CN112538092B - Preparation method of chiral Trost ligand - Google Patents
Preparation method of chiral Trost ligand Download PDFInfo
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- CN112538092B CN112538092B CN202110188675.3A CN202110188675A CN112538092B CN 112538092 B CN112538092 B CN 112538092B CN 202110188675 A CN202110188675 A CN 202110188675A CN 112538092 B CN112538092 B CN 112538092B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5095—Separation; Purification; Stabilisation
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- 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
Abstract
The invention relates to a preparation method of a chiral Trost ligand, which comprises the following steps: mixing a solvent and a racemic form Trost ligand to prepare a pretreatment solution; enabling the pretreatment solution to flow into an adsorbent for adsorption treatment, then enabling the pretreatment solution to flow out, heating the obtained effluent to 40-120 ℃ for heat treatment, cooling, then performing adsorption treatment, and circulating in the above way; after circulation is finished, collecting the adsorbent, eluting with an eluent, and collecting the eluent; wherein the adsorbent is macroporous resin. The preparation method can prepare the R, R configuration Trost ligand with ee value higher than 99%. Meanwhile, the preparation method of the chiral Trost ligand has simple steps and high production efficiency, and can effectively avoid the waste of the S and S configuration Trost ligand.
Description
Technical Field
The invention relates to a chiral catalyst, in particular to a preparation method of a chiral Trost ligand.
Background
Allylic alkylation is a method for synthesizing carbon-carbon single bonds and is widely used for constructing complex organic molecules. For example, the target product of the reaction is an intermediate for synthesizing paroxetine medicaments for treating depression, nervous disorder and other diseases, so the exploration of the allyl alkylation reaction has important practical significance and scientific value. Therefore, the carbon-containing nucleophilic reagent can easily attack allyl derivatives under the action of a catalyst formed by a chiral ligand and a transition metal, so that in recent years, efforts have been made to perform asymmetric allyl alkylation reactions under the catalysis of transition metal (such as molybdenum, platinum, palladium and the like) complexes.
In 1992, Trost et al discovered a chiral diphenylphosphine ligand (hereinafter referred to as chiral Trost ligand) that could be used in palladium-catalyzed allylic asymmetric substitution reactions. The original ligands were based on the coupling products of 2- (diphenylphosphino) benzoic acid with various chiral backbones, among which trans-1, 2-diphenylethylenediamine and trans-1, 2-diaminocyclohexane were the most catalytically effective, and in comparison, the ligands based on the trans-1, 2-diaminocyclohexane backbone were more widely used. Wherein, (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl) (structural formula shown below) is a ligand based on trans-1, 2-diaminocyclohexyl skeleton coupling, which is a more typical Trost ligand, and the structural formula is shown below:
the ligand is widely applied to asymmetric catalytic synthesis:
(1) asymmetric ring opening reaction of epoxy compound: the ligand is reacted with Pd2dba3-CHCl3The catalyst system is formed, the addition reaction of epoxide and p-methoxybenzyl alcohol (PMBOH) can be effectively catalyzed, and the reaction has higher yield and enantioselectivity;
(2) kinetic resolution of chiral compounds: the ligand is used as a ligand of a palladium catalyst, and a pair of enantiomers of the indoline derivative can be successfully resolved by utilizing the reactivity difference of the indoline derivative and the allyl derivative;
(3) palladium catalyzed asymmetric allylic substitution reaction: the ligand is used as the ligand of the palladium catalyst, and can successfully realize asymmetric intramolecular cyclization reaction;
(4) reaction with sulfur nucleophile: the ligand is used as a ligand of a palladium catalyst, and can realize the asymmetric substitution reaction of thiophenol p-allyl alcohol ester.
Therefore, chiral Trost ligands, particularly R, R configuration Trost ligands have very important significance in asymmetric catalytic reaction. While the traditional method usually adopts chiral synthesis or chemical resolution when preparing chiral Trost ligand. The methods have the defects of complicated steps, long time consumption and difficulty in obtaining the high-purity chiral Trost ligand, and the chemical resolution method can also cause the waste of a large amount of chiral Trost ligands with non-target configurations.
