CN106588565A - Synthesis method of chiral sec-allyl alcohol with hydroxyl ortho-position replaced with halogen atoms - Google Patents

Abstract

A method for synthesizing optically pure chiral secondary allyl alcohol by utilizing an improved Julia olefination reaction in the technical field of organic synthesis. The specific technical route is: the highly optically pure epihalohydrin is subjected to nucleophilic ring-opening by mercaptotetrazolium, then the hydroxyl group is protected, oxidized into an improved Julia olefination reagent, condensed with aldehyde or ketone, and then the hydroxyl protection is removed to obtain a series of compounds containing E-type carbon-carbon double bond, highly optically pure chiral secondary allyl alcohol.

Description

A kind of synthesis method of chiral secondary allyl alcohol replaced by halogen atom in ortho position of hydroxyl group

Technical field:

The invention belongs to the field of organic synthesis chemistry, in particular to a method for synthesizing chiral secondary allyl alcohol in which the ortho position of a hydroxyl group is replaced by a halogen atom.

Background technique:

Chiral secondary allyl alcohol and its derivative fragments widely exist in many natural products and drug molecules, such as statin drugs for lowering blood lipids, calcipotriol for psoriasis treatment, and calcipotriol for psoriasis. Bimatoprost (Bimatoprost) for glaucoma treatment, new anti-cancer drug Epothilone (Epothilone), etc. In addition, optically active allyl alcohol is also an important class of reaction intermediates, which can undergo many chemical transformations, such as Claisen rearrangement or SN2' substitution reaction. The chirality of the C–O bond in allyl alcohol will induce the chirality of the newly generated C–C bond, thereby achieving the transfer of chirality.

Based on the importance of the structure of chiral secondary allyl alcohols, many methods for the synthesis of optically pure secondary allyl alcohols have been developed. Such as kinetic resolution of racemates, asymmetric addition of alkenyl metal reagents to aldehydes, asymmetric reduction of α, β-alkenyl ketones, etc. Although the methods for the synthesis of chiral secondary allyl alcohols have been greatly developed, the direct and high stereoselective synthesis of high enantioselective secondary allyl alcohols is still a very challenging topic in the field of chemistry today. There are fewer studies on the synthesis of chiral secondary allyl alcohols substituted by hydroxyl ortho-halogen atoms. However, these chiral secondary allyl alcohols are extremely important in the synthesis of some chiral drugs, and these compounds can be easily converted into chiral α,β-Unsaturated oxirane. Therefore, it is very important to find an efficient method for synthesizing highly optically pure chiral secondary allyl alcohols with substituent groups adjacent to the hydroxyl group.

Invention content:

The purpose of the present invention is to aim at the deficiencies in the prior art, to provide a kind of synthesis method of chiral secondary allyl alcohol replaced by chlorine atom in the ortho position of the hydroxyl group, to solve the problem of low optical purity of existing chiral secondary allyl alcohol, E formula The technical problems of low stereoselectivity, greater difficulty in separation and purification, and lower yield.

The present invention is achieved through the following technical scheme. In the present invention, compound III is obtained by nucleophilic ring opening under the action of 1-phenyl-5-mercaptotetrazolium on epichlorohydrin I. The hydroxyl group in compound III is protected by a protecting reagent to obtain compound IV, and the improved Julia olefination reagent V is obtained after oxidation reaction, which is condensed with aldehydes or ketones under basic conditions to obtain compound VII, and further deprotection of the hydroxyl group is obtained. Carbon-carbon double bond, highly optically pure chiral secondary allyl alcohol.

Reaction formula of the present invention can be expressed as follows:

Wherein the dosage of compound II is 1.0-1.5 times of that of compound I, and the reaction temperature is -5-30°C. The dosage of compound II is preferably 1.1 times that of compound I, and the reaction temperature is preferably 15-25°C.

Described hydroxyl protection obtains compound IV, and its reaction formula is:

The hydrocarbon solvent is dichloromethane, chloroform or dichloroethane, preferably dichloromethane. The base is triethylamine, imidazole, sodium hydride, pyridine, preferably imidazole. The catalyst is 4-dimethylaminopyridine, methanesulfonic acid, Ru ₃ (CO) ₁₂ , preferably 4-dimethylaminopyridine.

Described oxidation reaction obtains compound sulfone V, and its reaction formula is:

The alcoholic solvent is methanol, ethanol, isopropanol, propanol or n-butanol, preferably ethanol.

The oxidizing agent is m-chloroperoxybenzoic acid or ammonium molybdate tetrahydrate/30% hydrogen peroxide system, preferably ammonium molybdate tetrahydrate/30% hydrogen peroxide system.

Reaction under described basic conditions refers to: in ether solvent, carry out condensation reaction under the effect of alkali, and its reaction formula is as follows:

Wherein: the amount of compound VI is 1.0-1.8 times that of compound V, and the reaction temperature is -78-0°C.

The amount of compound VI is preferably 1.5 times that of compound V, and the reaction temperature is preferably -78～-60°C.

The ether solvent is tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, preferably tetrahydrofuran.

