CN116283660A - Asymmetric synthesis method of chiral cyclopropane derivative - Google Patents

Asymmetric synthesis method of chiral cyclopropane derivative Download PDF

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CN116283660A
CN116283660A CN202310178379.4A CN202310178379A CN116283660A CN 116283660 A CN116283660 A CN 116283660A CN 202310178379 A CN202310178379 A CN 202310178379A CN 116283660 A CN116283660 A CN 116283660A
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asymmetric synthesis
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chiral cyclopropane
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严普查
周波
华允宇
程厚安
孙泽斌
付星锋
李原强
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

The invention provides an asymmetric synthesis method of chiral cyclopropane derivatives. The chiral cyclopropane derivative shown in the formula 1 is obtained by dissolving a compound 2 and an organic boride R-BXn in a solvent under the action of a catalyst, a ligand, an oxidant, an additive and alkali, and the reaction equation is shown as follows:

Description

Asymmetric synthesis method of chiral cyclopropane derivative
Technical Field
The invention relates to the technical field of asymmetric synthesis, in particular to an asymmetric synthesis method of chiral cyclopropane derivatives.
Background
Asymmetric synthesis includes substrate-induced asymmetric synthesis and catalyst-induced asymmetric synthesis, and among them, chiral catalyst-induced asymmetric synthesis is the most attractive and competitive, which requires only a catalytic amount of chiral compound to obtain a novel optically active substance. In particular, asymmetric catalytic reactions catalyzed by transition metal complexes are becoming increasingly important.
Cyclopropane derivatives are widely found in natural products and drug molecules and have good biological activity. For example, the sponge extract has antitumor activity, the pyrethroid vinegar has pesticidal activity, and the coronatine has plant growth regulating activity. In the pharmaceutical field, imipenem is one of the most promising B2 lactam antibiotics developed in recent years, and although it has high antibiotic activity and performs strongly on B2 lactam degradation, it is sensitive to metabolism of kidneys in animals and humans, which can be inhibited by use with Cilastatin. Cilastatin is an inhibitor of hydrolytic enzymes, and (+) -2, 2-dimethylcyclopropane carboxylic acid is an important intermediate for its synthesis.
The enantioselective C-H bond modification process is an important component in the asymmetric synthesis of chiral cyclopropane compounds. The method includes biomimetic methods such as the acquisition of H atoms from cytochrome P450, and enzymatic processes; metal nitriles and metal carbene insertion; transition metal mediated activation of C-H bonds. Activation with transition metals is mainly achieved by two methods: firstly, the dissymmetrization C-H bond is activated; and secondly, the recognition of an enantiomer position C-H bond of the transition metal complex to the methylene. Transition metal-catalyzed activation of C-H bonds is accomplished to a large extent by catalytic cycling, including palladium Pd (II/0), pd (II/IV), pd (0/II), pd (II/II), and the like. Although these methods greatly promote asymmetric hydrocarbon bond functionalization, achieving high levels of enantioselectivity in these reactions remains a significant challenge, mainly because the lack of a suitable ligand backbone can affect steric induction during CH cleavage.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides an asymmetric synthesis method of chiral cyclopropane derivatives, which solves the problem of low enantioselectivity caused by lack of a proper ligand framework in the prior art.
In one aspect of the invention, an asymmetric synthesis method of chiral cyclopropane derivatives is provided, which comprises the steps of dissolving a compound 2 and an organic boride R-BXn in a solvent, and obtaining chiral cyclopropane derivatives shown in a formula 1 under the action of a catalyst, a ligand, an oxidant, an additive and alkali, wherein the reaction equation is as follows:
Figure BDA0004101756870000021
wherein R' is selected from one of alkyl, alkoxy, aryl and substituted aryl, R is selected from one of alkyl, cycloalkyl and phenyl, X is selected from halogen, alkoxy or aryloxy, n is an integer from 1 to 3, and when n is 2 or 3, X can be the same or different.
Further, the organic boride R-BXn is selected from one of pinacol phenylborate, cyclohexene-1-boric acid pinacol ester and butyl potassium trifluoroborate.
Further, the catalyst is selected from Pd (OAc) 2 The oxidant is selected from 1, 4-benzoquinone, and the additive is Ag 2 CO 3 。
Further, the base is selected from NaHCO 3 、Na 2 CO 3 The solvent is selected from one of tert-amyl alcohol and DMSO.
Further, the chemical structure of the ligand is shown as formula 3:
Figure BDA0004101756870000022
wherein R is 2 Is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the ligand is prepared by reacting a 7-carboxyl-1, 1' -spiroindane compound shown in formula 4 with a compound shown in formula 5 in the presence of an organic solvent, an acylating agent, a catalyst and an organic base to prepare a compound shown in formula 3, wherein the reaction formula is as follows:
Figure BDA0004101756870000023
wherein R is 2 Is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the reaction includes at least one of the following conditions:
(1) The organic solvent is dichloromethane;
(2) The acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, and the organic base is triethylamine;
(3) The molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula 4 to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3; the 7-carboxyl-1, 1' -spirobiindane compound shown in the formula A comprises a catalyst in a ratio of 1:0.01 in mol/L;
