CN111620788B - Method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether - Google Patents
Method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether Download PDFInfo
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Abstract
The invention discloses a method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, which comprises the steps of taking 3-carbonyl-bicyclo [2.2.2] octane-2-formate as a raw material, and sequentially carrying out condensation, reduction, basic configuration inversion and acidic removal of a protecting group to obtain the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, wherein R is an organic substituent group. The synthesis route is short, the reaction condition is mild, and the total yield is more than 80%; by means of chiral induction, a high chiral pure intermediate can be obtained, and the chiral purity of a target product is improved to more than 99.5%; the used raw materials are easily available bulk raw materials, the equipment requirement is low, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis of medical intermediates, relates to a medical intermediate, and particularly relates to a method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate.
Background
The (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate is a small molecule drug intermediate with two chiral centers, and the chiral segment is widely used for developing new drugs of influenza virus RNA polymerase inhibitors, wherein the most representative is pimodivir developed by Vertex company in the United states, and the clinical phase III research stage is entered.
At present, the synthesis of a structural fragment of (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate is reported mainly by the following four routes, three of which use cyclohexadiene as starting material:
route one, as shown in the patent report route one below. According to the method, cyclohexadiene and maleic anhydride are used as starting materials, a Diels-Alder reaction (Diels-Alder reaction) is carried out to obtain cis-form anhydride, further selective alcoholysis is carried out to obtain cis-form carboxylic ester, the ester group configuration is reversed under the strong alkali condition, finally diphenyl azide phosphate is used for carrying out Cotiss rearrangement (Curtius rearrargement), and debenzylation oxycarbonyl is carried out to obtain a target product. However, the main disadvantages of this route include the high price of the chiral catalyst, quinoline butane, in selective alcoholysis; explosive azide is needed, so that potential safety hazards exist; the overall yield is less than 20%.
Route two, shown in the following patent report route two. The method also takes cyclohexadiene as a starting material, and after the cyclohexadiene and ethyl propiolate are subjected to Diels-Alder reaction, double bonds are selectively reduced by hydrogenation, and the cyclohexadiene and chiral amino anions are subjected to Michael addition reaction at low temperature, and finally two protecting groups are removed to obtain the target compound.
This route also has a number of disadvantages. Firstly, the use of the expensive propionate has higher cost; secondly, in the process of selectively reducing double bonds, a special metal catalyst is used; the subsequent addition reaction uses severe conditions such as ultralow temperature and the like, and the chiral selectivity is poor.
Route three, shown in the patent report route three below.
Although the route is short, the main problem is that the starting material is unstable, and the use of nitromethane and the intermediate containing the nitro group brings great safety risk to the production.
Route four, shown in the following patent report route four, is one of the routes invented by me. The route solves the problems of higher preparation cost, low material safety, difficult production amplification and the like of the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether, but the route still has a space for further improvement by using a high-temperature hydrogenation process.
Although the existing method can meet the requirements of the medical market on the intermediate, in order to further improve the chiral selectivity, simplify the production operation procedure and improve the production efficiency, a new synthesis method is still necessary.
Disclosure of Invention
Based on this, in view of the above disadvantages of the respective methods for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate, it is necessary to provide a method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate, which can further improve the chiral selectivity, simplify the production operation procedure and improve the production efficiency, in order to solve the problems of low chiral selectivity, low production efficiency and high production cost in the preparation process.
The invention relates to a method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, which takes 3-carbonyl-bicyclo [2.2.2] octane-2-formate as a raw material, and sequentially carries out condensation, reduction, ester group configuration inversion and protective group removal with S-tert-butyl sulfinamide to obtain the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, wherein the reaction process is as follows:
wherein R is an organic substituent group.
In one embodiment, R is selected from methyl, ethyl, propyl, butyl, phenyl or benzyl.
