CN111393329A - Preparation method of ritonavir and lopinavir intermediate - Google Patents

Preparation method of ritonavir and lopinavir intermediate Download PDF

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CN111393329A
CN111393329A CN202010301653.9A CN202010301653A CN111393329A CN 111393329 A CN111393329 A CN 111393329A CN 202010301653 A CN202010301653 A CN 202010301653A CN 111393329 A CN111393329 A CN 111393329A
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dibenzylamino
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diphenylhexane
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amino
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李天赋
祝飞
祝莉
丁杨杨
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Anhui Province Yifan Spice Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract

The invention discloses a preparation method of ritonavir and lopinavir intermediates, which comprises the steps of taking L-phenylalanine as a raw material, reacting with benzyl chloride in potassium carbonate and an alkaline aqueous solution to obtain N, N-dibenzylamino-L-benzyl phenylalanine, condensing with acetonitrile under the action of sodium amide, carrying out addition reaction with benzyl magnesium chloride, reducing enamine and carbonyl by sequentially using sodium borohydride/methanesulfonic acid and sodium borohydride/trifluoroacetic acid reagents, obtaining a stereoselective product dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane under the induction action of a chiral inducer, reacting a stereoselective product with di-tert-butyl methyl dicarbonate in a potassium carbonate/tetrahydrofuran solution, and carrying out reductive debenzylation by using ammonium formate and palladium/carbon to obtain an intermediate BDH.

Description

Preparation method of ritonavir and lopinavir intermediate
Technical Field
The invention relates to the technical field of synthesis of antiviral drug intermediates, and in particular relates to a preparation method of ritonavir and lopinavir intermediates.
Background
Ritonavir (Ritonavir) has the chemical name: (2S,3S,5S) -5- (N (((N-methyl-N- ((2-isopropyl-4-thiazole) methyl) amino) carbonyl) valinyl) amino) -2- (N- (5-thiazole) methoxycarbonyl) amino) -1, 6-diphenyl-3-hydroxyhexane, having the formula:
Figure BDA0002454218430000011
ritonavir has four chiral centers and, depending on its molecular structure, can be divided into three sections by a retrosynthetic design: the intermediates (2S,3S,5S) -2-amino-3-hydroxy-5-tert-butoxycarboxamido-1, 6-diphenylhexane, 5-HMT and 2-isopropyl-4- (((N-methyl) amino) methyl) thiazole. As follows:
Figure BDA0002454218430000021
BDH, i.e. (2S,3S,5S) -2-amino-3-hydroxy-5-tert-butoxycarboxamido-1, 6-diphenylhexane, [ CAS No. ]144163-85-9, is a common key intermediate for the production of ritonavir and lopinavir, and is also a core fragment of ritonavir and lopinavir, having the formula:
Figure BDA0002454218430000022
BDH, namely (2S,3S,5S) -2-amino-3-hydroxy-5-tert-butoxyformamido-1, 6-diphenylhexane, has 3 chiral centers per se, and the key to the synthesis lies in the introduction of the chiral centers. The patent publication No. CN101967130A discloses a method for synthesizing ritonavir intermediate, which provides a method for synthesizing intermediate BDH, (S, Z) -5-amino-2- (dibenzylamino) -1, 6-diphenylhexane-4-en-3-one, which is subjected to carbonyl reduction and C ═ C reduction to obtain (2S,3S,5S) -5-amino-2- (N, N-dibenzylamino) -3-hydroxy-1, 6-diphenylhexane, which is protected with t-butoxycarbonyl BOC to obtain (2S,3S,5S) -2- (N, N-dibenzylamino) -3-hydroxy-5- (t-butoxyformylamino) -1, 6-diphenylhexane, removing benzyl by catalysis to obtain a crude product of (2S,3S,5S) -2-amino-3-hydroxy-5- (tert-butoxy formylamino) -1, 6-diphenylhexane, performing alkali washing, sodium chloride washing, crystallizing by using n-heptane, filtering to obtain a wet product, and drying to obtain a pure product.