(4) The reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
Further, the molar equivalent ratio of the compound 2 to the organic boride R-BXn to the catalyst to the ligand to the additive to the oxidant to the base is 1:1:0.05:0.1:0.75:0.25:2.
Further, the solvent of the compound 2 is 1:2.5 in mol/L.
Further, the reaction temperature is 35-45 ℃ and the reaction time is 6-10h.
In one embodiment of the present invention, the preparation method of the 7-carboxy-1, 1' -spiroindanes compound represented by formula 4 comprises:
1,1 '-spiroindan-7, 7' -diol is used as an initiator, and is obtained through methylation reaction, first sulfonation reaction, first substitution reaction, demethylation reaction, second sulfonation reaction, second substitution reaction and hydrolysis reaction; the reaction process is as follows:
Figure BDA0004101756870000031
the method specifically comprises the following steps: (1) Adding 1,1 '-spiroindan-7, 7' -diol into an organic solvent 1, and generating a compound b under the action of a methylating reagent and a first base;
(2) Mixing the compound b with an organic solvent 2, and adding a first sulfonating reagent and a second base to generate a compound c;
(3) Adding the compound c into an organic solvent 3, and adding a first catalyst, a first reaction substrate and a third base in the presence of CO to perform a first substitution reaction to generate a compound d;
(4) Adding an organic solvent 4 into the compound d, and carrying out a demethylation reaction under the action of a demethylating reagent to generate a compound e;
(5) Adding an organic solvent 5 into the compound e, and adding a second sulfonation reagent and a fourth base to generate a compound f;
(6) Adding the compound f into an organic solvent 6, adding a second catalyst and a second reaction substrate in the presence of nitrogen, and performing a second substitution reaction to generate a compound g;
(7) And adding the compound g into an organic solvent 7, and hydrolyzing in the presence of a fifth base to obtain the 7-carboxyl-1, 1' -spiroindane compound shown in the formula 4.
Preferably, in the step (1), the organic solvent 1 is tetrahydrofuran, the methylating agent is methyl iodide, and the first base is sodium hydride; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (2), the organic solvent 2 is methylene dichloride, the first sulfonating agent is trifluoro methanesulfonic anhydride, and the second base is pyridine; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (3), the organic solvent 3 is acetonitrile and methanol; the third base is triethylamine; the first catalyst is PdCl 2 (dppf); the first reaction substrate is methanol; the reaction temperature is 80 ℃ and the reaction time is 16-24 hours;
in the step (4), the organic solvent 4 is DCM, and the demethylating agent is BBr 3 The reaction temperature is between 20 ℃ below zero and 10 ℃ below zero, and the reaction time is between 6 and 8 hours;
in the step (5), the organic solvent 5 is dichloromethane, the second sulfonation reagent is trifluoromethanesulfonic anhydride, the fourth base is pyridine, the reaction temperature is-0-10 ℃, and the reaction time is 6-12h;
in the step (6), the organic solvent 6 is methyl acetateAn alcohol; the second catalyst is PdCl 2 (dppf); the second reaction substrate is HCOONa;
in the step (7), the organic solvent 7 is DMSO; the fifth alkali is potassium hydroxide; the reaction temperature is 150 ℃ and the reaction time is 16-24 hours.
Preferably, in step (1), 1 '-spiroindan-7, 7' -diol in molar ratio: methylating agent: first base = 2:1:1;
in the step (2), the first sulfonating agent is compound 2, and the second base=10:13:15;
in the step (3), the compound 3 comprises a first catalyst, a first reaction substrate and a third base=10:0.5:100:30 in terms of mole ratio;
in step (4), compound 4: first demethylating agent = 1:3 in molar ratio;
in the step (5), the compound 5 comprises a second sulfonating agent and a fourth base=10:13:15 according to the mole ratio;
in the step (6), the compound 6 is a second catalyst and a second reaction substrate=10:0.5:30 in terms of molar ratio;
in step (7), compound 7: fifth base=1:10 in terms of molar ratio.
The technical principle of the invention is as follows: in the prior art, electron-deficient amides are used as weakly coordinating directing groups on cyclopropane substrates and electron-deficient carbamates on ligands, thus achieving high enantioselectivities. However, the method is limited to functionalization of the relatively acidic cyclopropyl C-H bond, whereas for less reactive C (sp 3 ) Enantioselective functionalization of the H bond, this method is more difficult to achieve. To solve this problem, it is necessary to design and synthesize a novel chiral ligand. The invention realizes methylene C (sp) in cyclopropane carboxylic acid derivatives through ligand 3 ) The H bond is cross-coupled with the organoboride.
Compared with the prior art, the invention has the following beneficial effects:
(1) Has very broad substrate application range and functional group compatibility;
(2) Has high selectivity and high yield;
(3) The method is simple and is suitable for mass production and post-modification of series medicines.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
EXAMPLE 1 Synthesis of ligands
Figure BDA0004101756870000051
Compound 4a (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of 4a, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with 5a (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), the acid chloride solution of 4a obtained in the previous step was slowly added dropwise to 5a and triethylamine, stirred at room temperature for 3-4 hours, and the product 3a was obtained by quench column chromatography in 95% yield.
