CN113402428B - Preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and intermediate thereof - Google Patents
Preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and intermediate thereof Download PDFInfo
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Abstract
The invention provides a preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and an intermediate thereof, which is characterized by comprising the following preparation steps: the invention adopts an intermediate obtained by condensing chiral ligand reagent tert-butyl sulfinyl amine and 4-oxocyclohexane carboxylic ester, so that the reduction reaction has high stereoselectivity, the proportion of trans products is more than 95 percent, and meanwhile, the tert-butyl sulfinyl group is stable under the alkaline condition and easy to leave under the acidic condition, the reaction condition is mild, the operation is simple and convenient, the yield is high, and the industrial production is easy.
Description
Technical Field
The invention relates to a preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and an intermediate trans-4-tert-butylsulfinamide cyclohexanecarboxylic acid ester thereof, belonging to the field of organic synthesis.
Background
4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid exists in two vertical isomers: cis-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid, wherein trans-4-aminocyclohexanecarboxylic acid (ACCA) and its derivatives are one of important pharmaceutical intermediates, and are mainly used for synthesizing short peptides, polypeptides, isoquinuclidinone and other drugs. Trans 4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is a derivative of ACCA and is one of the important building blocks for the construction of active drugs.
European journal of Medicinal Chemistry,2001, vol.36, #3, p.265-286 reports the use of 4-aminobenzoic acid as the reagentStarting material, ptO 2 Catalytic hydrogenation to obtain 4-cyclohexyl carboxylic acid cis-trans product ratio of 16:49.US2018148424 reports that rhodium-catalyzed reduction of a mixture of ethyl 4-aminocyclohexanecarboxylate with acetaldehyde condensation gives a ratio of cis-trans products of 4-cyclohexanecarboxylic acid derivatives of 10:1.US201240984 reports that the ratio of cis-trans products of 4-cyclohexanecarboxylic acid derivatives obtained by reduction of 4-oxocyclohexanecarboxylic acid ethyl ester with sodium triacetoxyborohydride is 5:2.WO200422541 reports yields of cis-trans products of ethyl 4-oxocyclohexanecarboxylate condensation products of 28% and 34%, respectively. CN109824545A adopts 4-oxocyclohexanecarboxylic acid triphenylmethyl ester as a raw material, and performs reductive amination reaction under the catalysis of Lewis acid, wherein the ratio of cis-trans products is 79:21, the highest yield can reach 92. After recrystallization and purification, deamination protection is carried out, and trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is obtained by condensation with (Boc) 2O (di-tert-butyl dicarbonate), but raw materials are not commercialized, the product yield still needs to be improved, the molecular weight of a protecting group is large, and carbon emission is not economical.
Therefore, there is a need to develop a suitable synthetic method to solve the problems of efficiently producing more trans-products or how to separate cis-trans isomers, and a preparation method which is easy to purify, safe to operate and suitable for industrial scale-up production.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of trans-4-tert-butyl sulfinyl amine cyclohexane carboxylic ester and a preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid, and the preparation method has the advantages of easily obtained raw materials, strong selectivity, high trans-product proportion and high yield.
In order to achieve the above first object of the present invention, the present invention provides a method for producing trans 4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid, comprising the steps of:
the method comprises the following steps of taking 4-oxocyclohexane carboxylic ester and a chiral ligand reagent, namely tert-butyl sulfinamide, as raw materials, and carrying out reductive amination under catalysis of Lewis acid to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester, wherein the reaction formula is as follows:
r is t-Bu.
Specifically, the method comprises the following steps: dissolving 4-oxo-cyclohexane carboxylate and tert-butyl sulfinamide in an organic solvent, reacting under the catalysis of Lewis acid, cooling to room temperature after the reaction is finished, adding a reducing agent, stirring for reduction reaction, quenching the reaction after the reaction is finished, washing, and concentrating under reduced pressure to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate. The step adopts 4-oxocyclohexane carboxylate and chiral ligand reagent tert-butyl sulfinamide to react under Lewis acid, so that the selectivity is strong, the proportion of trans-products is more than 95 percent, and the yield is high.
The organic solvent is selected from dichloromethane, toluene or a mixture thereof in any proportion; the reducing agent is selected from sodium borohydride or sodium triacetoxyborohydride; the Lewis acid reagent is selected from ethyl titanate or tetraisopropyl titanate; the 4-oxocyclohexanecarboxylate to Lewis acid molar ratio is 1.1 to 1.5; the molar ratio of the 4-oxocyclohexanecarboxylate to the tert-butyl sulfinamide is 1.05-1.5; the molar ratio of the ethyl 4-oxocyclohexanecarboxylate to the reducing agent is 1.5-2.0.