The invention aims at the following technical problems in the prior art to design and research a scheme: (1) when 3 chiral centers are introduced, a synthesis method with high De value and high stereoselectivity cannot be obtained; (2) in the production process of BDH, the problems of long reaction steps, low product yield and more three wastes are existed.
Disclosure of Invention
In order to overcome the technical problems, the invention aims to provide a preparation method of ritonavir and lopinavir intermediates, which uses L-phenylalanine as a raw material, and the raw material is reacted with benzyl chloride in potassium carbonate and an alkaline aqueous solution to obtain N, N-dibenzylamino-L-benzyl phenylalanine, then the benzyl phenylalanine is condensed with acetonitrile under the action of sodium amide, the benzyl chloride is subjected to addition reaction to obtain 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-ene, sodium borohydride/methanesulfonic acid reagents are sequentially used to reduce enamine and carbonyl, a stereoselective product dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane is obtained under the induction action of a chiral inducer, the stereoselective product is reacted with di-tert-butylmethyl dicarbonate in a potassium carbonate/tetrahydrofuran solution to obtain a (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, the stereoselective product is reduced with di-tert-butylmethyl dicarbonate to obtain a (2S,3S, 5-tert-butoxycarbonylamino-1, 6-diphenylhexane, a high-palladium-debenzoate-carbonate-ammonium-carbonate-potassium carbonate-potassium-carbonate intermediate-bromide-enriched product, a high-enriched stereoselective.
The purpose of the invention can be realized by the following technical scheme:
the invention provides a preparation method of ritonavir and lopinavir intermediates, which comprises the following synthetic steps:
step one, L-phenylalanine is used as a raw material and reacts with benzyl chloride in potassium carbonate catalysis, an alkaline solution and a solvent to obtain N, N-dibenzylamino-L-phenylalanine benzyl ester, wherein the reaction formula is as follows:
Figure BDA0002454218430000041
step one is to select L-one with 1 chiral centerPhenylalanine is used as a raw material, 1S chiral center of the product is used as the product, the time and the cost of later chiral resolution are reduced, under the alkaline environment and the catalysis of potassium carbonate, carboxyl of one molecule of L-phenylalanine generates carboxyl negative ions, amino generates amino negative ions, and the amino generates amino negative ions which are equivalent to three times of PhCH of benzyl chloride2 +Nucleophilic substitution reaction is carried out, three benzyl methyl groups are generated simultaneously, the reaction activity of the step is good, the post-treatment is simple, and the yield is high.
Step two, carrying out condensation reaction on N, N-dibenzylamino-L-benzyl phenylalanine ester and acetonitrile in sodium amide and a solvent to obtain 4-S-N, N-dibenzylamino-3-oxo-5-phenyl valeronitrile, wherein the reaction formula is as follows:
Figure BDA0002454218430000042
and step two, selecting strong base type ionic compound sodium amide, wherein the amino has a lone electron pair and is easy to combine with the proton of acetonitrile to generate acetonitrile anions, and the acetonitrile anions and benzyloxy undergo nucleophilic substitution reaction to generate acetonitrile condensation products.
Step three, 4-S-N, N-dibenzylamino-3-oxo-5-phenyl valeronitrile and benzyl magnesium chloride are added in a solvent to react to obtain an intermediate I2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenyl hexane-2-alkene, wherein the reaction formula is as follows:
Figure BDA0002454218430000043
step four, sequentially carrying out reduction reaction on 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene by using a sodium borohydride/methanesulfonic acid reagent and a sodium borohydride/trifluoroacetic acid reagent to obtain a stereoselective product intermediate II dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane under the induction action of a chiral inducer, wherein the reaction formula is as follows:
Figure BDA0002454218430000051
and step four, reducing enamine to form a primary amino group by using a sodium borohydride/methanesulfonic acid reagent, and reducing carbonyl to form hydroxyl group by using a sodium borohydride/trifluoroacetic acid reagent, and the inventor conducts a large amount of screening on a chiral inducer to find that when (S) -2-methyl-CBS-oxazole borane is selected, a good chiral induction effect is achieved during a reduction reaction, and a product has a good diastereomer excess (de%) value and stereoselectivity.