Wherein, the synthesis method of the compound 4a comprises the following steps:
Figure BDA0004101756870000052
compound a (10 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask under nitrogen protection, naH (5 mmol) was added to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. Then, THF solution (5mmol MeI in 60mL THF) of methyl iodide is added into the system dropwise, the temperature is controlled to be 0-10 ℃, the reaction is carried out for 6-12 hours after the completion of the addition, and the reaction liquid is subjected to quenching column chromatography to obtain a product b with the yield of 77%.
Compound b (10 mmol) and methylene chloride (100 mL) were added to a reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, reacting for 6-12 hours after dripping, and obtaining the product through quenching column chromatography of the reaction liquidProduct c was found to be 91% yield.
Compound c (10 mmol) and methanol (100 mmol), acetonitrile (100 mL), triethylamine (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), CO was replaced three times after the addition, the reaction was carried out under pressure of 2.5MPa at 80℃for 16-24 hours, and the reaction mixture was subjected to quenching column chromatography to give product d in 80% yield.
Compound d (10 mmol) and DCM (500 mL) were added to the reaction flask under nitrogen. Subsequently, BBr is added into the system in a dropwise manner 3 (30 mmol) and controlling the temperature to-20-10 ℃. After the addition, the reaction is carried out for 6 to 8 hours, and the compound e is obtained by the reaction liquid through quenching column chromatography, and the yield is 65 percent.
Compound e (10 mmol) and methylene chloride (100 mL) were added to the reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, reacting for 6-12 hours after dripping, and obtaining the compound f by quenching column chromatography of the reaction liquid, wherein the yield is 88%.
Compound f (10 mmol) and methanol (100 mmol), HCOONa (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), after the addition of nitrogen was replaced three times, the reaction was carried out at 80℃for 16-24 hours, and the reaction mixture was subjected to quenching column chromatography to give Compound g in 84% yield.
Compound g (10 mmol) and DMSO (500 mL) were added to the reaction flask under nitrogen. Then 60% aqueous potassium hydroxide solution (100 mmol) was added to the system, the temperature was raised to 150℃after the addition, the reaction was carried out for 16-24 hours, and the reaction mixture was subjected to quenching column chromatography to give product 4a in 80% yield.
EXAMPLE 2 Synthesis of ligands
Figure BDA0004101756870000061
Under the protection of nitrogen, the compound 4b (9 mmol), N-dimethylformamide (DMF, 90. Mu.L) and dichloromethane (DCM, 10 mL) were added to a reaction flask, oxalyl chloride (13 mmol) was added dropwise to the reaction system, and the mixture was added dropwiseThe temperature is controlled to be 0-10 ℃ in the process. After the dripping, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of 4b, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with 5b (10 mmol), triethylamine (Et) 3 N,27 mmol) and dichloromethane (30 mL), the acid chloride solution of 4b obtained in the previous step was slowly added dropwise to 5b and triethylamine, stirred at room temperature for 3-4 hours, and the product 3b was obtained by quench column chromatography in 91% yield.
EXAMPLE 3 Synthesis of ligands
Figure BDA0004101756870000071
Compound 4c (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of 4c, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with 5c (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), the acid chloride solution of 4c obtained in the previous step was slowly added dropwise to 5c and triethylamine, stirred at room temperature for 3-4 hours, and the product 3c was obtained by quench column chromatography in 93% yield.
Example 4N- (4-cyano-2, 3,5, 6-tetrafluorophenyl) -1-methyl-2-phenyl-2λ 3 Synthesis of cyclopropane-1-carboxamide
Figure BDA0004101756870000072
Under nitrogen, 1mmol of Compound 2-1, 1mmol of pinacol phenylboronate, 0.05mmol of palladium acetate (Pd (OAc) 2 ) 0.1mmol of the ligand prepared in example 1, 0.75mmolAg 2 CO 3 0.25mmol 1, 4-Benzoquinone (BQ), 2mmol NaHCO 3 And 2.5ml of tertiary amyl alcohol are mixed and reacted for 8 hours at 40 ℃ to obtain the target product 1-1. The yield of the target product 1-1 is 95% and the ee value is 98% through detection.
Example 5 1- (benzyl) -N- (4-cyano-)2,3,5, 6-tetrafluorophenyl) -2-phenyl-2λ 3 Synthesis of cyclopropane-1-carboxamide
Figure BDA0004101756870000073
Under nitrogen, 1mmol of Compound 2-2, 1mmol of pinacol phenylboronate, 0.05mmol of palladium acetate (Pd (OAc) 2 ) 0.1mmol of the ligand prepared in example 1, 0.75mmolAg 2 CO 3 0.25mmol 1, 4-Benzoquinone (BQ), 2mmol NaHCO 3 And 2.5ml of tertiary amyl alcohol are mixed and reacted for 6 hours at 45 ℃ to obtain the target product 1-2. The yield of the target product 1-2 is 94% and the ee value is 96% through detection.
Example 6 2-butyl-N- (4-cyano-2, 3,5, 6-tetrafluorophenyl) -1-methoxy-2λ 3 Synthesis of cyclopropane-1-carboxamide
Figure BDA0004101756870000081
Under nitrogen, 1mmol of Compound 2-3, 1mmol of potassium butyltrifluoroborate, 0.05mmol of palladium acetate (Pd (OAc) 2 ) 0.1mmol of the ligand prepared in example 1, 0.75mmolAg 2 CO 3 0.25mmol 1, 4-Benzoquinone (BQ), 2mmol NaHCO 3 And 2.5ml of tertiary amyl alcohol are mixed and reacted for 10 hours at 40 ℃ to obtain the target product 1-3. The detection shows that the yield of the target product 1-3 is 90% and the ee value is 95%.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.