Disclosure of Invention
Based on the chiral Trost ligand, the invention provides a preparation method of the chiral Trost ligand. The preparation method can prepare the R, R configuration Trost ligand with high ee value, has simple steps and high production efficiency, and can avoid the waste of the chiral Trost ligand with non-target configuration (S, S configuration).
The specific technical scheme is as follows:
a preparation method of chiral Trost ligand comprises the following steps:
mixing a solvent and a racemic form Trost ligand to prepare a pretreatment solution;
enabling the pretreatment solution to flow into an adsorbent for adsorption treatment, then enabling the pretreatment solution to flow out, heating the obtained effluent to 40-120 ℃ for heat treatment, cooling, then performing adsorption treatment, and circulating in the above way;
after circulation is finished, collecting the adsorbent, eluting with an eluent, and collecting the eluent;
wherein, the adsorbent is macroporous adsorption resin.
In one embodiment, the temperature of the heat treatment is 60 ℃ to 120 ℃.
In one embodiment, the solvent is at least one of an alkane and an aromatic solvent.
In one embodiment, the concentration of the racemic Trost ligand in the pretreatment solution is 5 g/L-200 g/L.
In one embodiment, the adsorbent is an XDA ultra-crosslinked macroporous resin.
In one embodiment, the adsorbent is used in an amount of 10 to 50 times the weight of the racemic Trost ligand.
In one embodiment, the temperature of the system is controlled to be below 30 ℃ during the adsorption treatment.
In one embodiment, the circulation time is 2-6 h.
In one embodiment, the eluent is at least one of ethanol and dichloromethane.
In one embodiment, the pretreatment liquid is heated to 40-120 ℃, and then an adsorbent flows into the pretreatment liquid for adsorption treatment.
In one embodiment, the racemic Trost ligand is 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl).
In one embodiment, the preparation method of the chiral Trost ligand further comprises the following steps: after circulation is finished, collecting a liquid phase, and heating the liquid phase to 40-120 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of chiral Trost ligand, which comprises the steps of enabling racemized Trost ligand to flow through a macroporous adsorbent resin for adsorption treatment, enabling R and R configuration Trost ligands in the racemized Trost ligand to be continuously adsorbed in the adsorption treatment process, then heating effluent liquid under a certain temperature condition, and enabling a system to be recovered to a racemization state, namely S and S configuration Trost ligands are continuously converted into R and R configuration Trost ligands, so that the R and R configuration Trost ligands are continuously increased on the whole system, then cooling and repeating the adsorption treatment. By circulating in this way, the R, R configuration Trost ligand in the system is increased continuously and is adsorbed by the macroporous adsorption resin. And after circulation is finished, eluting the R and R configuration Trost ligand in the adsorbent by using an eluent, and collecting to obtain the R and R configuration Trost ligand with high ee value. Meanwhile, the preparation method of the chiral Trost ligand has simple steps and high production efficiency, and the S and S configuration Trost ligands in the racemic form of the Trost ligand are continuously converted into the R and R configuration Trost ligands, so that the waste of the S and S configuration Trost ligands can be effectively avoided.
Detailed Description
The preparation of the chiral Trost ligand of the present invention is described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The invention provides a preparation method of a chiral Trost ligand, which comprises the following steps:
mixing a solvent and a racemic form Trost ligand to prepare a pretreatment solution;
enabling the pretreatment solution to flow into an adsorbent for adsorption treatment, then enabling the pretreatment solution to flow out, heating the obtained effluent to 40-120 ℃ for heat treatment, cooling, then performing adsorption treatment, and circulating in the above way;
after circulation is finished, collecting the adsorbent, eluting with an eluent, and collecting the eluent;
wherein, the adsorbent is macroporous adsorption resin.
The method is based on the current situation that the traditional method generally has the defects of complicated steps, long time consumption and difficulty in obtaining the chiral Trost ligand with high purity, and a chemical resolution method can cause the waste of a large amount of chiral Trost ligands with non-target configurations.
