CN112279791A - Method for preparing chiral tert-butyl sulfinamide - Google Patents
Method for preparing chiral tert-butyl sulfinamide Download PDFInfo
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- CN112279791A CN112279791A CN202011601694.6A CN202011601694A CN112279791A CN 112279791 A CN112279791 A CN 112279791A CN 202011601694 A CN202011601694 A CN 202011601694A CN 112279791 A CN112279791 A CN 112279791A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
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- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/04—Sulfinic acids; Esters thereof
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Abstract
The invention belongs to the technical field of chemical synthesis, and provides a preparation methodR) -a process of tert-butyl sulfenamide, said process comprising the steps of: step (1): preparing a Grignard compound by taking halogenated tert-butane as an initial raw material through a Grignard reaction, and introducing sulfur dioxide gas into a Grignard reaction solution to react to obtain tert-butyl sulfinic acid; step (2): converting tert-butyl sulfinic acid into tert-butyl sulfinyl chloride by using thionyl chloride; and (3): converting t-butylsulfinyl chloride to t-butylsulfinate ester by an alcoholic reagent and a alkaloid compound; and (4): converting tert-butylsulfinate to chiral in the presence of iron nitrate, lithium metal or sodium metal: (R) -tert-butylsulfinylamine. The process of the present invention avoids the disadvantages of the prior art, does not use malodorous tert-butyl mercaptan, uses halogenated compoundsThe tert-butane and the like are common and cheap materials, and the alkaloid compound can be recycled, so that the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of (A)R) -tert-butylsulfinamide.
Background
The chiral amine compound has important application value in the synthesis of medicaments and natural products. Since 75% or more of drugs and drug candidates have amine functional groups, compounds containing amine groups have received much attention in recent years from pharmacologists and synthetic chemists. Tert-butyl sulfenamide is a novel chiral compound designed and synthesized in Ellman 1997, and as a chiral auxiliary reagent in a plurality of asymmetric synthesis reactions, the tert-butyl sulfenamide shows good induction effect (reference: Ellman, J.A.; owens, T.D.: Tang, T.P. Acc. chem. Res.,2002,35, 984.), and better realizes the synthesis of high-activity chiral amine compounds.
Chiral tertiary butyl sulfenamides includeRThe two chiral configurations of the type and the S type, and the synthetic route is mainly divided into the following types.
One type of synthetic route is as follows: the preparation method comprises the steps of using tert-butyl mercaptan as a raw material, oxidizing the tert-butyl mercaptan by using a catalyst and hydrogen peroxide, then carrying out asymmetric oxidation by using the hydrogen peroxide, a vanadium catalyst and a chiral ligand to obtain chiral tert-butyl thiosulfinate, and then obtaining optically pure tert-butyl sulfinamide under the cryogenic condition of liquid ammonia, metal lithium and ferric nitrate.
The reaction equation is as follows:
in the above process, t-butyl disulfide takes too long (about 4 days) in the asymmetric chiral oxidation process. The method has the main problems that the consumption of liquid ammonia is too large, the liquid ammonia is not suitable to be recycled in the ammonia discharging process, and the environment is polluted. In addition, the malodorous tert-butyl mercaptan in the reaction process poses serious environmental problems.
In another synthesis process, cis-chiral indene amine alcohol is used as a raw material, is protected by amino, reacts with thionyl chloride, carries out nucleophilic attack with tert-butyl Grignard reagent, and finally reacts with liquid ammonia, lithium and ferric nitrate under the condition of deep cooling to obtain chiral tert-butyl sulfinamide. The reaction equation of the process is as follows:
in the process method, although tert-butyl mercaptan with foul smell is not used, other materials used in the process have high cost and long integral steps, and are not beneficial to industrial production.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a new chiral preparation (A)R) -tert-butylsulfinamide, the synthetic route of which is as follows:
x is selected from Cl, Br and I;
r is selected from methyl, ethyl, isobutyl, n-butyl, isopropyl, n-propyl, 3-pentyl and benzyl;
the method comprises the following steps:
step (1): adding magnesium metal and halogenated tert-butane sm into an organic solvent 1, preparing a compound 1 through a Grignard reaction, introducing sulfur dioxide gas into a Grignard reaction solution containing the compound 1, and reacting to obtain a compound 2;
step (2): adding the compound 2 and N, N-Dimethylformamide (DMF) into an organic solvent 2, and dropwise adding thionyl chloride at the temperature of 5-10 ℃ to react to obtain a compound 3;
and (3): adding an alcohol reagent and a chiral alkaloid compound into an organic solvent 3, and dropwise adding a solution of the compound 3 in the organic solvent 3 at the temperature of minus 35 +/-5 ℃ to react to obtain a compound 4; wherein the alcohol reagent is selected from at least one of methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, 3-pentanol and benzyl alcohol; the chiral alkaloid compound is at least one of quinidine, cinchonine, cinchonidine and quinine;
and (4): adding ferric nitrate, metallic lithium or metallic sodium and a solution of the compound 4 in the organic solvent 4 into liquid ammonia, and reacting to obtain a compound TM.