The second object of the present invention is achieved by:
a preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is characterized by comprising the following preparation steps:
1) The method comprises the following steps of taking 4-oxocyclohexane carboxylate and chiral ligand reagent tert-butyl sulfinamide as raw materials, and carrying out reductive amination under catalysis of Lewis acid to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate, wherein the reaction formula is as follows:
2) Deprotection and amino protection:
comprises a step of removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinyl amine cyclohexane carboxylic ester under an acidic condition to obtain trans-4-aminocyclohexane carboxylic acid or ester or salt thereof, a step of condensing with di-tert-butyl dicarbonate under an alkaline condition, and a step of hydrolyzing the ester under an alkaline condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid;
and R is methyl, ethyl or tert-butyl.
Specifically, the method comprises the following steps: the deprotection and amino protection steps are as follows:
the deprotection and amino protection steps are as follows:
in the presence of a solvent, removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester under an acidic condition to obtain trans-4-aminocyclohexane carboxylic acid and ester, then condensing with di-tert-butyl dicarbonate under an alkaline condition, and finally hydrolyzing the ester under the alkaline condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid, wherein the reaction formula is as follows:
the R is methyl or ethyl, and the solvent is selected from ethanol, dioxane, dichloromethane, ethyl acetate and dimethylformamide; the acid is selected from one of trifluoroacetic acid, hydrogen chloride or aqueous solution thereof; the base is selected from triethylamine, sodium hydroxide and lithium hydroxide; the molar weight of the acid is 1.0-5.0 equivalent of the dosage of the trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid ethyl ester, the molar weight of the base is 1.0-2.0 equivalent of the dosage of the di-tert-butyl dicarbonate, and the molar weight of the hydrolysis base is 1.0-2.0 equivalent of the dosage of the trans-4-tert-butoxycarbonylamino cyclohexane carboxylate.
In the scheme, the method comprises the following steps: the R is tert-butyl ester, the acid is trifluoroacetic acid, trans-4-aminocyclohexane carboxylic acid is obtained by removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester under an acidic condition, and then the trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid is obtained by condensing with di-tert-butyl dicarbonate under an alkaline condition, and the reaction formula is as follows:
or: the method comprises the following steps of (1) removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester under an acidic condition to obtain trans-4-aminocyclohexane carboxylic acid and ester in the presence of a solvent, condensing with di-tert-butyl dicarbonate under an alkaline condition, and finally hydrolyzing the ester under the alkaline condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid, wherein the reaction formula is as follows:
or the deprotection and amino protection steps are as follows: in the presence of a solvent, dissolving trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester in trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid obtained by ester hydrolysis under alkaline conditions; then, under the acid condition, tert-butyl sulfinyl is removed to obtain trans-4-aminocyclohexane carboxylic acid, and finally, under the alkali condition, the trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is obtained by condensation with di-tert-butyl dicarbonate, wherein the reaction formula is as follows:
the solvent is selected from ethanol, methanol, dioxane, dichloromethane, ethyl acetate and dimethylformamide, and the acid is selected from trifluoroacetic acid, hydrogen chloride or aqueous solution thereof; the base is selected from triethylamine, sodium hydroxide and lithium hydroxide; the molar weight of the alkali added for the first time is 1.0-2.0 equivalent of the dosage of the trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid ethyl ester, the molar weight of the acid is 1.0-5.0 equivalent of the dosage of the trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid, and the molar weight of the alkali added in the condensation step of the di-tert-butyl dicarbonate is 1.0-2.0 equivalent of the dosage of the di-tert-butyl dicarbonate.