Step five, reacting dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane with di-tert-butyl methyl dicarbonate in a solvent under the catalysis of potassium carbonate to obtain an intermediate III (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, wherein the reaction formula is as follows:
Figure BDA0002454218430000052
and step five, protecting the primary amino group by adopting a common BOC protection reaction, using potassium carbonate as an acid-binding agent, coating the Boc group on the amino group, and generating carbon dioxide and tert-butyl alcohol as byproducts without influencing hydroxyl groups, wherein the yield is high and the selectivity is good.
Step six, (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane was reductively debenzylated using ammonium formate, palladium/carbon in a solvent to give the intermediate, the reaction formula being as follows:
Figure BDA0002454218430000053
sixthly, ammonium formate is used as a hydrogen source, and the benzyl is removed through palladium/carbon catalytic reduction to obtain a primary amino group, so that the product yield is high, and the diastereomer excess (de%) value and stereoselectivity are good.
According to a further scheme of the invention, in the first step, the alkaline solution is 25-40 wt% of sodium hydroxide or potassium hydroxide aqueous solution, the solvent is tetrahydrofuran or N, N-dimethylformamide, the molar ratio of L-phenylalanine, benzyl chloride, potassium carbonate, the alkaline solution and the solvent is 1: 3.2-3.6: 0.2-0.8: 2-3: 5-10, the reaction temperature is 50-80 ℃, and the reaction time is 3-6 hours.
According to a further scheme of the invention, the solvent in the second step is one or a mixture of more of methyl tert-butyl ether, tetrahydrofuran and N, N-dimethylformamide, the molar ratio of N, N-dibenzylamino-L-benzyl phenylalanine, sodium amide, acetonitrile and the solvent is 1: 1-2: 1.2-1.6: 5-10, the reaction temperature is 0-10 ℃, and the reaction time is 18-22 hours.
As a further scheme of the invention, the solvent in the third step is one or a mixture of more of diethyl ether, methyl tert-butyl ether and tetrahydrofuran, and the molar ratio of 4-S-N, N-dibenzylamino-3-oxo-5-phenyl valeronitrile, benzyl magnesium chloride and the solvent is 1: 1.2-1.6: 5-10 ℃, the reaction temperature is-10 ℃, and the reaction time is 6-12 hours.
As a further scheme of the invention, the chiral inducer in the step four is (S) -2-methyl-CBS-oxazaborolidine, 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene, sodium borohydride, methanesulfonic acid and the chiral inducer, wherein the molar ratio of the chiral inducer to the chiral inducer is 1: 1.2-2: 1.2-2: 0.2-0.5, wherein the reaction temperature is 0-10 ℃ when the sodium borohydride/methanesulfonic acid reagent is reduced, and the reaction time is 1-2 hours; the mol ratio of the 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene to the sodium borohydride to the trifluoroacetic acid is 1: 1-1.5: 1-1.5, wherein the reaction temperature is 0-10 ℃ and the reaction time is 1-2 hours when the sodium borohydride/trifluoroacetic acid reagent is reduced.
As a further embodiment of the present invention, the step five solvent is a mixture of one or more of toluene, dichloromethane and tetrahydrofuran, and the molar ratio of dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane, potassium carbonate and di-tert-butyl methyl dicarbonate is 1: 1-2: 0.8-1.3, the reaction temperature is 0-20 ℃, and the reaction time is 6-12 hours.
