CN111484523B - Preparation method of optically pure trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid - Google Patents

Abstract

The invention discloses a preparation method of optically pure trans-2- (diphenylphosphine) -1-cyclohexanecarboxylic acid, which comprises the steps of carrying out addition reaction on 1-cyclohexene-1-methyl formate and diphenylphosphine oxide to obtain a first intermediate, and reducing the first intermediate to obtain cis-2- (diphenylphosphine) -1-cyclohexanecarboxylic acid methyl ester; adding a turning agent and a solvent into cis-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid methyl ester, heating, refluxing, extracting and drying to obtain trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid methyl ester, hydrolyzing, acidifying, and extracting to obtain optically pure trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid. The invention creatively researches the preparation method of the optically pure trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid, fills the vacancy of the optically active pure trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid in the phosphine ligand, and effectively promotes the catalytic effect of the asymmetric Lewis acid and the transition metal.

Description

A kind of preparation method of optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid

technical field

The invention belongs to the technical field of chemical preparation, in particular to a preparation method of optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid.

Background technique

Chirality is a common phenomenon in nature (common in natural products and pharmaceuticals). Asymmetric catalysis, the most important and direct strategy to construct chiral centers, has always been one of the research hotspots in the field of organic chemistry. Since 2000, on the one hand, chiral small molecule catalysis has made remarkable achievements; on the other hand, asymmetric Lewis acid and transition metal catalysis still occupy an important position and are extremely effective supplements. The design and development of chiral ligands is the main driving force for the development of asymmetric Lewis acids and transition metal catalysis.

Among the many ligands, phosphine ligands are one of the most important types of ligands, and have attracted the attention and in-depth research of scientists from all over the world. In 2001, Stelzer et al. reported the preparation of racemic trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid (Eur. J. Inorg. Chem. 2001, 1251-1259). However, the synthesis method of optically pure trans-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid has not been reported.

SUMMARY OF THE INVENTION

Purpose of the invention: The purpose of the present invention is to provide a preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid in view of the deficiencies of the prior art, and another purpose of the present invention is to provide a method for preparing Optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid.

Technical scheme: the preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid described in the present invention is composed of methyl 1-cyclohexene-1-carboxylate and diphenylphosphine An addition reaction occurs to obtain the first intermediate, and then the first intermediate is reduced to obtain cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, such as formula (I) or formula (II) as shown; adding a turning agent and a solvent to cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, heating under reflux, extraction and drying to obtain trans-2-(diphenylphosphine)- Methyl 1-cyclohexanecarboxylate, as shown in formula (III) or formula (IV), is subjected to hydrolysis, acidification and re-extraction to obtain optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, Formula (V) or formula (VI);

Further, the preparation method of the optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid comprises the following steps:

(1) Add methyl 1-cyclohexene-1-carboxylate and diphenylphosphine oxygen with a molar ratio of 1～2:1 into the reaction flask, add a solvent and a catalyst, and react at -30～-15°C 40～50h, add a quencher after the reaction, and remove the solvent after extraction to obtain the first intermediate, such as formula (VII) or formula (VIII);

(2) adding a solvent to the first intermediate, adding a composite reducing agent, reacting at 90-110 ° C for 15-20 h, adding a quenching agent, and separating by column chromatography with n-hexane/ethyl acetate after the reaction is completed , to obtain cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, as shown in formula (I) or formula (II);

(3) Add tumbler sodium methoxide and solvent methanol to the pure cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester system, heat under reflux for 20-30 h, the product is acidified with acetic acid, and the solvent is removed , extraction, drying and concentration to obtain trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, as shown in formula (III) or formula (IV);

(4) hydrolyzing methyl trans-2-(diphenylphosphine)-1-cyclohexanecarboxylate under potassium hydroxide condition, after completion of the reaction, acidify, extract, dry, filter and remove the solvent under reduced pressure to obtain Optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, represented by formula (V) or formula (VI);

The specific reaction process is as follows:

。

.

Further, in order to improve the reaction efficiency and product purity, the solvent described in the step (1) is tetrahydrofuran, the catalyst is Bu ₂ Mg/(R or S)-H ₈ -BINOL and H ₂ O, and the quencher is saturated chlorination Ammonium; the composite reducing agent described in the step (2) is a mixture of trichlorosilane and triethylamine whose molar ratio is 2:3; the solvent is toluene;

Further, after removing the solvent under reduced pressure in step (3), adding saturated sodium bicarbonate to the system for treatment, extracting with dichloromethane, drying over anhydrous sodium sulfate, filtering and concentrating to obtain trans-2-(diphenylphosphine)- Methyl 1-cyclohexanecarboxylate, as shown in formula (III) or formula (IV).

Further, in step (4), after the reaction is completed, acidify with hydrochloric acid, extract with dichloromethane, dry with anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to obtain optically pure trans-2-(diphenylphosphine)-1-ring. Hexanoic acid, represented by formula (V) or formula (VI).