The invention takes 4-oxocyclohexanecarboxylic acid ester as a raw material, and the raw material is condensed and reduced with a chiral ligand reagent tert-butyl sulfinyl amine to obtain trans-4-tert-butyl sulfinyl amine cyclohexanecarboxylic acid ester, then tert-butyl sulfinyl and tert-butyloxycarbonyl protected amino are respectively removed through two ways, and ester hydrolysis is carried out to obtain trans-4- (tert-butyloxycarbonylamino) cyclohexanecarboxylic acid, namely trans-4-tert-butyl sulfinyl amine cyclohexanecarboxylic acid is subjected to tert-butyl sulfinyl protection removal and di-tert-butyl dicarbonate condensation, and ester hydrolysis is carried out to obtain trans-4- (tert-butyloxycarbonylamino) cyclohexanecarboxylic acid, or tert-butyl sulfinyl protection removal and ester hydrolysis are carried out firstly, and di-tert-butyl dicarbonate condensation is carried out to obtain trans-4- (tert-butyloxycarbonylamino) cyclohexanecarboxylic acid.
Has the advantages that: the invention adopts an intermediate obtained by condensing a chiral ligand reagent, namely tert-butyl sulfinamide and 4-oxocyclohexanecarboxylic acid tert-butyl ester, so that the reduction reaction has high stereoselectivity, the proportion of trans-products is more than 95%, a very small amount of cis-products are removed through a post-treatment step, and meanwhile, the tert-butyl sulfinyl group is stable under an alkaline condition and is easy to leave under an acidic condition, the reaction is easy to control, the reaction condition is mild, the operation is simple and convenient, the yield is high, and the industrial production is easy to realize.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples.
EXAMPLE 1 preparation of trans-4-tert-butylsulfinamide cyclohexanecarboxylic acid ester
To 150ml of a toluene solution of 17g of ethyl 4-ketocyclohexanecarboxylate were added 14.5g (1.2 eq) of (R) -tert-butylsulfinamide and 44ml (1.2 eq) of ethyl titanate at room temperature, and the mixture was stirred at 70 ℃ for 1 hour. After the reaction, cooling to room temperature, adding 6.4g (1.5 eq) of sodium borohydride in portions, stirring for 2 hours, adding 50ml (quenching) of methanol after the reaction, and continuing stirring for 30 minutes, wherein the ratio of the trans-product to the cis-product is 90:10, the mixture was washed with brine and the organic phase was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to give 22g of the desired product in 80% yield. LC/MS:275.
EXAMPLE 2 preparation of trans-4-tert-Butylsulfonamide cyclohexanecarboxylate
14.5g (1.2 eq) of (R) -tert-butylsulfinamide and 44ml (1.2 eq) of ethyl titanate were added to 150ml of a toluene solution of 19.8g of tert-butyl 4-ketocyclohexanecarboxylate at room temperature, and the mixture was stirred at 70 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding 6.4g (1.5 eq) of sodium borohydride in batches, stirring for 2 hours, adding 50ml of methanol after the reaction is finished, and continuing stirring for 30 minutes, wherein the ratio of the trans-product to the cis-product is 98:2, the mixture was washed with brine and the organic phase was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to give 28g of the desired product in 92.5% yield. LC/MS 303.
EXAMPLE 3 preparation of trans-4-tert-butylsulfinamide cyclohexanecarboxylate
To 150ml of a toluene solution containing 15.6g of methyl 4-ketocyclohexanecarboxylate was added 14.5g (1.2 eq) of (R) -tert-butylsulfinamide and 44ml (1.2 eq) of ethyl titanate at room temperature, and the mixture was stirred at 70 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding 6.4g (1.5 eq) of sodium borohydride in batches, stirring for 2 hours, adding 50ml of methanol after the reaction is finished, and continuing stirring for 30 minutes, wherein the proportion of the trans-product to the cis-product is 91:9 washing with saturated brine, filtering off insoluble matter from the organic phase, and concentrating under reduced pressure to obtain 20.6g of the objective compound with a yield of 79%. LC/MS:261.
EXAMPLE 4 preparation of trans-4-tert-Butylsulfonamide cyclohexanecarboxylate
19.8g of tert-butyl 4-ketocyclohexanecarboxylate and 12.7g (1.05 eq) of (S) -tert-butylsulfenamide, 50ml of dichloromethane and 31.7ml (1.1 eq) of tetraisopropyl titanate are added into a reaction bottle at 0 ℃, the temperature is raised to 60 ℃, stirring is carried out for reaction for 12 hours, the temperature is lowered to 0 ℃ after the reaction is finished, 25.5g (2 eq) of sodium triacetoxyborohydride is added, the temperature is raised to 60 ℃, and stirring is carried out for reaction for 1 hour. TLC followed the progress of the reaction, and the ratio of trans to cis product was 95: after the reaction, a saturated sodium bicarbonate solution was added, a 10% methanol/dichloromethane mixed solvent was added, liquid separation was performed, drying was performed with anhydrous sodium sulfate, and concentration was performed under reduced pressure to obtain 27.2g of the objective compound with a yield of 90%. LC/MS 303.