Claims (10)

1. An asymmetric synthesis method of chiral cyclopropane derivatives is characterized in that: the chiral cyclopropane derivative shown in the formula 1 is obtained by dissolving a compound 2 and an organic boride R-BXn in a solvent under the action of a catalyst, a ligand, an oxidant, an additive and alkali, and the reaction equation is shown as follows:
Figure FDA0004101756860000011
wherein R' is selected from one of alkyl, alkoxy, aryl and substituted aryl, R is selected from one of alkyl, cycloalkyl and phenyl, X is selected from halogen, alkoxy or aryloxy, n is an integer from 1 to 3, and when n is 2 or 3, X can be the same or different.
2. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the organic boride R-BXn is selected from one of pinacol phenylborate, cyclohexene-1-pinacol borate and butyl potassium trifluoroborate.
3. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the catalyst is selected from Pd (OAc) 2 The oxidant is selected from 1, 4-benzoquinone, and the additive is Ag 2 CO 3 。
4. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the base is selected from NaHCO 3 、Na 2 CO 3 The solvent is selected from one of tert-amyl alcohol and DMSO.
5. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the chemical structure of the ligand is shown as formula 3:
Figure FDA0004101756860000012
wherein R is 2 Is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
6. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 5, characterized in that: the ligand is prepared by reacting 7-carboxyl-1, 1' -spiroindane compound shown in formula 4 with compound shown in formula 5 in the presence of organic solvent, acylating agent, catalyst and organic base to prepare compound shown in formula 3, wherein the reaction formula is as follows:
Figure FDA0004101756860000021
wherein R is 2 Is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
7. The asymmetric synthesis method of chiral cyclopropane derivatives as claimed in claim 6, wherein: the reaction includes at least one of the following conditions:
(1) The organic solvent is dichloromethane;
(2) The acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, and the organic base is triethylamine;
(3) The molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula 4 to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3; the 7-carboxyl-1, 1' -spirobiindane compound shown in the formula A comprises a catalyst in a ratio of 1:0.01 in mol/L;
(4) The reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
8. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the molar equivalent ratio of the compound 2 to the organic boride R-BXn to the catalyst to the ligand to the additive to the oxidant to the base is 1:1:0.05:0.1:0.75:0.25:2.
9. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the mol/L of the compound 2 is 1:2.5.
10. A process for the asymmetric synthesis of chiral cyclopropane derivatives as claimed in claim 1, characterized in that: the reaction temperature is 35-45 ℃ and the reaction time is 6-10h.
CN202310178379.4A 2023-02-28 2023-02-28 Asymmetric synthesis method of chiral cyclopropane derivative Pending CN116283660A (en)

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