In one embodiment, the step of preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate is:
s1, in the presence of a catalyst, carrying out condensation reaction on 3-carbonyl-bicyclo [2.2.2] octane-2-formate and S-tert-butyl sulfinamide to obtain (2R,3S) -3- ((S) -tert-butyl sulfinylamino) -bicyclo [2.2.2] octene-2-formate;
s2, reducing or catalytically hydrogenating (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octene-2-carboxylate obtained in S1 under the condition of a reducing agent to obtain (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate;
s3, under the strong alkali condition, the ester group configuration of the (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate obtained in the S2 is reversed to obtain (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate;
s4, removing the protecting group from the (2S,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate obtained in S3 under an acidic condition to obtain (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate.
In one embodiment, the catalyst is ethyl titanate.
In one embodiment, the reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, or sodium trifluoroacetyloxyborohydride.
In one embodiment, the strong base is at least one of sodium tert-amylate, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
In one embodiment, the acidic conditions are selected from a methanol/hydrogen chloride system, an ethanol/hydrogen chloride system, or a dioxane/hydrogen chloride system.
Compared with the prior art, the method for preparing the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether has the following beneficial effects:
1. the method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether has the advantages of short synthetic route, mild reaction conditions and total yield of more than 80%;
2. the method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether can obtain a high chiral pure intermediate in a chiral induction mode, and the chiral purity of a target product is improved to more than 99.5%;
3. the raw materials used in the method for preparing the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether are easily available bulk raw materials, have low equipment requirement and are suitable for large-scale industrial production.
Detailed Description
The embodiments in the description are only for illustrating the present invention and do not limit the scope of the present invention. The scope of the present invention is defined only by the appended claims, and any omissions, substitutions, or modifications made based on the embodiments disclosed herein will fall within the scope of the present invention.
As used herein, the terms "comprises," "comprising," "includes," "including," "contains," "characterized by," and grammatical equivalents thereof are inclusive or open-ended terms that do not exclude additional unrecited elements or method steps, but also include the more limiting terms "consisting of and" consisting essentially of, and grammatical equivalents thereof. As used herein, the term "may" when used in reference to a material, structure, feature, or method acts means that it is contemplated to implement an embodiment of the invention and such term is used in preference to the more limiting term "is" to avoid any implication: other compatible materials, structures, features and methods that may be used in combination therewith should or must be excluded.
The present invention will be further described in detail with reference to the following examples, which are provided for illustration only and are not to be construed as limiting the scope of the present invention.
The invention relates to a method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, which takes 3-carbonyl-bicyclo [2.2.2] octane-2-formate as a raw material, and sequentially carries out condensation, reduction, ester configuration inversion and protective group removal with S-tert-butyl sulfenamide to obtain the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, wherein the reaction process is as follows:
wherein R is an organic substituent group.
The term "organic substituent" refers to a group that replaces a hydrogen atom in an organic compound in organic chemistry.
The 3-carbonyl-bicyclo [2.2.2] octane-2-formate can obtain high chiral purity (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate in a chiral induction mode, the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate is a key intermediate for synthesizing an influenza virus RNA polymerase inhibitor pimodivir,
while 3-carbonyl-bicyclo [2.2.2] octane-2-carboxylate can be obtained by sequentially carrying out catalytic hydrogenation and condensation using 2- (4-alkoxycarbonylcyclohexylidene) acetate as a starting material, 2- (4-alkoxycarbonylcyclohexylidene) acetate is very common and easily available, and the process for obtaining 3-carbonyl-bicyclo [2.2.2] octane-2-carboxylate is short and the total yield is more than 80%, so that 3-carbonyl-bicyclo [2.2.2] octane-2-carboxylate is also easily obtained.
The term "catalytic hydrogenation" refers to the reaction of molecular addition of hydrogen to unsaturated groups of an organic compound under the action of a catalyst.