EXAMPLE 5 preparation of trans-4-tert-Butylsulfonamide cyclohexanecarboxylate
18.1g (1.5 eq) of (R) -tert-butylsulfinamide and 55ml (1.5 eq) of ethyl titanate were added to 150ml of a toluene solution of 19.8g of tert-butyl 4-ketocyclohexanecarboxylate at room temperature, and the mixture was stirred at 70 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding 8.5g (2 eq) of sodium borohydride in batches, stirring for 2 hours, wherein the ratio of the trans-product to the cis-product is 95: after completion of the reaction, 50ml of ethanol was added thereto, and the mixture was stirred for 30 minutes, followed by addition of saturated brine, filtration of insoluble matter and concentration under reduced pressure to obtain 27.5g of the objective compound (yield: 90.8%). LC/MS 303.
EXAMPLE 6 preparation of trans 4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid
30.3g of tert-butyl trans-4-tert-butylsulfinylcyclohexanecarboxylate and 100mL of methanol were added at 0 ℃ and 100mL of 1M aqueous lithium hydroxide (1 eq) was added dropwise with stirring and stirred overnight. After TLC monitoring of the reaction, 5ml of water was added and the pH was adjusted to 3 with 1M HCl solution. The mother liquor solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 6.71g of 4-tert-butylsulfinylaminocyclohexanecarboxylic acid in 27.2% yield. HPLC:99.4%, LC/MS:247.
Under ice bath, 24.7g of 4-tert-butylsulfinylcyclohexanecarboxylic acid and 150ml of dichloromethane were added, 37ml (5 eq) of trifluoroacetic acid was slowly added, and the mixture was stirred at room temperature for 1 hour, the solvent was distilled under reduced pressure, methyl tert-butyl ether was added, and the mixture was slurried and filtered to obtain 14g of the objective 4-aminocyclohexanecarboxylic acid with a yield of 99%. 143 for LC/MS.
14.3g of trans-4-aminocyclohexanecarboxylic acid, 70ml of dimethylformamide, 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 16.7ml (1.2 eq) of triethylamine were added at room temperature, and the mixture was stirred and reacted for 18 hours, after the reaction was completed, a saturated ammonium chloride solution was added, and the mixture was filtered, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 23g of the objective compound with a yield of 95%. HPLC:99.3%, LC/MS:243.
EXAMPLE 7 preparation of trans 4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid
30.3g of tert-butyl trans-4-tert-butylsulfinylcyclohexanecarboxylate and 100mL of ethanol were added at 0 ℃ and 100mL of 2M aqueous sodium hydroxide (2 eq) were added dropwise with stirring and stirred overnight. After TLC monitoring of the reaction, 5ml of water was added and the pH was adjusted to 3 with 1M HCl solution. The mother liquor solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 5.68g of 4-tert-butylsulfinylaminocyclohexanecarboxylic acid in 23% yield. HPLC:99.4%, LC/MS:247.
Under ice bath, 24.7g of 4-tert-butylsulfinylcyclohexanecarboxylic acid and 150ml of dichloromethane are added, 37ml (5 eq) of trifluoroacetic acid is slowly added, the mixture is stirred for 1 hour at room temperature, the solvent is distilled under reduced pressure, methyl tert-butyl ether is added, the mixture is pulped and filtered to obtain 14g of the target 4-aminocyclohexanecarboxylic acid with the yield of 99 percent. 143 for LC/MS.
14.3g of trans 4-aminocyclohexanecarboxylic acid, 70ml of dimethylformamide, 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 27.8ml (2 eq) of triethylamine were added at room temperature, and the mixture was stirred and reacted for 18 hours, and after the reaction, a saturated ammonium chloride solution was added, followed by filtration, extraction with dichloromethane, drying over anhydrous sodium sulfate and concentration under reduced pressure to obtain 22.3g of the objective compound with a yield of 91.7%. HPLC:99.3%, LC/MS:243.