The inventors have discovered, by chance, that macroporous adsorbent resins are capable of directed adsorption of Trost ligands in the R, R configuration, possibly due to: the special nanometer size pore canal of the macroporous resin can directionally adsorb the ligand with R and R configuration. The invention provides a preparation method of chiral Trost ligand, which comprises the steps of enabling a solution of racemic Trost ligand to flow through a macroporous resin adsorbent for adsorption treatment, enabling R and R configuration Trost ligands in the racemic Trost ligand to be directionally adsorbed during the adsorption treatment, enabling the R and R configuration Trost ligands to flow out, heating at a proper temperature, enabling S and S configuration Trost ligands to be dynamically converted into R and R configuration Trost ligands to form a new racemic state in order to maintain the balance of a racemic system, and then performing adsorption treatment, and repeating the steps. In the circulation process, S, S configuration Trost ligand is continuously converted into R, R configuration Trost ligand, and the R, R configuration Trost ligand is continuously increased and continuously adsorbed by the macroporous resin. And after circulation is finished, eluting the R and R configuration Trost ligand in the adsorbent by using an eluent, and collecting to obtain the R and R configuration Trost ligand with high ee value.
The preparation method of the chiral Trost ligand has the characteristics of simple steps and high production efficiency while the obtained R, R configuration Trost ligand has high ee value. Meanwhile, the S and S configuration Trost ligand in the racemic form Trost ligand is continuously converted to the R and R configuration Trost ligand, so that the waste of the S and S configuration Trost ligand can be effectively avoided.
In one specific example, the temperature of the heat treatment is 60 ℃ to 120 ℃. Specifically, the temperature of the pretreatment includes, but is not limited to, the following temperatures: 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃, 65 ℃, 67 ℃, 70 ℃, 73 ℃, 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 87 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 117 ℃, 118 ℃, 119 ℃, 120 ℃. Preferably, the temperature of the heat treatment is 75 ℃ to 120 ℃.
In one specific example, the solvent is at least one of an alkane and an aromatic solvent. As a preferred solvent, n-hexane is used. The n-hexane is used as a base solution of the racemic form Trost ligand, so that the inversion of the form can be effectively avoided, and the conversion of the S and S form Trost ligand to the R and R form Trost ligand is promoted continuously.
In one specific example, the concentration of the racemic Trost ligand in the mixture is 5 g/L-200 g/L. Preferably, the concentration of the racemic Trost ligand in the mixture is 5 g/L-10 g/L. Specifically, the concentration of racemic Trost ligand in the mixture includes, but is not limited to: 5g/L, 6g/L, 7g/L, 7.5g/L, 8g/L, 8.5g/L, 9g/L, 9.5g/L, 10 g/L.
In one specific example, the adsorbent is an XDA ultra-crosslinked macroporous resin. This facilitates the highly selective adsorption of R, R-configured TROST ligands in racemic TROST ligands by the adsorbent, and in particular, the morphology and distribution of the pore size thereof, and is particularly suitable for the adsorption of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl).
In one specific example, the adsorbent is used in an amount of 10 to 50 times the weight of the racemic Trost ligand. Thus being beneficial to the high-selectivity adsorption of the adsorbent to R, R configuration TROST ligand in racemic state TROST ligand. Specifically, the amount of adsorbent used is in multiples by weight of the racemic Trost ligand including, but not limited to: 10 times, 13 times, 15 times, 26 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 32 times, 35 times, 40 times, 45 times, 50 times. Preferably, the amount of the adsorbent is 20 to 45 times the weight of the racemic Trost ligand. More preferably, the amount of adsorbent is 35 to 45 times the weight of the racemic Trost ligand.
In one specific example, the temperature of the system is controlled to be below 30 ℃ during the adsorption treatment. As will be understood, the term "system" refers to the integration of pretreatment fluid and adsorbent that is continuously circulated through the adsorbent. The chiral Trost ligand after adsorption can be effectively prevented from racemizing in the pore channel by controlling the temperature of the system within the range.