Further synthesizing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate, 3-carbonyl-bicyclo [2.2.2] octane-2-formate is taken as a raw material, condensation, reduction, ester configuration inversion and protective group removal with S-tertiary butyl sulfinamide are sequentially carried out, wherein the condensation with S-tert-butylsulfinamide is a condensation reaction of 3-carbonyl-bicyclo [2.2.2] octane-2-formate with S-tert-butylsulfinamide in the presence of a catalyst, and further reduction reaction can be carried out after the condensation reaction, so as to selectively generate (2R,3S) -3- ((S) -tert-butylsulfenamide) -bicyclo [2.2.2] octene-2-formate; the reduction is carried out by reducing the carbon-carbon double bond of (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octene-2-carboxylate using a reducing agent to form (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate; then under the strong alkali condition, the ester group configuration inversion occurs to generate (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate; the removal of the protecting group is carried out by removing the protecting group from (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate under acidic conditions to obtain (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate.
The method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether has the advantages of short synthetic route, mild reaction conditions and total yield of more than 80%; by means of chiral induction, a high chiral purity intermediate can be obtained, and the chiral purity of a target product is improved to more than 99.5%; the raw materials used in the preparation process are easily available bulk raw materials, the equipment requirement is low, and the method is suitable for large-scale industrial production.
In view of the above, it can be concluded that the steps for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate are as follows:
s1, in the presence of a catalyst, carrying out condensation reaction on 3-carbonyl-bicyclo [2.2.2] octane-2-formate and S-tert-butylsulfinamide to obtain (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octene-2-formate;
s2, reducing or catalytically hydrogenating (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octene-2-carboxylate obtained in S1 under the condition of a reducing agent to obtain (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate;
s3, under the strong alkali condition, the ester group configuration of the (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate obtained in the S2 is reversed to obtain (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate;
s4, deprotecting the (2S,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate obtained in S3 under acidic conditions to obtain (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate.
And R is selected from methyl, ethyl, propyl, butyl, phenyl or benzyl.
R is preferably ethyl in view of availability of materials.
The catalyst is ethyl titanate.
Under the action of catalyst ethyl titanate, 3-carbonyl-bicyclo [2.2.2] octane-2-formate and S-tert-butyl sulfenamide are subjected to condensation reaction, and then reduction reaction is continuously carried out to generate (2R,3S) -3- ((S) -tert-butyl sulfenamide) -bicyclo [2.2.2] octane-2-formate.
Ensure that the 3-carbonyl-bicyclo [2.2.2] octane-2-formate reacts with S-tert-butylsulfinamide to obtain (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate.
The reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride or sodium trifluoroacetyloxyborohydride.
To improve selectivity, the reducing agent is preferably sodium borohydride.
The strong base is at least one of sodium tert-amylate, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide.
The strong base is preferably sodium tert-amylate.
The acidic conditions are selected from a methanol/hydrogen chloride system, an ethanol/hydrogen chloride system or a dioxane/hydrogen chloride system.
The acidic conditions are preferably an ethanol/hydrogen chloride system.
For further details, the specific steps for preparing 3-carbonyl-bicyclo [2.2.2] octane-2-carboxylate are as follows:
synthesis of (2R,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate
Adding tetrahydrofuran, 3-carbonyl-bicyclo [2.2.2] octane-2-formate, ethyl titanate and S-tert-butyl sulfenamide into a reaction bottle, and heating and carrying out reflux reaction for 3-5 hours under the protection of nitrogen; cooling, distilling under reduced pressure to remove tetrahydrofuran, adding isobutyric acid into the residue, cooling to 0-10 ℃, controlling the reaction temperature, and adding a reducing agent; after the reaction is finished, 20% of sodium hydroxide aqueous solution is dropwise added, the pH value is adjusted to be 7-8, ethyl acetate is extracted (500mL x 2), the combined organic phase is filtered through silica gel, and the organic phase is concentrated under reduced pressure to obtain (2R,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-ethyl formate which is directly used in the next step;
synthesizing (2S,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester in a reaction bottle, adding tetrahydrofuran and strong base, dropwise adding the obtained tetrahydrofuran solution of (2R,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester (the proportion of 100g dissolved in 300mL of tetrahydrofuran) under the protection of nitrogen, and reacting at room temperature for 2-3 hours after dropwise adding; transferring the reaction solution into an acetic acid aqueous solution for quenching; adding ethyl acetate for extraction, standing, layering, extracting the water layer with ethyl acetate, drying the combined organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure for the next step;
synthesis of ethyl (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate
Dissolving the (2S,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-ethyl formate obtained in the step into ethanol, dropwise adding a 15% system solution under an acidic condition at room temperature under the protection of nitrogen, and reacting for 8-9 hours at room temperature after dropwise adding; concentrating under reduced pressure to remove the solvent, adding ethyl acetate into the residue, stirring at room temperature for 2-3 hours, filtering, washing the filter cake with ethyl acetate, suspending the filter cake in ethyl acetate, adding water, adjusting the pH value to 8-9 with 15% sodium hydroxide solution, standing, and separating an organic layer; the aqueous layer was extracted once with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester.