EXAMPLE 8 preparation of trans 4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid
Adding 30.3g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid tert-butyl ester and 150ml of dichloromethane under ice bath, stirring for dissolving, slowly adding 37ml of trifluoroacetic acid (5 eq), stirring at room temperature for 1 hour, concentrating the solvent under reduced pressure after the reaction is finished, cooling to 0 ℃, adding 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 16.7ml (1.2 eq) of triethylamine, stirring for reacting for 20 hours, adding a saturated ammonium chloride solution after the reaction is finished, washing with a saturated sodium bicarbonate solution, and drying with anhydrous sodium sulfate. Vacuum concentrating to obtain 21.87g of target product with yield of 90%. LC/MS 243.
Example 9
Adding 30.3g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid tert-butyl ester and 135ml of absolute ethanol under ice bath, stirring for dissolving, slowly adding 20ml (2 eq) of a dioxane solution of 4M hydrogen chloride, stirring at room temperature for 6 hours, concentrating the solvent under reduced pressure after the reaction is finished, adding 300ml of dichloromethane, cooling to 0 ℃, adding 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 16.7ml (1.2 eq) of triethylamine, stirring for reacting for 20 hours, adding a saturated ammonium chloride solution after the reaction is finished, washing with a saturated sodium bicarbonate solution, and drying with anhydrous sodium sulfate. Vacuum concentration to obtain 21.5g of target product with yield of 72%. 299 LC/MS.
30g of tert-butyl 4- (tert-butoxycarbonylamino) cyclohexanecarboxylate and 100mL of methanol were added at 0 ℃ and 50mL (2 eq) of an aqueous solution of 2M lithium hydroxide was added dropwise with stirring and stirred overnight for 4 hours. After TLC monitoring of the reaction, 5ml of water was added and the pH was adjusted to 3 with 1M HCl solution. The mother liquor solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6.92g of the target product in 28.5% yield. HPLC:99.4%, LC/MS:243.
EXAMPLE 10 preparation of trans 4- (tert-Butoxycarbonylamino) cyclohexanecarboxylic acid
Adding 30.3g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid tert-butyl ester and 150ml of dichloromethane under ice bath, stirring for dissolving, slowly adding 37ml of trifluoroacetic acid (5 eq), stirring at room temperature for 1 hour, concentrating the solvent under reduced pressure after the reaction is finished, cooling to 0 ℃, adding 43.6g (2 eq) of di-tert-butyl dicarbonate and 27.8ml (2 eq), stirring for reacting for 20 hours, adding a saturated ammonium chloride solution after the reaction is finished, washing with the saturated sodium bicarbonate solution, and drying with anhydrous sodium sulfate. Vacuum concentrating to obtain target product 21.8g, yield 89.9%. LC/MS 243.
Example 11
27.5g of ethyl trans-4-tert-butylsulfinylcyclohexanecarboxylate and 100mL of methanol were added at 0 ℃ and 2M aqueous sodium hydroxide solution (50 mL (1 eq)) was added dropwise with stirring and stirred overnight for 4 hours. After TLC monitoring of the reaction, 5ml of water was added and the pH was adjusted to 3 with 1M HCl solution. The mother liquor solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 21.76g of the target 4-tert-butylsulfinylcyclohexanecarboxylic acid in 88% yield. HPLC:99.4%, LC/MS:247.
Example 12
26.1g of methyl trans-4-tert-butylsulfinylcyclohexanecarboxylate and 100mL of methanol were added at 0 ℃ and 100mL of 1M aqueous solution of lithium hydroxide (1 eq) was added dropwise with stirring and stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to 1 with 1M HCl solution. The mother liquor solution is extracted by dichloromethane, dried by anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain 21g of the target product, namely the trans-4-tert-butylsulfinylcyclohexanecarboxylic acid, the yield is 85 percent, and LC/MS is 247.
Example 13
Adding 27.5g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid ethyl ester and 150ml of dichloromethane into the mixture under ice bath, stirring the mixture for dissolving, slowly adding 37ml of trifluoroacetic acid (5 eq) into the mixture, stirring the mixture at room temperature for 1 hour, concentrating the solvent under reduced pressure after the reaction is finished, cooling the mixture to 0 ℃, adding 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 16.7ml (1.2 eq) of triethylamine into the mixture, stirring the mixture for reacting for 20 hours, adding a saturated ammonium chloride solution into the mixture after the reaction is finished, washing the mixture with a saturated sodium bicarbonate solution, and drying the mixture with anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to give 16.2g of ethyl trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylate as a target substance in a yield of 60%. LC/MS:271.