In one specific example, the circulation time is 2 h-6 h. In the time range, the feasible chiral Trost ligand adsorption capacity can be ensured to a greater extent, and the method has high efficiency. Specifically, the time of the adsorption treatment includes, but is not limited to: 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h and 6 h. Preferably, the circulation time is 4-6 h.
In one specific example, the eluent is at least one of ethanol and dichloromethane. Further, the eluent is dichloromethane.
In one specific example, the racemic Trost ligand is selected from one of 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl).
Trans-1, 2-diaminocyclohexane skeleton (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl) contained in racemic form Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl) has a very broad asymmetric catalytic activity, and can form a catalyst system with a palladium catalyst or be used as a ligand of the palladium catalyst to synergistically perform asymmetric ring-opening reaction of an epoxy compound, kinetic resolution of a chiral compound, asymmetric allyl substitution reaction catalyzed by palladium, reaction with a sulfur nucleophile and the like.
In one specific example, the pretreatment solution is heated to 40-120 ℃, and then an adsorbent is flowed in for adsorption treatment. Thus, the racemic Trost ligand can be mixed in the solvent system fully and uniformly. Preferably, the pretreatment solution is heated to 60-120 ℃. Specifically, the temperature at which the pretreatment solution is first heated includes, but is not limited to, the following temperatures: 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃, 65 ℃, 67 ℃, 70 ℃, 73 ℃, 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 87 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 117 ℃, 118 ℃, 119 ℃, 120 ℃. More preferably, the pretreatment solution is heated to 75-120 ℃.
In one specific example, the preparation method of the chiral Trost ligand further comprises the following steps: after circulation is finished, collecting a liquid phase, and heating the liquid phase to 40-120 ℃.
The collected liquid phase can be heated to 40-120 ℃ again for pretreatment, so that the balance of a racemization system can be promoted, and then, the racemized Trost ligand can be directly recovered according to needs, and can also be recycled.
In the following, specific examples are shown, and all the raw materials used are commercially available products unless otherwise specified.
XDA ultra-crosslinked macroporous resin was purchased from New science and technology materials, Inc., of Xian blue, dawn.
Example 1
This example is a method for preparing a chiral Trost ligand, comprising the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after the completion of the circulation treatment, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.2% by HPLC.
Example 2
This example is a method for preparing a chiral Trost ligand, comprising the following steps:
(1) taking 70g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl) and adding 10000mL of liquid phase recovered according to the preparation method of example 1, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.2% by HPLC.
It can be seen that the recovery process of example 1 and the preparation process of example 2 were combined to achieve a total yield of 82%, indicating that the more the recovery was repeated, the higher the total yield.
Example 3
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the pretreatment and heating temperatures were changed from 80 ℃ to 60 ℃.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 60 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh crosslinked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 60 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh crosslinked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after the completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 60g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 85.0% by HPLC.
Example 4
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the pretreatment and heating temperatures were changed from 80 ℃ to 40 ℃.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 40 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh crosslinked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 40 ℃ again, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh crosslinked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 60g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and the ee value was 70.0% by HPLC.
Example 5
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the pretreatment and heating temperatures were changed from 80 ℃ to 120 ℃.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 120 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh crosslinked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 120 ℃ again, then cooling to below 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh crosslinked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.0% by HPLC.
Example 6
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the time of the adsorption treatment was changed from 4h to 6 h.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 6h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.0% by HPLC.
Example 7
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the time of the adsorption treatment was changed from 4h to 8 h.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 8h in such a way, and maintaining the temperature of the system to be lower than 30 ℃ in the period;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) which was found to have an ee value of 80.0% by HPLC.
Example 8
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the time of the adsorption treatment was changed from 4h to 2 h.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 2h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 50g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.0% by HPLC.
Example 9
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the amount of adsorbent used was changed from 2000 grams to 4000 grams.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) 4000 g of XDA super-crosslinked macroporous resin is added into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after the completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.6% by HPLC.
Example 10
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: the amount of adsorbent used was changed from 2000 grams to 5000 grams.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) 5000 g of XDA ultrahigh cross-linked macroporous resin is added into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 65g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 99.0% by HPLC.