The solvent used primarily in the present invention is tetrahydrofuran, but other solvents such as methanol, ethanol, isopropanol, t-amyl alcohol, toluene or tetrahydrofuran are also suitable.
It should be noted that the temperature of heating reflux mentioned in the present invention is the boiling point of the solvent used in the preparation process.
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more clearly understand the advantages and features of the present invention and to clearly define the scope of the present invention.
Example 1
When R is selected from methyl, the synthetic route is as follows:
the specific synthesis steps are as follows:
1. synthesis of ethyl (2R,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate
Adding 1L of tetrahydrofuran, 93g of 3-carbonyl-bicyclo [2.2.2] octane-2-ethyl formate, 232.5g of ethyl titanate and 64.9g S-tert-butylsulfinamide into a 2L reaction bottle, heating and refluxing for reaction for 3 hours under the protection of nitrogen, cooling, distilling out THF under reduced pressure, adding 600mL of isobutyric acid into a residue, cooling to 0-10 ℃, controlling the reaction temperature, and adding 21.2g of sodium borohydride; after the reaction is finished, 20% of sodium hydroxide aqueous solution is dropwise added, the pH is adjusted to 7-8, ethyl acetate is extracted (500mL x 2), the combined organic phases are filtered through silica gel, and the organic phases are concentrated under reduced pressure to obtain 127.26g of (2R,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-ethyl formate which is directly used in the next step;
2. synthesis of ethyl (2S,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate
A2L reaction flask was charged with 500mL of tetrahydrofuran, 73.6g of sodium tert-amylate, and a tetrahydrofuran solution of ethyl (2R,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-carboxylate (100g dissolved in 300mL of tetrahydrofuran) was added dropwise under nitrogen. After the dropwise addition, reacting at room temperature for 2 hours; transferring the reaction solution into an acetic acid aqueous solution for quenching; adding 500mL of ethyl acetate for extraction, standing, layering, extracting the water layer with 300mL of ethyl acetate once again, drying the combined organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to be directly used in the next step;
3. synthesis of ethyl (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate
Dissolving the (2S,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-ethyl formate obtained in the step into 400mL of ethanol, dropwise adding 200mL of 15% hydrogen chloride ethanol solution at room temperature under the protection of nitrogen, and reacting for 8 hours at room temperature after dropwise adding; concentrating under reduced pressure to remove the solvent, adding 200mL of ethyl acetate into the residue, stirring at room temperature for 2 hours, filtering, washing the filter cake with 100mL of ethyl acetate, suspending the filter cake in 200mL of ethyl acetate, adding 50mL of water, submitting to pH 8-9 with 15% sodium hydroxide solution, standing, and separating an organic layer; the aqueous layer was extracted once with 100mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 57.40g of (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester.
Example 1 yield 86.4%, chiral purity 99.6%.