The present invention also provides optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid prepared by the above-mentioned preparation method, as shown in formula (V) or formula (VI).

Beneficial effects: (1) The present invention has pioneered research on the preparation method of optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, which fills in the optically active pure trans-2-( The vacancy of diphenylphosphine)-1-cyclohexanecarboxylic acid effectively promotes the catalytic effect of asymmetric Lewis acid and transition metal; (2) In the present invention, through the inventor's research on the properties of raw materials, the addition catalyst is selected pertinently , reduction catalyst, hydrolysis agent, and the corresponding solvent, not only ensure the smooth progress of the reaction process, but also help to improve the yield and purity of the product.

Description of drawings

Fig. 1 is the ¹ H NMR spectrogram of the product in embodiment 1;

Figure 2 is the ¹³ C NMR spectrum of the product in Example 1;

Figure 3 is the ³¹ P NMR spectrum of the product in Example 1;

Figure 4 is the ¹ H NMR spectrum of the product in Example 2;

Figure 5 is the ¹³ C NMR spectrum of the product in Example 2;

FIG. 6 is a ³¹ P NMR spectrum of the product in Example 2. FIG.

Detailed ways

The technical solutions of the present invention will be described in detail below with reference to the accompanying drawings, but the protection scope of the present invention is not limited to the embodiments. The reaction drugs used in the examples are all commercially available.

Example 1: Preparation of methyl trans-2-(diphenylphosphine)-1-cyclohexanecarboxylate

At room temperature and under the protection of N ₂ , 1.76 g (R)-H ₈ -BINOL, 72 μL H ₂ O were added to 40 mL of anhydrous tetrahydrofuran, vigorously stirred at room temperature for 5 min, and 4 mmol of dibutylmagnesium dissolved in heptane was added. Add dropwise to the reaction system, then add 8.1 g of diphenylphosphine oxygen to the reaction system, stir vigorously for 5 min at room temperature, and after stirring, cool down the reaction system to -20 ° C, keep at this temperature for 5 min, cyclohexane Methyl enolate (5.88 g, 42 mmol) was added dropwise to the reaction system, and the dropwise addition was completed at -20 °C for 48 h; after the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, the solvent was removed under reduced pressure, and the aqueous phase Extracted with chloroform three times, the organic phase obtained by extraction was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was recrystallized with ether to obtain 8.65 g of cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid Methyl ester, yield 62.5%, ee value 100%, dr value 100%;

Under the protection of N at room temperature, 2.1g, 6.4mmol of cis- _2- (diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester and 1.74g, 32.2mmol of sodium methoxide were added to the reaction flask, and then 45mL was added Anhydrous methanol, heated to reflux for 24 h, then the mixture was cooled to room temperature, acidified with acetic acid until the cloudy liquid became clear, the solvent was removed under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added and extracted with 30 mL×3 dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure, and subjected to column chromatography, eluent: n-hexane:ethyl acetate=50:1～20:1, and the crude product was purified to obtain 2.1 g methyl trans-2-(diphenylphosphino)-1-cyclohexanecarboxylate, 100% yield, 100% ee, enantiomeric purity determined by chiral HPLC analysis.

The structural characterization data of the product obtained in Example 1 are as follows:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80-7.44 (m, 4H), 7.39-7.18 (m, 6H), 3.50 (s, 3H), 2.67-2.61 (m, 1H), 2.37-2.30 ( m,1H), 2.01-1.91(m,1H), 1.82-1.58(m,4H), 1.41-1.28(m,1H), 1.27-1.15(m,1H), 1.03-0.87(m,1H).

¹³ C NMR(100MHz,CDCl ₃ ):δ175.74,136.14,136.02,135.32,134.86,134.66,132.82, 132.65,129.14,128.35,128.29,128.24,128.21,128.17,51.45,46.32,46.13,35.62,35.48, 30.07, 29.96, 27.06, 25.51, 24.81.

³¹ P NMR (161 MHz, CDCl ₃ ): δ-3.04.

The successful synthesis of trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester was proved by the H NMR, C and P spectra of the product.

The specific optical rotation of the compound of formula (III): [α] _D ²⁰ =36.9 (c=0.10, MeOH).

HRMS:calculated for C ₂₀ H ₂₃ O ₂ P(M+H) ⁺ :327.1514found:327.1508.

The specific optical rotation of the compound of formula (IV): [α] _D ²⁰ =-36.9 (c=0.10, MeOH).

HRMS: calculated for C ₂₀ H ₂₃ O ₂ P(M+H) ⁺ : 327.1514, found: 327.1508.