Example 11
This example is a preparation method of chiral Trost ligand, which has the same steps as example 1, and mainly differs therefrom in that: in the adsorption treatment process, the temperature of the system is controlled to be 40 ℃.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g XDA super cross-linked macroporous resin into a packed column;
(3) circularly flowing the pretreatment liquid through the packed column filled with the XDA ultrahigh cross-linked macroporous resin in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃, then cooling to be lower than 30 ℃, and then flowing into the packed column filled with the XDA ultrahigh cross-linked macroporous resin for adsorption treatment; the circulation is carried out for 4 hours, and the temperature of the system is maintained to be 40 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 70g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) which was found to have an ee value of 80.0% by HPLC.
Comparative example 1
The comparative example is a preparation method of chiral Trost ligand, and the steps are the same as those of example 1, and the main difference is that: the XDA ultrahigh crosslinked macroporous resin is replaced by Tulsimer ADS-750.
The method comprises the following steps:
(1) taking 100 g of racemic Trost ligand 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl), adding 10000mL of N-hexane, heating the obtained mixture to 80 ℃ for pretreatment, and then cooling to be lower than 30 ℃ to obtain a pretreatment solution;
(2) adding 2000 g of Tulsimer ADS-750 into the packed column;
(3) circularly flowing the pretreatment liquid through the filling columns filled with Tulsimer ADS-750 in the step (2) for adsorption treatment, then flowing out, heating the effluent liquid to 80 ℃ again, then cooling to below 30 ℃, and then flowing into the Tulsimer ADS-750 filling columns for adsorption treatment; circulating for 4h, and maintaining the temperature of the system to be lower than 30 ℃;
(4) after completion of the circulation, the liquid phase was recovered, and the packed column was washed with methylene chloride, and the methylene chloride phase was collected and concentrated under reduced pressure to obtain 40g of (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinyl-1-naphthoyl) and ee value was 0% by HPLC.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (12)
1. A preparation method of chiral Trost ligand is characterized by comprising the following steps:
mixing a solvent and a racemic form Trost ligand to prepare a pretreatment solution;
enabling the pretreatment solution to flow into an adsorbent for adsorption treatment, then enabling the pretreatment solution to flow out, heating the obtained effluent to 75-120 ℃ for heat treatment, cooling, then performing adsorption treatment, and circulating in the above way;
after circulation is finished, collecting the adsorbent, eluting with an eluent, and collecting the eluent;
wherein, the adsorbent is XDA ultrahigh cross-linked macroporous resin;
the racemic form Trost ligand is 1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl);
the chiral Trost ligand is (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphino-1-naphthoyl).
2. The method for preparing the chiral Trost ligand according to claim 1, wherein the temperature of the heat treatment is 75-85 ℃.
3. The method of claim 1, wherein the solvent is at least one of an alkane solvent and an aromatic solvent.
4. The method of claim 3, wherein the solvent is n-hexane.
5. The method for preparing the chiral Trost ligand according to claim 1, wherein the concentration of the racemic Trost ligand in the pretreatment solution is 5g/L to 200 g/L.
6. The method of claim 1, wherein the adsorbent is used in an amount of 10 to 50 times the weight of the racemic Trost ligand.
7. The method of claim 6, wherein the adsorbent is used in an amount of 20 to 45 times the weight of the racemic Trost ligand.
8. The method for preparing a chiral Trost ligand according to claim 1, wherein the temperature of the system is controlled to be 30 ℃ or lower during the adsorption treatment.
9. The method for preparing a chiral Trost ligand according to claim 1, wherein the cycle time is 2-6 h.
10. The method of preparing a chiral Trost ligand according to claim 1, wherein the eluent is at least one of ethanol and dichloromethane.
11. The method for preparing the chiral Trost ligand according to any one of claims 1 to 10, wherein the pretreatment solution is heated to 40 ℃ to 120 ℃ and then flows into an adsorbent for adsorption treatment.
12. The method for preparing the chiral Trost ligand according to any one of claims 1 to 10, further comprising the steps of: after circulation is finished, collecting a liquid phase, and heating the liquid phase to 40-120 ℃.
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