Example 2
When R is selected from ethyl, the synthetic route is as follows:
1. synthesis of ethyl (2R,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate
Adding 1L of tetrahydrofuran, 100g of 3-carbonyl-bicyclo [2.2.2] octane-2-ethyl formate, 232.5g of ethyl titanate and 64.9g S-tert-butylsulfenamide into a 2L reaction bottle, heating and refluxing for reaction for 3 hours under the protection of nitrogen, cooling, distilling under reduced pressure to remove THF, adding 600mL of isobutyric acid into a residue, cooling to 0-10 ℃, controlling the reaction temperature, and adding 21.2g of sodium borohydride; after the reaction was completed, 20% aqueous sodium hydroxide solution was added dropwise to adjust PH 7-8, ethyl acetate was extracted (500mL × 2), and the combined organic phases were filtered through silica gel and concentrated under reduced pressure to obtain 143.42g of ethyl (2R,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-carboxylate, which was used in the next step with a yield of 94%;
2. synthesis of ethyl (2S,3S) -3- (S-tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate
500mL of tetrahydrofuran and 73.6g of sodium tert-amylate are added into a 2L reaction flask, a tetrahydrofuran solution of ethyl (2R,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-carboxylate (100g is dissolved in 300mL of tetrahydrofuran) is dropwise added under the protection of nitrogen, and the mixture reacts for 2 hours at room temperature after the dropwise addition; transferring the reaction solution into an acetic acid aqueous solution for quenching; adding 500mL of ethyl acetate for extraction, standing, layering, extracting the water layer with 300mL of ethyl acetate once again, drying the combined organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to be directly used in the next step;
3. synthesis of ethyl (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate
Dissolving the (2S,3S) -3- (S-tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-ethyl formate obtained in the step into 400mL of ethanol, dropwise adding 200mL of 15% hydrogen chloride ethanol solution at room temperature under the protection of nitrogen, and reacting for 8 hours at room temperature after dropwise adding; the solvent was removed by concentration under reduced pressure, and 200mL of ethyl acetate was added to the residue, which was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 100mL of ethyl acetate. The filter cake was suspended in 200mL of ethyl acetate, 50mL of water was added, and the pH was raised to 8-9 with 15% sodium hydroxide solution. Standing, and separating an organic layer; the aqueous layer was extracted once with 100mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 59.30g of ethyl (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-carboxylate.
Example 2 yield 90%, chiral purity 99.8%.
The technical features of the above embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the above embodiments are not described, but should be considered as the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above embodiments are described in more detail and with reference to specific details, but the invention is not to be construed as being limited thereto. 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 (1)
1. A method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate is characterized in that 3-carbonyl-bicyclo [2.2.2] octane-2-formate is used as a raw material, and the (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate is obtained by sequentially carrying out condensation, reduction, ester group configuration inversion and protecting group removal, wherein the reaction process is as follows:
the preparation method comprises the following steps:
s1, reacting 3-carbonyl-bicyclo [2.2.2] octane-2-formate with S-tert-butyl sulfenamide in the presence of a catalyst to obtain (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octene-2-formate;
s2, in the presence of a reducing agent, reducing or catalytically hydrogenating the (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octene-2-carboxylate obtained in S1 to obtain (2R,3S) -3- ((S) -tert-butylsulfonamido) -bicyclo [2.2.2] octane-2-carboxylate;
s3, under the strong alkali condition, the ester group configuration of the (2R,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate obtained in the S2 is reversed to obtain (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate;
s4, removing a protecting group from the (2S,3S) -3- ((S) -tert-butylsulfinylamino) -bicyclo [2.2.2] octane-2-formate obtained in S3 under an acidic condition to obtain (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate;
wherein R is methyl, ethyl, propyl or butyl;
the catalyst is ethyl titanate, the reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride or sodium trifluoroacetyloxyborohydride, the strong base is at least one of sodium tert-amylate, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide, and the acidic condition is selected from a methanol/hydrogen chloride system, an ethanol/hydrogen chloride system or a dioxane/hydrogen chloride system.
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