According to some embodiments of the invention, in step (1), the grignard reaction is carried out in the presence of magnesium turnings, wherein magnesium turnings: halogenated tert-butane: sulfur dioxide = 1.0: 1.2-1.3: 2-2.5; the halogenated tert-butane is tert-butyl bromide or tert-butyl iodide; preferably, sulfur dioxide gas is introduced into the Grignard reaction solution at a temperature of-5 ℃ to 5 ℃. The lower temperature can improve the solubility of the gas and improve the utilization rate of the raw materials.
According to some embodiments of the present invention, in the step (1), the organic solvent 1 is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, isopropyl ether.
According to some embodiments of the invention, in step (2), compound 2: thionyl chloride: N, N-Dimethylformamide (DMF) = 1.0: 1.1-1.4: 0.1; preferably, thionyl chloride is added dropwise at a temperature of 5 ℃ to 10 ℃.
According to some embodiments of the invention, in step (2), the organic solvent 2 is selected from at least one of dichloromethane, dichloroethane.
According to some embodiments of the invention, in step (3), compound 3: alcohol reagent: chiral alkaloid compound =1: 3.0-5.0: 1.05-1.2; preferably, a solution of compound 3 in organic solvent 3 is added dropwise at a temperature of-35 ℃. + -. 5 ℃. In step (3), the alcohol reagent is preferably a less hindered alcohol, such as isobutanol. Highly hindered alcohol reagents (e.g., t-butanol) are nearly unreactive under some conditions. Higher yields can be obtained with isobutanol than with several other alcohol reagentsRThe ee% value of the product with the configuration can be as high as 95%.
According to some embodiments of the invention, in step (3), the chiral alkaloid compound is selected from at least one of quinidine, cinchonine, cinchonidine, quinine. In the invention, a single alkaloid compound is adopted to obtain a good chiral catalytic effect without combining other types of catalysts. One or more alkaloid compounds are independently adoptedAll can obtain ideal chiral yield. Furthermore, the inventors have found that higher ratios (relative to the ratio obtained with quinidine as the reactant) can be obtainedSProportion of configuration) ofRAnd (5) configuring a product. In the crude reaction productRConfiguration product andSthe proportion of configuration products can be up to about 96%. In addition, the chiral alkaloid compound quinidine is convenient to recover, and the recovery rate can reach 99%.
According to some embodiments of the invention, in reaction step (3), the chiral alkaloid compound has a molar equivalent of 1.0 to 2.0 based on compound 3. In the step (3) of the invention, after the reaction is finished, most of the added chiral alkaloid compound can be recycled and reused, so that the production cost can be greatly reduced.
According to some embodiments of the present invention, in the step (3), the organic solvent 3 is at least one selected from isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate, and toluene. In this step, isopropyl ether or methyl tert-butyl ether, which is a common ether solvent, is preferably used. The selection of these solvents not only results in high yield, but also is low cost and suitable for industrial production.
In some embodiments of the invention, in step (4), the molar ratio of compound 4, lithium metal, and ferric nitrate is 1: 0.07-0.01: 3-5. Liquid ammonia is used as a solvent for dissolving ferric nitrate so that the ferric nitrate reacts with metallic sodium or metallic lithium.
According to some embodiments of the present invention, in the step (4), the organic solvent 4 is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, isopropyl ether.
The invention has the advantages of
The invention adopts a new method to prepare chiral (A)R) The method avoids the defects of the prior art, malodorous tert-butyl mercaptan is not used, the used raw materials of halogenated tert-butane, a solvent and the like are common reagents and cheap materials, and the chiral alkaloid compound can be recycled and is more suitable for industrial production.