Example 2: Preparation of trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid

0.9 g, 2.76 mmol of methyl trans-2-(diphenylphosphine)-1-cyclohexanecarboxylate were dissolved in 50 mL of N degassed ₁₁ mL of ethanol at room temperature under _N2 protection, and then 10 mL of , 4.96 mmol, 0.5 M, _N2 degassed aqueous potassium hydroxide solution. The mixture was reacted overnight under reflux conditions. The mixture was then cooled to room temperature, the solvent was removed under reduced pressure, 20 mL of _H2O was added, the solution was acidified to pH=1 with 2M hydrochloric acid, extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed to give 0.7 g of Formula-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, 81% yield.

The structural characterization data of implementation example 2 products therefrom are as follows:

¹ H NMR (400 MHz, CHCl ₃ ): δ 7.56-7.44 (m, 4H), 7.39-7.23 (m, 6H), 2.73-2.68 (m, 1H), 2.40-2.28 (m, 1H), 2.10- 1.98(m,1H),1.91-1.59(m,4H),1.44-1.21(m,2H),1.06-0.95(m,1H).

¹³ C NMR(100MHz,CDCl ₃ ):δ181.64,136.26,136.14,135.41,135.27,134.92,134.71, 132.95,132.77,129.28,128.53,128.46,128.40,128.32,45.47,45.28,35.04,34.91,29.36, 29.26, 26.57, 26.52, 25.01, 24.97, 24.64.

³¹ P NMR (161 MHz, CDCl ₃ ): δ-4.04.

The successful synthesis of trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid was proved by the H NMR, C and P spectra of the product.

The specific optical rotation of the compound of formula (V): [α] _D ²⁰ =34.3 (c=0.10, MeOH).

HRMS:calculated for C ₁₉ H ₂₁ O ₂ P(M+H) ⁺ :313.1357,found:313.1356.

The specific optical rotation of the compound of formula (VI): [α] _D ²⁰ =-34.3 (c=0.10, MeOH).

HRMS:calculated for C ₁₉ H ₂₁ O ₂ P(M+H) ⁺ :313.1357,found:313.1356.

The invention groundbreakingly studies the preparation method of optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, and fills in the optically active pure trans-2-(diphenylphosphine)- The vacancy of 1-cyclohexanecarboxylic acid effectively promotes the catalytic effect of asymmetric Lewis acid and transition metal.

As mentioned above, although the present invention has been shown and described with reference to specific preferred embodiments, this should not be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims (4)

1. a preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, is characterized in that: by 1-cyclohexene-1-methyl formate and diphenylphosphine, add The first intermediate is obtained by the reaction, and then the first intermediate is reduced to obtain cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, as shown in formula (I) or formula (II) ; Add tumbler and solvent to cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, extract and dry after heating to reflux to obtain trans-2-(diphenylphosphine)-1- Methyl cyclohexanecarboxylate, as shown in formula (III) or formula (IV), is subjected to hydrolysis, acidification and re-extraction to obtain optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, formula ( V) or formula (VI);

Specifically include the following steps: (1) Add 1-cyclohexene-1-methyl carboxylate and diphenylphosphine oxygen with a molar ratio of 1～2:1 into the reaction flask, add a solvent and a catalyst, and react at -30～-15°C 40～50h, add a quencher after the reaction, and remove the solvent after extraction to obtain the first intermediate, such as formula (VII) or formula (VIII); (2) adding a solvent to the first intermediate, adding a composite reducing agent, reacting at 90-110 ° C for 15-20 h, adding a quenching agent, and separating by column chromatography with n-hexane/ethyl acetate after the reaction is completed , to obtain cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, as shown in formula (I) or formula (II); (3) Add tumbler sodium methoxide and solvent methanol to the pure cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester system, heat under reflux for 20-30 h, the product is acidified with acetic acid, and the solvent is removed , extraction, drying and concentration to obtain trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, as shown in formula (III) or formula (IV); (4) hydrolyzing methyl trans-2-(diphenylphosphine)-1-cyclohexanecarboxylate under potassium hydroxide condition, after completion of the reaction, acidify, extract, dry, filter and remove the solvent under reduced pressure to obtain Optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, represented by formula (V) or formula (VI); The specific reaction process is as follows:

. 2. the preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid according to claim 1, is characterized in that: solvent described in step ( ₁ ) is tetrahydrofuran, and catalyzer is Bu Mg/(R or S)-H ₈ -BINOL and H ₂ O, the quenching agent is saturated ammonium chloride; the composite reducing agent described in the step (2) is trichlorosilane and triethyl trichlorosilane with a molar ratio of 2:3 Amine mixture; the solvent is toluene. 3. the preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid according to claim 1, is characterized in that: after removing solvent under reduced pressure in step (3), add to system Treated with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain methyl trans-2-(diphenylphosphine)-1-cyclohexanecarboxylate, such as formula (III) or formula (IV) shown. 4. the preparation method of optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid according to claim 1, is characterized in that: acidify with hydrochloric acid after completion of reaction in step (4), dichloromethane Extraction, drying over anhydrous sodium sulfate, filtration under reduced pressure to remove the solvent to obtain optically pure trans 2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, represented by formula (V) or formula (VI).

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