As a further embodiment of the present invention, the solvent in step six is one or more of methanol, ethanol and isopropanol, the palladium content in palladium/carbon is 5% to 15%, and the molar ratio of (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, ammonium formate and palladium/carbon is 1: 1-2: 0.3-0.6, the reaction temperature is 60-100 ℃, and the reaction time is 1-3 hours.
The invention has the beneficial effects that:
the invention relates to a preparation method of ritonavir and lopinavir intermediates, which comprises the steps of taking L-phenylalanine as a raw material, reacting with benzyl chloride in potassium carbonate and an alkaline aqueous solution to obtain N, N-dibenzylamino-L-benzyl phenylalanine, condensing with acetonitrile under the action of sodium amide, carrying out addition reaction with benzyl magnesium chloride to obtain 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene, reducing enamine and carbonyl by using sodium borohydride/methanesulfonic acid and sodium borohydride/trifluoroacetic acid reagents in sequence, obtaining a stereoselective product dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane under the induction action of a chiral inducer, reacting the stereoselective product with di-tert-butyl methyl dicarbonate in a potassium carbonate/tetrahydrofuran solution to obtain (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, reducing benzyl with ammonium formate/carbon to obtain a (2S,3S,5S, 2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, reducing benzyl with ammonium formate/carbon to obtain a high stereoselective product, and obtaining a high yield of a stereodiastereomeric product (BDH).
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding L-phenylalanine 16.5g (0.1mol), tetrahydrofuran 57.6g (0.8mol), 32 wt% sodium hydroxide solution 29.7g and potassium carbonate 8.28g (0.6mol) into a dry three-neck flask, carrying out mechanical stirring and water bath heating, adding 41.77g (3.3mol) of benzyl chloride into a constant-pressure dropping funnel, slowly dropwise adding the benzyl chloride at normal temperature, heating the water bath to 65 ℃ after the dropwise adding is finished, carrying out heat preservation stirring reaction for 5 hours, standing the reaction product to normal temperature, dropwise adding triethylamine to adjust the pH value to be neutral, carrying out vacuum filtration, extracting the filtrate for 2 times by using dichloromethane, washing the filtrate by using saturated salt solution, drying the anhydrous sodium sulfate, filtering the filtrate, and recrystallizing the filtrate by using petroleum ether to obtain 40.04g of N, N-dibenzylamino-L-benzyl phenylalanine with the yield of 92%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 435.2198[M+H]+
Example 2
Adding 43.52g (0.1mol) of N, N-dibenzylamino-L-benzyl phenylalanine ester, 5.85g (0.15mol) of sodium amide and 70.4g (0.8mol) of methyl tert-butyl ether into a dry three-neck flask, preparing a mechanical stirring and ice-ethanol bath, adding 6.15g of acetonitrile (0.15mol) into a constant-pressure dropping funnel, slowly dropwise adding the acetonitrile, keeping the temperature of a reaction system at 6 ℃, stirring for reaction for 20 hours, standing and stirring for layering, extracting the acetonitrile, concentrating an organic layer, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing ethyl acetate to separate out 4-S-N, N-dibenzylamino-3-oxo-5-phenylpentanenitrile 33.51g, and obtaining the yield of 91%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 368.1889[M+H]+
Example 3
4-S-N, N-dibenzylamino-3-oxo-5-phenylpentanenitrile 36.82g (0.1mol), diethyl ether 59.3g (0.8mol) and benzylmagnesium chloride 21.12g (0.14mol) are added into a dry reaction bottle, the mixture is kept warm in an ice bath at 5 ℃, stirred and reacted for 10 hours, then kept stand for layering, washed by dichloromethane for 2 times, concentrated by organic phase pressure, washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, and recrystallized by petroleum ether to separate out 40.50g of 2-amino-5- (dibenzylamino) -4-keto-1, 6-diphenylhexane-2-alkene with the yield of 88%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 460.2515[M+H]+
Example 4
46.03g (0.1mol) of 2-amino-5- (dibenzylamino) -4-keto-1, 6-diphenylhexane-2-ene, 32g (0.1mol) of methanol, 4.92g (0.13mol) of sodium borohydride, 14.42g (0.15mol) of methanesulfonic acid, 11.1g (S) -2-methyl-CBS-oxazaborolidine, and 11.5 g (6 ℃ C.) were added to a dry reaction flask, followed by stirring and reaction at 5 ℃ for 1.5 hours, followed by addition of 5.3g (0.14mol) of sodium borohydride and 15.96g (0.14mol) of trifluoroacetic acid, stirring and reaction at 5 ℃ for 1.6 hours, followed by standing and separation, extraction with ethyl acetate for 2 times, concentration under reduced pressure of the organic phase, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, and recrystallization with ethyl acetate to obtain 43.18g of dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane, the yield thereof was found to be 93%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 464.2828[M+H]+