Drawings
FIG. 1 is a normal phase HPLC chromatogram of crude compound 4-3 prepared in example 4 of the present invention;
FIG. 2 is a solution of (R) -normal phase HPLC profile of tertiary butyl sulfinamide standard;
FIG. 3 shows a compound prepared by the method of the present inventionR) -normal phase HPLC profile of tert-butyl sulfinamide;
FIG. 4 is a graph of a compound prepared by the example of the present inventionR) Of tert-butylsulfinamides1HNMR atlas.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
Preparation of Compound 2
In a dry glass reactor, magnesium turnings (24 g, 1.0 eq) were added under nitrogen blanket and heated to 45-55 ℃. And adding tert-butyl bromide (177 g, 1.3 eq) and 2-methyltetrahydrofuran (MeTHF) (500 g) into another preparation bottle, uniformly mixing, dropwise adding part of the mixed solution into a reaction bottle to form a Grignard reaction system, cooling to 40-50 ℃, dropwise adding the tert-butyl bromide mixed solution, stirring for reacting for more than 5 hours after dropwise adding, cooling the Grignard reaction solution to-5 ℃, introducing sulfur dioxide into the reaction kettle, wherein the weight of the introduced sulfur dioxide is (171 g, 2.5 eq). Keeping the temperature at about 0 ℃ for reaction for 1h, dropwise adding concentrated sulfuric acid into the reaction kettle to quench the reaction, carrying out reduced pressure distillation at the temperature of 30-45 ℃, carrying out reduced pressure distillation to dry the reaction product to a viscous liquid (removing excessive sulfur dioxide), then adding tetrahydrofuran and ethyl acetate, dropwise adding water, adding salt, stirring at room temperature for 10-30 minutes to saturate the system, standing for layering, and keeping an organic phase. The organic phase was distilled at 30-45 ℃ under reduced pressure to give an oil. Dichloromethane was added to the kettle, followed by addition of anhydrous sodium sulfate for drying. The mixture in the reaction vessel was discharged, filtered with suction, and the solvent was distilled off at a temperature of 35 to 50 ℃ under reduced pressure to obtain 85g of compound 2, tert-butylsulfinic acid (yield 65%).
Preparation of Compound 3
Adding the compound 2 (15 g, 1.0 eq), N-dimethylformamide (DMF, 0.9g, 0.1 eq) and dichloroethane (75 mL, 5V) in sequence into a dry reaction flask, stirring under the protection of nitrogen, cooling to 5-10 ℃, slowly dropping thionyl chloride (20 g, 1.4 eq) into the reaction flask, and after dropping, raising the temperature to 20-25 ℃. And vacuumizing the reaction bottle, continuously reducing the pressure, and keeping the reaction bottle until no bubbles are generated. The external temperature of the reaction flask was raised to 50-55 ℃ and distilled using an oil pump to give 12g of compound 3 with a yield of 70%.
Preparation of Compound 4-1 (n-propyl ester)
5g (1.0 eq) of Compound 3 was dissolved in 20ml of methyl t-butyl ether to prepare a methyl t-butyl ether solution of Compound 3 for use.
Adding 10.7g (5.0 eq) of n-propanol, 12.5g (1.2 eq) of cinchonine and 150mL of methyl tert-butyl ether into a 500mL three-neck flask, reducing the temperature to minus 35 ℃ (± 5 ℃) under the protection of nitrogen, and dropwise adding a methyl tert-butyl ether solution of the compound 3, wherein the temperature is controlled to be about minus 35 ℃ (± 5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 1h at the temperature of about minus 35 ℃, and the reaction is finished.
And (3) post-treatment: adding water into a reaction system, dropwise adding a 10wt% sulfuric acid aqueous solution to adjust the pH, finally stirring until the system is clarified and layered, extracting the lower-layer water phase once with methyl tert-butyl ether, adding water into an organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate aqueous solution and a saturated NaCl aqueous solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the methyl tert-butyl ether under reduced pressure to obtain 6.3g of a crude product of the compound 4-1. Detection by normal phase HPLC chromatography can seeRConfiguration product andSof a shaped productThe ratio was 82: 18.
Preparation of Compound TM
In a 300mL four-port bottle, a dry ice bath, an ammonia condensing device and an ammonia tail gas absorbing device are arranged under the protection of nitrogen.
Introducing ammonia gas into the bottle by using an ammonia gas cylinder at the temperature of about-75 ℃, and collecting about 150mL of dry liquid ammonia. 0.51g (0.1 eq) of iron nitrate nonahydrate was added, dissolved with stirring and clarified. A total of 14.7g (5.0 eq) of sodium metal was added in portions. Then 21g (1.0 eq) of methyl tert-butyl ether solution of the compound 4-1 is added dropwise, the temperature is controlled to be minus 65 to minus 55 ℃, after the reaction is finished, 23g of solid ammonium chloride is added in batches, the temperature is controlled to be below minus 50 ℃, the dry ice bath is removed, an ammonia tail gas absorption device is communicated, and the ammonia gas is removed by a water pump under reduced pressure. Adding water, adding tetrahydrofuran and ethyl acetate, extracting, separating liquid, and temporarily storing an organic phase. The aqueous phase was extracted twice with methyl tert-butyl ether, the organic phases were combined, washed once with half-saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was not distilled off under reduced pressure from the oil pump, at which time about 20g of crude product was obtained. 400mL of n-heptane was added to the crude product and heated to about 65 ℃ to clear the solid; filtering while the solution is hot, and discarding a filter cake. Distilling the filtrate at 65 deg.C under reduced pressure to 130mL, crystallizing at room temperature (25 deg.C), and cooling to below 10 deg.C for 2 hr. Filtering, and discarding the filtrate. The crystals were dried to obtain 14.5g of a pure compound TM.
