatives as well as synthesis method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
C-H Functionalization/Asymmetric Michael Addition Cascade Enabled by Relay Catalysis: Metal Carbenoid Used for C-C Bond Formation;Dian-Feng Chen et al.;《Angew. Chem. Int. Ed.》;20140821;第53卷;第10763-10767页 *

Also Published As

Publication number Publication date
CN107216241A (en) 2017-09-29

Similar Documents

Publication Publication Date Title
CN102276673A (en) Preparation method of 2-deoxy-beta-D-glucopyranosyl triazole compound
Takao et al. Total synthesis of clavilactones
CN110128257B (en) 1-phenyl-4-pentene-1-one derivative and synthesis method and application thereof
CN107216241B (en) Optically active 1, 5-pentanediol derivative and synthetic method and application thereof
CN110092769B (en) Chromene derivative and synthesis method and application thereof
CN101824037A (en) Preparation method of Januvia free base
CN104557665B (en) Optical activity 3-substituted indole derivant and synthetic method thereof and application
CN106631976A (en) 3-amino-3-hydroxymethyloxindole derivative as well as preparation method and application thereof
CN108440384B (en) Process for the preparation of trifluoromethylated derivatives of isoindolones
CN106831474B (en) One kind-the α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method and application
CN102070510B (en) 3-hydroxyindole derivatives and synthesis method and use thereof
CN111196791B (en) Chiral gamma-butyrolactone derivative and synthesis method and application thereof
CN106565578A (en) Optically active tetrahydropyrrole derivative, and synthetic method and application thereof
Blaser et al. Ethyl 2, 4-dioxo-4-phenylbutyrate: a versatile intermediate for the large-scale preparation of enantiomerically pure α-hydroxy and α-amino acid esters
CN110963937B (en) Asymmetric synthesis method of colchicine and allocolchicine
CN104910034A (en) Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof
CN102295582A (en) Preparation method of alpha, beta-diamino acid derivatives with alpha-quaternary carbon
CN104649917B (en) A kind of three-membered ring derivative containing beta-amino ester and synthetic method thereof and application
CN105315167A (en) 2,2,3-triaryl-3-aryl amino methyl propionate derivative and synthetic method therefor and application thereof
Jia et al. Biology-Oriented Synthesis of Decahydro-4, 8-epoxyazulene Scaffolds
CN105801466A (en) Beta-alkoxy-beta-quaternary carbon center-alpha-amino acid derivative and synthetic method and application thereof
CN111004145A (en) Chiral optical amide substituted α -diamino acid derivative and preparation method and application thereof
CN111056915A (en) Synthesis method of 1, 2-dialkyl-1, 2-diaryl acetylene cyclobutane
CN107903262A (en) A kind of synthetic method of 5 azaindole
CN104513117B (en) A kind of catalysis method of asymmetric synthesis of chiral beta-acetenyl ketonic compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP02 Change in the address of a patent holder

Address after: 200241 No. 500, Dongchuan Road, Shanghai, Minhang District

Patentee after: EAST CHINA NORMAL University

Address before: 200062 No. 3663, Putuo District, Shanghai, Zhongshan North Road

Patentee before: EAST CHINA NORMAL University

CP02 Change in the address of a patent holder