The base is lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), bis(trimethylsilyl) ) lithium amide (LiHMDS), n-butyl lithium (n-BuLi). Sodium bis(trimethylsilyl)amide (NaHMDS) is preferred.

The deprotection of the hydroxyl group refers to obtaining the optically pure chiral secondary allyl alcohol of the E formula under acidic or alkaline conditions, and its reaction formula is:

The acid or base is hydrofluoric acid, pyridinium hydrofluoride, tetrabutylammonium fluoride, tetrabutylammonium bromide, carbon tetrabromide. Preference is given to tetrabutylammonium fluoride.

The beneficial effects of the present invention are: by the method of the present invention, chiral secondary allyl alcohol with high optical purity and high E stereoselectivity can be synthesized at a relatively low cost under relatively mild reaction conditions, which is a drug intermediate It provides an economical and convenient method for the synthesis of body and related organic synthesis.

detailed description

The embodiments of the present invention are described in detail below: the present embodiment is implemented under the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided, but the protection scope of the present invention is not limited to the following implementation example.

1. The synthetic reaction formula of (R)-1-chloro-3-(1-phenyl-5-mercaptotetrazole)-2-propanol:

Steps

Add 1-phenyl-5-mercaptotetrazolium (50g, 280.6mmol), methanol (350mL), epichlorohydrin (23mL, 294.6mmol) and triethylamine (59mL, 420.8mmol) into a 1000mL round bottom flask , and the reaction was stirred overnight at room temperature. Concentrate the reaction solution, add 150mL ethyl acetate, wash with water, 0.1M hydrochloric acid, saturated NaHCO ₃ , and saturated brine respectively, separate the layers, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain product III (70.5g, 96% ).

2. The synthetic reaction formula of 5-(2-(tert-butyldimethylsilyloxy)-3-chloropropyl)-1-phenyltetrazolium:

Steps

Add 1-chloro-3-(1-phenyl-5-thiotetrazole)-2-propanol (130g, 480.2mmol) and CH ₂ Cl ₂ (500mL) in a 1000mL round bottom flask, under ice bath condition , DMAP (5.8g, 48mmol), imidazole (65.3g, 960.4mmol), tert-butyldimethylsilyl chloride (79.6g, 528.2mmol) were added. Stir overnight at room temperature. Add 200 mL of water, extract the reaction solution with CH ₂ Cl ₂ (2×100 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and recrystallize to obtain product IV (170.1 g, 92%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.58(s,5H),4.33-4.38(m,1H),3.56-3.71(m,4H),0.88(s,9H),0.11(s,3H) ,0.08(s,3H). ¹³ C NMR(400MHz,CDCl ₃ ):δ154.1,133.6,130.2,129.8,123.8,70.1,47.4,37.7,25.7,18.01,-4.6,-4.7

3. The synthetic reaction formula of 5-(2-(tert-butyldimethylsilyloxy)-3-chloropropyl)-1-phenyltetrazolium sulfone:

Add 5-(2-(tert-butyldimethylsilyloxy)-3-chloropropyl)-1-phenyltetrazolium (50g, 129.9mmol), ethanol (100mL) into a 500mL round bottom flask, Under ice-bath condition, add ammonium molybdate tetrahydrate (32.1g, 26.0mmol), 30% hydrogen peroxide aqueous solution (118mL, 104mmol), stir at room temperature for 4h, add saturated sodium sulfite 50mL, ethyl acetate (3×100mL) The reaction solution was extracted, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain product V (43.6 g, 80.5%). ¹ HNMR (400MHz, CDCl ₃ ): δ7.60-7.69 (m, 5H), 4.64 (t, J = 5.2Hz, 1H), 4.1 (t, J = 5.2Hz, 2H), 3.65 (dd, J ₁ ＝4.4Hz, J ₂ ＝1.2Hz, 2H), 0.85(s, 9H), 0.11(s, 3H), 0.05(s, 3H). ¹³ C NMR (400MHz, CDCl ₃ ): δ154.1, 133.0, 131.5, 129.8, 125.1, 67.1, 60.0, 47.4, 25.6, 17.9.

4. The synthetic reaction formula of 1-phenyl-3-tert-butyldimethylsilyloxy-4-chlorobutene:

In a 100mL three-necked flask, add 5-(2-(tert-butyldimethylsilyloxy)-3-chloropropyl)-1-phenyl tetrazolium sulfone (0.8g, 1.9mmol), benzaldehyde (0.29mL, 2.9mmol), THF (10mL) was cooled to -78°C, and NaHMDS (1.0M solution in tetrahydrofuran, 2eq) was added via syringe. The reaction solution was stirred at -78°C for 30 min, and left at room temperature for 1 h. Add saturated NaHCO ₃ , extract the reaction solution with ethyl acetate (3×15 mL), wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate, and column chromatography to obtain product VI (0.54 g, 95%). ¹ H NMR (400MHZ, CDCl ₃ ) δ7.14-7.30 (m, 5H), 6.54 (d, J = 15.6Hz, 1H), 6.09 (dd, J ₁ = 16Hz, J ₂ = 6.4Hz, 1H), 4.36(dd, J ₁ ＝11.6, J ₂ ＝5.6Hz, 1H), 3.41(dd, J ₁ ＝6.4Hz, J ₂ ＝2.8Hz, 2H), 0.84(s, 9H), 0.04(s, 3H) ,0.00(s,3H). ¹³ CNMR(400MHz,CDCl ₃ ):δ136.5,131.7,129.2,128.6,127.8,126.6,73.9,49.0,25.8,18.3,-4.4,-4.7.