Example 2
Preparation of Compound 2
Adding magnesium chips (10 g, 1.0 eq) into a dry glass reaction kettle under the protection of nitrogen, heating to 45-55 ℃, taking another preparation bottle, adding tert-butyl iodide (98 g, 1.3 eq) and methyl tert-butyl ether (300 g), uniformly mixing, dropwise adding the mixed solution into the reaction bottle to form a Grignard reaction system, cooling to 40-50 ℃, continuously dropwise adding the tert-butyl bromide mixed solution, stirring for reacting for more than 5 hours after dropwise adding, cooling the Grignard reaction solution to-5 ℃, introducing sulfur dioxide into the reaction kettle, wherein the weight of the introduced sulfur dioxide is (60 g, 2.3 eq). Keeping the temperature at about 0 ℃ for reaction for 1h, dropwise adding concentrated sulfuric acid into the reaction kettle to quench the reaction, carrying out reduced pressure distillation at the temperature of 30-45 ℃, carrying out reduced pressure distillation to dry the reaction product to a viscous liquid (removing excessive sulfur dioxide), then adding tetrahydrofuran and ethyl acetate, dropwise adding water, adding salt, stirring at room temperature for 10-30 minutes to saturate the system, standing for layering, and keeping an organic phase. Distilling the organic phase at 30-45 deg.C under reduced pressure to obtain oil, adding dichloromethane into the reaction kettle, and drying with anhydrous sodium sulfate. Discharging the mixture in the reaction kettle, filtering, and distilling at 35-50 ℃ under reduced pressure to obtain 50g of compound 2-tert-butyl sulfinic acid with the yield of 20%.
Preparation of Compound 3
Adding combined 2 (150 g, 1.0 eq), N-dimethylformamide (9 g, 0.1 eq) and dichloroethane (750 mL, 5V) into a dry reaction kettle in sequence, stirring under the protection of nitrogen, cooling to 5-10 ℃, slowly dropping thionyl chloride (190 g, 1.3 eq) into a reaction bottle, heating to room temperature of 20-25 ℃ after dropping is finished, vacuumizing the reaction kettle, continuously reducing the pressure until no bubbles are generated in the reaction bottle, heating the outside of the reaction kettle to 50-55 ℃, and distilling by using an oil pump to obtain 121g of compound 3, wherein the yield is 70%.
Preparation of Compound 4-2 (isopropyl ester)
A solution of Compound 3 in methyl t-butyl ether was prepared by dissolving 15g of Compound 3 in 60ml of methyl t-butyl ether, and was used.
Adding 26g of isopropanol, 38g of quinine and 400mL of methyl tert-butyl ether into a 1000mL three-neck flask, cooling to-35 ℃ (± 5 ℃) under the protection of nitrogen, and dropwise adding a methyl tert-butyl ether solution of a compound 3, wherein the temperature is controlled to-35 ℃ (± 5 ℃) in the dropwise adding process; after the dripping is finished, the temperature is kept at minus 35 ℃ for 1 hour.
And (3) post-treatment: adding water into a reaction system, dropwise adding a 10wt% sulfuric acid aqueous solution to adjust the pH value to 2, finally stirring until the system is clarified and layered, extracting the lower aqueous phase once with methyl tert-butyl ether, adding water into an organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate aqueous solution and a saturated NaCl aqueous solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the methyl tert-butyl ether under reduced pressure to obtain 18g of a crude product of the compound 4-2 (isopropyl ester). Detection by normal phase HPLC chromatography can seeRConfiguration product andSthe ratio of the products of the configuration was 9.7: 90.3.
Preparation of Compound TM
In a 500mL four-port bottle, a dry ice bath, an ammonia condensing device and an ammonia tail gas absorbing device are arranged under the protection of nitrogen.
Ammonia gas was introduced into a four-necked flask using an ammonia gas cylinder at about-75 deg.C, and about 22mL of dry liquid ammonia was collected. 0.6g of ferric nitrate nonahydrate was added, dissolved with stirring and clarified. A total of 3.2g of metallic lithium were added in portions. Then 25g of 2-methyltetrahydrofuran solution of the compound 4-2 is dripped, the temperature is controlled to be minus 65 to minus 55 ℃, after the reaction is finished, 30g of solid ammonium chloride is added in batches to quench the generated lithium amide, the temperature is controlled to be below minus 50 ℃, the dry ice bath is removed, an ammonia tail gas absorption device is communicated, and the water pump is used for reducing the pressure to remove the ammonia. Adding water, adding tetrahydrofuran and ethyl acetate, extracting, separating liquid, and temporarily storing an organic phase. The aqueous phase was extracted twice, the organic phases were combined, washed once with half-saturated brine, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure from an oil pump until no solvent was removed, at which time about 21g of crude product was obtained. The crude product was purified with n-heptane to yield compound TM (, (R) (R))R) -tert-butylsulfinamide) 11g, yield 60%.