Example 5
Into a dry reaction flask were charged 46.43g (0.1mol) of dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane, 22.08g (0.16mol) of potassium carbonate and 72g (1mol) of tetrahydrofuran, 26.19g (0.12mol) of di-tert-butylmethyl dicarbonate was slowly dropped from a constant pressure dropping funnel, and after completion of the dropping, the mixture was stirred and reacted at 16 ℃ for 11 hours with warming, and the reaction mixture was allowed to stand for layering, concentrated under reduced pressure to remove the solvent, extracted with ethyl acetate 3 times, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane 49.66g, with a yield of 88%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 564.3352[M+H]+
Example 6
Adding 56.48g of (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane into an autoclave, adding 200m L of methanol, stirring and dissolving, then adding 5.32g (0.05mol) of palladium/carbon with 10% of palladium content and 10.09g (0.16mol) of ammonium formate, introducing hydrogen to replace the air in the autoclave until the pressure reaches 0.5MPa, heating to 66 ℃, carrying out heat preservation reaction for 2.5 hours, standing to the normal temperature, filtering, concentrating, adding ethyl acetate, stirring and dissolving, slowly adding 120m L of 5 wt% sodium carbonate solution for washing, washing with saturated common salt solution, drying with anhydrous sodium sulfate, filtering, concentrating an organic layer at 60 ℃ under reduced pressure to obtain 37.73g of an intermediate BDH, wherein the yield is 92%, and the de% value is detected to be 98.2%.
HRMS m/z(ESI+)calcd for C14H17NO5([M]+),found 384.2413[M+H]+
The preparation method of the ritonavir and the lopinavir intermediate does not need harsh reaction conditions, has high stereoselectivity, high diastereomer excess (de%) value of the chiral product, short reaction steps, high product yield and less three wastes.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.

Claims (7)

1. A preparation method of ritonavir and lopinavir intermediates is characterized by comprising the following synthetic steps:
step one, L-phenylalanine is used as a raw material and reacts with benzyl chloride in potassium carbonate catalysis, an alkaline solution and a solvent to obtain N, N-dibenzylamino-L-phenylalanine benzyl ester, wherein the reaction formula is as follows:
Figure FDA0002454218420000011
step two, carrying out condensation reaction on N, N-dibenzylamino-L-benzyl phenylalanine ester and acetonitrile in sodium amide and a solvent to obtain 4-S-N, N-dibenzylamino-3-oxo-5-phenyl valeronitrile, wherein the reaction formula is as follows:
Figure FDA0002454218420000012
step three, 4-S-N, N-dibenzylamino-3-oxo-5-phenyl valeronitrile and benzyl magnesium chloride are added in a solvent to react to obtain an intermediate I2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenyl hexane-2-alkene, wherein the reaction formula is as follows:
Figure FDA0002454218420000013
step four, sequentially carrying out reduction reaction on 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene by using a sodium borohydride/methanesulfonic acid reagent and a sodium borohydride/trifluoroacetic acid reagent to obtain a stereoselective product intermediate II dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane under the induction action of a chiral inducer, wherein the reaction formula is as follows:
Figure FDA0002454218420000021
step five, reacting dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane with di-tert-butyl methyl dicarbonate in a solvent under the catalysis of potassium carbonate to obtain an intermediate III (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, wherein the reaction formula is as follows:
Figure FDA0002454218420000022
step six, (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane was reductively debenzylated using ammonium formate, palladium/carbon in a solvent to give the intermediate, the reaction formula being as follows:
Figure FDA0002454218420000023
2. the method for preparing ritonavir and lopinavir intermediates according to claim 1, wherein the alkaline solution in the first step is 25-40 wt% aqueous solution of sodium hydroxide or potassium hydroxide, the solvent is tetrahydrofuran or N, N-dimethylformamide, the molar ratio of L-phenylalanine, benzyl chloride, potassium carbonate, the alkaline solution and the solvent is 1: 3.2-3.6: 0.2-0.8: 2-3: 5-10, the reaction temperature is 50-80 ℃, and the reaction time is 3-6 hours.