Example 14
Adding 26.1g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid methyl ester and 150ml of dichloromethane under ice bath, stirring for dissolving, slowly adding 37ml of trifluoroacetic acid (5 eq), stirring for 1 hour at room temperature, concentrating the solvent under reduced pressure after the reaction is finished, cooling to 0 ℃, adding 26.2g (1.2 eq) of di-tert-butyl dicarbonate and 16.7ml (1.2 eq) of triethylamine, stirring for reacting for 20 hours, adding a saturated ammonium chloride solution after the reaction is finished, washing with a saturated sodium bicarbonate solution, and drying with anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to give 14.3g of the desired methyl 4- (tert-butoxycarbonylamino) cyclohexanecarboxylate (yield: 55.8%). And 257 LC/MS.
The above description is for the purpose of describing the invention in more detail with reference to specific preferred embodiments, and it should not be construed that the embodiments of the invention are limited to those described herein, and it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (2)
1. A preparation method of trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester is characterized by comprising the following preparation steps:
the reaction formula is as follows:
r is t-Bu;
dissolving 4-oxocyclohexane carboxylate and tert-butyl sulfinamide in an organic solvent at room temperature, heating to 70 ℃ under the catalysis of Lewis acid for reaction, cooling to room temperature after the reaction is finished, adding a reducing agent, stirring for reduction reaction, quenching the reaction after the reaction is finished, washing, and concentrating under reduced pressure to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate; the organic solvent is selected from dichloromethane, toluene or a mixture thereof in any proportion; the reducing agent is selected from sodium borohydride or sodium triacetoxyborohydride; the Lewis acid reagent is selected from ethyl titanate or tetraisopropyl titanate; the molar ratio of the 4-oxocyclohexanecarboxylate to the Lewis acid is 1.1 to 1.5; the molar ratio of the 4-oxocyclohexanecarboxylic acid ester to the tert-butyl sulfenamide is 1.05-1.5; the molar ratio of the ethyl 4-oxocyclohexanecarboxylate to the reducing agent is 1.5-2.0.
2. A preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is characterized by comprising the following preparation steps:
1) The method according to claim 1, wherein 4-oxocyclohexane carboxylate and chiral ligand reagent tert-butyl sulfinamide are used as raw materials, and are subjected to reductive amination under catalysis of Lewis acid to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate, and the reaction formula is as follows:
r is methyl, ethyl or tert-butyl;
2) Deprotection and amino protection:
comprises a step of removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinyl cyclohexane carboxylic ester under an acidic condition to obtain trans-4-aminocyclohexane carboxylic acid or ester thereof, a step of condensing with di-tert-butyl dicarbonate under an alkaline condition, and a step of hydrolyzing ester under an alkaline condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid when ester group exists;
specifically, the method comprises the following steps: when R is methyl or ethyl, the deprotection and amino protection steps are as follows:
in the presence of a solvent, removing tert-butyl sulfinyl from trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester under an acidic condition to obtain trans-4-aminocyclohexane carboxylic ester, then condensing with di-tert-butyl dicarbonate under a basic condition, and finally performing ester hydrolysis under the basic condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid, wherein the reaction formula is as follows:
the solvent is selected from ethanol, dioxane, dichloromethane, ethyl acetate and dimethylformamide; the acid is one of trifluoroacetic acid, hydrogen chloride or aqueous solution thereof; the base is selected from triethylamine, sodium hydroxide and lithium hydroxide; the molar weight of the acid is 1.0-5.0 equivalent of the dosage of the trans-4-tert-butylsulfinylamine cyclohexanecarboxylate, the molar weight of the base is 1.0-2.0 equivalent of the dosage of the di-tert-butyl dicarbonate, and the molar weight of the base for hydrolysis is 1.0-2.0 equivalent of the dosage of the trans-4-tert-butoxycarbonylamino cyclohexanecarboxylate;
when R is tert-butyl, the deprotection and amino protection steps are as follows:
the acid is trifluoroacetic acid, trans-4-tert-butyl sulfinyl amine cyclohexane carboxylic ester is subjected to tert-butyl sulfinyl removal under an acidic condition to obtain trans-4-aminocyclohexane carboxylic acid, and then is condensed with di-tert-butyl dicarbonate under an alkaline condition to obtain trans-4- (tert-butoxycarbonylamino) cyclohexane carboxylic acid, wherein the reaction formula is as follows:
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| CN202110655879.3A CN113402428B (en) | 2021-06-11 | 2021-06-11 | Preparation method of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and intermediate thereof |
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