Example 3
In this example, the other steps are the same as in example 1 except that compounds 4-3 are prepared by the following method.
Preparation of compound 4-3 (isobutyl ester)
2g (14.2 mmol, 1.0 eq) of compound 3 are dissolved in 6ml of methyl tert-butyl ether for further use; adding 3.2g (42.6 mmol, 3.0 eq) of isobutanol, 5.07g (15.6 mmol, 1.1 eq) of quinidine and 60mL of methyl tert-butyl ether into a 200mL three-necked bottle, reducing the temperature to minus 50 +/-5 ℃ under the protection of nitrogen, dropwise adding a methyl tert-butyl ether solution of the compound 3, and controlling the temperature to be below minus 30 ℃ (± 5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 2 hours at the temperature of minus 35 ℃, and the reaction system is found to be viscous and can not be stirred continuously. Heating the reaction system to-25 ℃, continuing the reaction for two hours, and detecting that the raw materials are completely reacted.
And (3) post-treatment: adding ice water, dropwise adding a 10% sulfuric acid aqueous solution to adjust the pH to be =2, finally stirring until the system is clarified and layered, extracting the lower-layer water phase once with methyl tert-butyl ether, adding an organic phase into an aqueous solution, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate aqueous solution and a saturated NaCl aqueous solution, layering, adding an organic phase into anhydrous sodium sulfate, drying, filtering, and distilling off the methyl tert-butyl ether under reduced pressure to obtain 2.1g of a crude product of the compound 4-3 (isobutyl ester). Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the products of the configuration was 94.5: 5.5.
Recovery of chiral alkaloid compound quinidine: the aqueous phase obtained in the work-up was extracted with ethyl acetate and the organic phase was discarded. And (3) adjusting the pH value of the water phase to 11-12 by adopting a sodium hydroxide solution, collecting the precipitated solid, washing with water or pulping, and filtering to obtain 5.02g of recovered quinidine with a recovery rate of 99%.
Example 4
In this example, the other steps are the same as in example 3, except that compound 4-3 is prepared by the following method:
preparation of compound 4-3 (isobutyl ester)
2g (14.2 mmol, 1.0 eq) of compound 3 are dissolved in 60ml of isopropyl ether for further use; adding 3.2g (42.6 mmol, 3.0 eq) of isobutanol, 40mL of isopropyl ether, 5.07g (15.6 mmol, 1.1 eq) of recovered quinidine and 60mL of isopropyl ether into a 200mL three-necked bottle, reducing the temperature to minus 50 +/-5 ℃ under the protection of nitrogen, dropwise adding the isopropyl ether solution of the compound 3, and controlling the temperature to be below minus 30 ℃ (-5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 2 hours at the temperature of minus 35 ℃, and the raw materials are detected to be completely reacted.
And (3) post-treatment: adding ice water into a reaction system, dropwise adding a 10% sulfuric acid aqueous solution to adjust the pH to be =2, finally stirring until the system is clarified and layered, extracting the lower-layer water phase once with isopropyl ether, adding water into an organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate aqueous solution and a saturated NaCl aqueous solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the isopropyl ether under reduced pressure to obtain 2.2g of a crude product of the compound 4-3 (isobutyl ester product). Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the products of the configuration was 95.35: 4.65 (see FIG. 1).
With reference to example 1, compound TM was prepared using compounds 4-3. By normal phase HPLC detection, in compound 4-3,Rconfiguration product andSthe proportion (ee%) of the product of configuration was 99.81%.
When the normal phase HPLC profile of the commercially available standard product of the compound TM (see fig. 2) and the normal phase HPLC profile of the compound TM obtained in this example (see fig. 3) were compared, it was found that the peak appearance position and the peak area of both were substantially the same. FIG. 4 shows a reaction scheme of (R) Of tert-butylsulfinamides1H NMR spectrum. From the profile data, it was determined that the compound TM prepared by the method of the present invention is (A), (B), (C), (D), (E), (R) -tert-butyl sulfenamide.
The chiral alkaloid compound was recovered according to the method of the example.
Example 5
In this example, the other steps are the same as in example 3 except that compound 4-3 is prepared by the following method.