3. The preparation method of ritonavir and lopinavir intermediates as claimed in claim 1, wherein the solvent in the step two is selected from one or more of methyl tert-butyl ether, tetrahydrofuran and N, N-dimethylformamide, the molar ratio of N, N-dibenzylamino-L-benzyl phenylalanine, sodium amide, acetonitrile and solvent is 1: 1-2: 1.2-1.6: 5-10, the reaction temperature is 0-10 ℃, and the reaction time is 18-22 hours.
4. The process of claim 1, wherein the third solvent is a mixture of one or more of ethyl ether, methyl tert-butyl ether, tetrahydrofuran, 4-S-N, N-dibenzylamino-3-oxo-5-phenylpentanenitrile, benzylmagnesium chloride, solvent in a molar ratio of 1: 1.2-1.6: 5-10 ℃, the reaction temperature is-10 ℃, and the reaction time is 6-12 hours.
5. The process for preparing ritonavir and lopinavir intermediates as claimed in claim 1, wherein the chiral inducing agent in step four is (S) -2-methyl-CBS-oxazaborolidine, 2-amino-5- (dibenzylamino) -4-one-1, 6-diphenylhexane-2-ene, sodium borohydride, methanesulfonic acid, chiral inducing agent in a molar ratio of 1: 1.2-2: 1.2-2: 0.2-0.5, wherein the reaction temperature is 0-10 ℃ when the sodium borohydride/methanesulfonic acid reagent is reduced, and the reaction time is 1-2 hours; the mol ratio of the 2-amino-5- (dibenzylamino) -4-ketone-1, 6-diphenylhexane-2-alkene to the sodium borohydride to the trifluoroacetic acid is 1: 1-1.5: 1-1.5, wherein the reaction temperature is 0-10 ℃ and the reaction time is 1-2 hours when the sodium borohydride/trifluoroacetic acid reagent is reduced.
6. The process of claim 1, wherein the solvent in step five is a mixture of one or more of toluene, dichloromethane and tetrahydrofuran, and the molar ratio of dibenzylamino-3-hydroxy-5-amino-1, 6-diphenylhexane, potassium carbonate and di-tert-butylmethyl dicarbonate is 1: 1-2: 0.8-1.3, the reaction temperature is 0-20 ℃, and the reaction time is 6-12 hours.
7. The process of claim 1, wherein the solvent in step six is a mixture of one or more of methanol, ethanol, isopropanol, and the palladium content in palladium/charcoal is 5% to 15%, and the molar ratio of (2S,3S,5S) -2-N, N-dibenzylamino-3-carbonyl-5-tert-butoxycarbonylamino-1, 6-diphenylhexane, ammonium formate, and palladium/charcoal is 1: 1-2: 0.3-0.6, the reaction temperature is 60-100 ℃, and the reaction time is 1-3 hours.
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