5. The synthetic reaction formula of 1-phenyl-3-hydroxy-4-chlorobutene:

Steps

In a 50mL round bottom flask, add 1-phenyl-3-tert-butyldimethylsilyloxy-4-chlorobutene (0.3mmol, 0.1g, 1.0eq) and add 5mL of THF solution, weigh tetrabutylene Ammonium fluoride (0.7mmol, 0.1g, 1.0eq) was added to the reaction solution in an ice bath, stirred for 10 minutes, and left at room temperature for 1 hour, then 5 mL of saturated sodium bicarbonate was added to the reaction solution, and the reaction solution was washed once. . Then 8 mL of ethyl acetate was added to the aqueous phase to extract the product dissolved in the aqueous phase. After collecting the organic phase, it was dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain product VII (0.5 g, 82%). ¹ H NMR (400MHZ, CDCl ₃ ): δ7.24-7.40 (m, 5H), 6.72 (dd, J ₁ = 16Hz, J ₂ = 0.8Hz, 1H), 6.20 (dd, J ₁ = 16Hz, J ₂ = 0.8Hz, 1H), 6.20 (dd, J ₁ = 16Hz, J ₂ = 6Hz, 1H), 4.51-4.55 (m, 1H), 3.71 (dd, J ₁ = 11.2Hz, J ₂ = 4Hz, 1H) , 3.59 (dd, J ₁ =11.2Hz, J ₂ =7.6Hz, 1H), 2.44 (s, 1H). ¹³ C NMR (400MHz, CDCl ₃ ): δ136.0, 132.8, 128.7, 127.2, 126.7, 72.3, 49.7 .

Claims (6)

1. a synthetic method of chiral secondary allyl alcohol replaced by a halogen atom at the ortho position of a hydroxyl group, characterized in that it comprises the steps of: utilizing optically pure epihalohydrin as a starting raw material, through mercaptotetrazolium nucleophilic opening The hydroxyl group is protected after the ring, and then oxidized to the improved Julia olefination reagent, condensed with aldehydes and ketones, and the hydroxyl protection is removed to obtain a series of high optically pure chiral secondary allyl alcohols containing E-type carbon-carbon double bonds. The chemical reaction simplified formula of synthetic method is as follows: Wherein, R is a substituent such as a halogen atom, an alkyl group, an alkoxyl group; R' is a substituent group such as a methyl group, a phenyl group, a tert-butyl group, a 2-pyridyl group, or a 2-benzothiazolyl group; X is a chlorine atom, Bromine atom, iodine atom and other substituents. 2. a kind of hydroxyl ortho position according to claim 1 is the synthetic method of the chiral secondary allyl alcohol that halogen atom replaces, it is characterized in that: 1-phenyl-5-mercaptotetrazolium is close to epichlorohydrin When the nuclear ring is opened, the alkali used is one of sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine or diisopropylethylamine, and the solvent used is methanol, ethanol, isopropanol , tetrahydrofuran, acetone or any two mixed solvents. 3. a kind of hydroxyl ortho-position according to claim 1 is the synthetic method of the chiral secondary allyl alcohol that halogen atom replaces, it is characterized in that: hydroxyl protection is mainly protected into silicon ether, benzyl ether, alkoxy by protection reagent One of methyl ether or alkoxy substituted methyl ether. 4. a kind of hydroxyl ortho position according to claim 1 is the synthetic method of the chiral secondary allyl alcohol that halogen atom replaces, it is characterized in that: when compound IV is oxidized to V, used oxidizing agent is peroxytrifluoroacetic acid , one of m-chloroperoxybenzoic acid or ammonium molybdate tetrahydrate/30% hydrogen peroxide system. 5. a kind of hydroxyl ortho-position according to claim 1 is the synthetic method of the chiral secondary allyl alcohol that halogen atom replaces, it is characterized in that: when the improved Julia olefination reagent and aldehyde ketone condensation, used alkali diisopropyl Lithium amide, (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), n-Butyllithium (n-BuLi). Sodium bis(trimethylsilyl)amide (NaHMDS) is preferred. The solvent used is one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether. The reaction temperature is -78°C-0°C. 6. a kind of hydroxyl ortho position according to claim 1 is the synthetic method of the chiral secondary allyl alcohol that halogen atom replaces, it is characterized in that: the reagent used during hydroxyl deprotection is hydrofluoric acid, hydrofluoric acid pyridinium , Tetrabutylammonium fluoride, tetrabutylammonium bromide, carbon tetrabromide. Preference is given to tetrabutylammonium fluoride.