Preparation of compound 4-3 (isobutyl ester)
In a 50mL three-necked flask, 0.5g of Compound 3 (3.56 mmol, 1.0 eq), 0.79g of isobutanol (10.68 mmol, 3.0 eq), 10mL of ethyl acetate (20V), 1.27g of quinidine (3.92 mmol, 1.1 eq), and stirring were added until the solid was not completely dissolved. And (5) cooling to minus 15 +/-5 ℃ under the protection of nitrogen. Dropwise adding an ethyl acetate (4V) solution of the compound 3, and controlling the temperature to be below minus 10 ℃ (-5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 3 hours at the temperature of minus 15 ℃, and the raw materials are detected to be completely reacted.
And (3) post-treatment: adding ice water into a reaction system, dropwise adding 1M HCl to adjust the pH value to be =2, finally stirring until the system is clear and layered, extracting the lower-layer water phase once with ethyl acetate, adding water into the organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate water solution and a saturated NaCl water solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the ethyl acetate under reduced pressure to obtain 0.5g of a crude product of the compound 4-3 (isobutyl ester). Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the products of the configuration was 89.6: 10.4.
Example 6
In a 250mL three-necked flask, 5.0g of Compound 3 (35.56 mmol, 1.0 eq), 89g of isobutanol (10.7 mmol, 3.0 eq), 150mL of isopropyl ether (30V), and 12.7g of quinine (39.1 mmol, 1.1 eq) were added and stirred. And (5) cooling to minus 50 +/-5 ℃ under the protection of nitrogen. Dropwise adding an isopropyl ether solution of the compound 3, and controlling the temperature to be below minus 30 ℃ (-5 ℃) in the dropwise adding process; after the dripping is finished, the temperature is kept at minus 25 ℃ for 2 hours, and the raw materials are detected to be reacted completely.
And (3) post-treatment: adding ice water into the reaction system, dropwise adding a 10% sulfuric acid solution to adjust the pH =2-3, finally stirring until the system is clear and layered, and obtaining a lower-layer water phaseAnd extracting with isopropyl ether once, adding water into the organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate aqueous solution and a saturated NaCl aqueous solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the isopropyl ether under reduced pressure to obtain a crude product of the compound 4-3 (isobutyl ester product), wherein the crude product is 4.9 g. Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the products of the configuration was 8.2: 91.8. .
Example 7
The procedure and the addition ratio in this example were the same as in example 5, except that: the ethyl acetate in the reaction step was replaced with toluene.
Preparation of compound 4-3 (isobutyl ester)
In a 100mL three-necked flask, 1.0g of compound 3 (7.11 mmol, 1.0 eq), 1.6g of isobutanol (21.3 mmol, 3.0 eq), 20mL of toluene (20V), and 2.54g of quinidine (7.832 mmol, 1.1 eq) were added and stirred. And (5) cooling to minus 15 +/-5 ℃ under the protection of nitrogen. Dropwise adding a toluene (4V) solution of the compound 3, and controlling the temperature to be below minus 10 ℃ (-5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 15 ℃, and the raw materials are detected to be completely reacted.
And (3) post-treatment: adding ice water into a reaction system, dropwise adding a 10wt% sulfuric acid solution to adjust the pH =2, finally stirring until the system is clarified and layered, extracting the lower-layer water phase once with toluene, adding water into an organic phase, stirring and washing the organic phase for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate water solution and a saturated NaCl water solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off the toluene under reduced pressure to obtain 1.4g of a crude product of the compound 4-3 (isobutyl ester). Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the products of the configuration was 91.4: 8.6.
Example 8
The procedure and the addition ratio of the present example were the same as those of example 5, except that: the ethyl acetate in the reaction step was replaced with tetrahydrofuran.
Preparation of compound 4-3 (isobutyl ester)
In a 50mL three-necked flask, 0.5g of Compound 3 (3.56 mmol, 1.0 eq), 0.79g of isobutanol (10.68 mmol, 3.0 eq), 10mL of tetrahydrofuran (20V), 1.27g of quinidine (3.92 mmol, 1.1 eq), and stirring were added until the solid was not completely dissolved. And (5) cooling to minus 15 +/-5 ℃ under the protection of nitrogen. Dripping tetrahydrofuran (4V) solution of the compound 3, and controlling the temperature to be below minus 50 ℃ (-5 ℃) in the dripping process; after the dripping is finished, the temperature is kept at minus 55 ℃ for 2 hours, and the raw materials are detected to be reacted completely.
And (3) post-treatment: adding ice water into a reaction system, dropwise adding 1M HCl to adjust pH =2, finally stirring until the system is clear and layered, extracting a lower-layer water phase once with 25mL ethyl acetate, adding water into an organic phase, stirring and washing for 10 minutes, respectively stirring and washing the organic phase with a saturated sodium bicarbonate water solution and a saturated NaCl water solution, layering, drying the organic phase with anhydrous sodium sulfate, filtering, and distilling off tetrahydrofuran under reduced pressure to obtain 0.67g of a crude product of the compound 4-3 (isobutyl ester). Detection by normal phase HPLC can seeRConfiguration product andSthe ratio of the configuration products was 92.5: 7.5.
Example 9
The procedure and the addition ratio of this example were the same as those of example 8, except that: isobutanol was replaced with tert-butanol.
In a 50mL three-necked flask, 0.5g of Compound 3 (3.56 mmol, 1.0 eq), 0.80g of t-butanol (10.68 mmol, 3.0 eq), 10mL of tetrahydrofuran (20V), 1.27g of quinidine (3.92 mmol, 1.1 eq), and stirring were added until the solid was not completely dissolved. And (5) cooling to minus 55 +/-5 ℃ under the protection of nitrogen. Dripping tetrahydrofuran (4V) solution of the compound 3, and controlling the temperature to be below minus 50 ℃ (-5 ℃) in the dripping process; after the dripping is finished, the temperature is kept at minus 60 ℃ for 1 hour, and the raw materials are detected to be unreacted.
The temperature of the reaction system is increased to-30 ℃ to-25 ℃, the reaction is continued for 1h, and the raw materials are not reacted through detection.
The temperature of the reaction system is increased to 0 ℃ to 5 ℃, the reaction is continued for 2.5 hours, and the raw materials are not reacted through detection.
And (3) raising the temperature of the reaction system to room temperature, continuing to react for 2 hours, and detecting that the raw materials are not reacted. It is analyzed that t-butyl alcohol is difficult to react with compound 3 to form t-butyl ester, probably because t-butyl alcohol has a large steric hindrance.
Example 10
The procedure and the addition ratio of this example were the same as those of example 8, except that: the isobutanol in the reaction step is replaced by 3-pentanol.
After reaction and post-treatment, 0.72g of crude compound 4-10 was obtained, which was detected by normal phase HPLC chromatographyRConfiguration product andSthe ratio of the products of the configuration was 60: 40.
Example 11
The procedure and the addition ratio of this example were the same as in example 8, except that: the isobutanol in the reaction step is replaced with benzyl alcohol.
Following the procedure and operation of example 8, reaction and workup gave 0.81g of crude compound 4-11 as seen by normal phase HPLC chromatographyRConfiguration product andSthe ratio of the products of the configuration was 90.3: 9.7.
Example 12
In this example, the other steps are the same as in example 4 except that compound 4-3 is prepared by the following method:
preparation of Compound 4-3 (isobutyl ester).
3g (21.4 mmol, 1.0 eq) of compound 3 were dissolved in 6ml (2V) isopropyl ether for use. Adding 4.8g (64.0 mmol, 3.0 eq) of isobutanol, 60mL of isopropyl ether, 3.5g (1.74 mmol, 0.5 eq) of quinidine, 1.75g (25.7 mmol, 1.2 eq) of imidazole and 60mL of isopropyl ether into a 200mL three-necked bottle, reducing the temperature to minus 35 +/-5 ℃ under the protection of nitrogen, dropwise adding the isopropyl ether solution of the compound 3, and controlling the temperature to be below minus 20 ℃ (-5 ℃) in the dropwise adding process; after the dripping is finished, the reaction is carried out for 2 hours at the temperature of minus 35 ℃, and the raw materials are detected to be completely reacted.
The working-up was the same as in example 4. After work-up, 2.2g of crude 4-3 (isobutyl ester product) was obtained. Detecting by normal phase HPLC to obtain a racemic product,Rconfiguration andSthe products of the configuration each accounted for 50%, and the next reaction was not continued.
Example 13
In this example, the procedure and the addition ratio were the same as in example 12 except that the imidazole was replaced with DMAP (N, N-dimethyl-4-pyridylamine). Detecting the reaction product by normal phase HPLC to obtain a racemic product,Rconfiguration andSthe products of the configuration each accounted for 50%, and the next reaction was not continued.
Example 14
In this example, the procedure and the addition ratio were the same as in example 12 except that imidazole was replaced with DBN (1, 5-diazabicyclo [4.3.0 ]]-5-nonene). Detecting the reaction product by normal phase HPLC to obtainRThe configuration product accounts for 60 percent,Sthe product of the configuration accounts for 40 percent, and the next reaction is not continued.
Example 15
In this example, the procedure and the addition ratio were the same as in example 12 except that imidazole was replaced with 1-methylpyrrolidine. Detecting the reaction product by normal phase HPLC to obtainRThe configuration product accounts for 70.4 percent,Sthe product of the configuration accounted for 29.6%, and the next reaction was not continued.
Example 16
The difference in this example compared to example 12 is that imidazole was replaced with N, N-diphenylpropylamine and N, N-diphenylpropylamine was substitutedThe amount of compound 3 charged was 0.8 eq. Detecting the reaction product by normal phase HPLC to obtainRThe product of the configuration accounts for 80.3,Sthe product of the configuration accounted for 19.7%, and the reaction was not continued further.
As can be seen from examples 12-16, the feed mole ratio of the chiral alkaloid compound quinidine has a greater effect on the ratio of the R configuration product to the S configuration product in the chiral product. When the feeding mol ratio of the chiral alkaloid compound is small, the chiral alkaloid compound is difficult to obtainRAnd (5) configuring a product.
Example 17
In this example, the other steps are the same as in example 4, except that the amount of quinidine charged relative to compound 3 is 1.0eq, and the reaction product is detected by normal phase HPLC to give the productRThe formed product accounts for 94.0 percent,Sthe product of the configuration accounted for 6.0%, and the reaction was not continued to the next step.
Example 18
In this example, the other steps are the same as in example 4, except that the quinidine is dosed at 2.0eq relative to compound 3, and the reaction product is detected by normal phase HPLC to give the productRThe configured product accounts for 95.2 percent,Sthe product of the configuration accounted for 4.8%, and the reaction was not continued to the next step.
As can be seen from examples 12-18, the feed mole ratio of the chiral alkaloid compound quinidine has a greater effect on the ratio of R-configuration product to S-configuration product in the chiral product. When the feeding mol ratio of the chiral alkaloid compound is small, the chiral alkaloid compound is difficult to obtainRAnd (5) configuring a product.
The invention provides a preparation methodR) A process for preparing tert-butylsulfinamide from halogenated tert-butane as starting material and chiral alkaloid compound as reactant (I)R) Tert-butylsulfinamide, with higher chiral purity(s) (ii)R) The chiral alkaloid compound can be recycled, the recovery rate of the chiral alkaloid compound is high, and the method has good industrial prospect.
Claims (10)
1. A process for the preparation of chiral tert-butyl sulfinamide, said process comprising the following synthetic route:
x is selected from Cl, Br and I;
r is selected from methyl, ethyl, isobutyl, n-butyl, isopropyl, n-propyl, 3-pentyl and benzyl;
the method comprises the following steps:
step (1): adding magnesium metal and halogenated tert-butane sm into an organic solvent 1, preparing a compound 1 through a Grignard reaction, introducing sulfur dioxide gas into a Grignard reaction solution containing the compound 1, and reacting to obtain a compound 2;
step (2): adding the compound 2 and N, N-dimethylformamide into the organic solvent 2, dropwise adding thionyl chloride, and reacting to obtain a compound 3;
and (3): adding an alcohol reagent and a chiral alkaloid compound into an organic solvent 3, dropwise adding a solution of the compound 3 in the organic solvent 3, and reacting to obtain a compound 4; wherein the alcohol reagent is selected from at least one of methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, 3-pentanol and benzyl alcohol; the chiral alkaloid compound is at least one of quinidine, cinchonine, cinchonidine and quinine;
and (4): adding ferric nitrate, metallic lithium or metallic sodium and a solution of the compound 4 in the organic solvent 4 into liquid ammonia, and reacting to obtain a compound TM.
2. The process of claim 1, wherein in step (1), the grignard reaction is carried out under catalysis of magnesium turnings, wherein magnesium turnings halogenated tert-butane sulfur dioxide = 1.0: 1.2-1.3: 2-2.5; the halogenated tert-butane is tert-butyl bromide or tert-butyl iodide.
3. The method according to claim 1, wherein the organic solvent 1 is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and isopropyl ether.
4. The method according to claim 1, wherein in step (2), the compound 2: thionyl chloride: N, N-dimethylformamide = 1.0: 1.1-1.4: 0.1.
5. The method according to claim 1, wherein in the step (2), the organic solvent 2 is at least one selected from dichloromethane and dichloroethane.
6. The method according to claim 1, wherein in step (3), the compound 3: alcohol reagent: chiral alkaloid compound =1: 3.0-5.0: 1.05-1.2; at a temperature of-35 ℃. + -. 5 ℃, a solution of compound 3 in organic solvent 3 is added dropwise.
7. The method according to claim 1, wherein in step (3), the chiral alkaloid compound has a molar equivalent of 1.0-2.0 based on the compound 3, and the chiral alkaloid compound is recovered after the reaction is finished.
8. The method according to claim 1, wherein in step (3), the organic solvent 3 is at least one selected from isopropyl ether and methyl tert-butyl ether.
9. The method according to claim 1, wherein in step (4), the molar ratio of compound 4, metallic lithium or metallic sodium to ferric nitrate is 1: 0.07-0.01: 3-5.
10. The method according to claim 1, wherein in the step (4), the organic solvent 4 is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, and isopropyl ether.
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