CN116041265A - Preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester - Google Patents

Preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester Download PDF

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CN116041265A
CN116041265A CN202310136393.8A CN202310136393A CN116041265A CN 116041265 A CN116041265 A CN 116041265A CN 202310136393 A CN202310136393 A CN 202310136393A CN 116041265 A CN116041265 A CN 116041265A
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piperazine
cyanomethyl
reaction
stirring
preparation
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陈建芳
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Nanjing Youfu Pharmaceutical Technology Co ltd
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Nanjing Youfu Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester. The preparation method provided by the invention has scientific and reasonable design, avoids the use of dangerous reagents, highly toxic reagents and valuable reagents in the preparation process, and can realize the safe preparation of the (R) -2- (cyanomethyl) piperazine-1-benzyl carboxylate with lower cost.

Description

Preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester.
Background
(R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is an important pharmaceutical intermediate, and the corresponding CAS is 2306255-32-1, and the chemical formula is C 14 H 17 N 3 O 2 Molecular weight 259.3 and density 1.163+ -0.06 g/cm 3 Boiling point is 450.9 +/-30.0 ℃ and acidity coefficient is 7.69+/-0.40. The prior preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester has few reports, only has synthesis reports of intermediates, and has the defects, and highly toxic control reagents (methanesulfonyl chloride and potassium cyanide) are used.
Thus, there is a need to provide a process for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate which avoids the use of hazardous, highly toxic and valuable reagents, and which is safer and less costly.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
the preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is characterized in that (S) -1-BOC-3-hydroxymethyl piperazine is used as a starting material, and the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is subjected to Cbz protection, hydroxyl activation, cyanation and hydrochloric acid Boc removal to obtain a finished product.
Further, as described above for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate, the reaction in the first step is shown in formula (I), and intermediate A is obtained after the reaction:
Figure BDA0004085840290000021
。
further, as described above, the preparation method of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester comprises the following specific steps: adding (S) -1-BOC-3-hydroxymethyl piperazine and methylene dichloride into a reaction bottle, stirring, adding triethylamine, cooling to 0 ℃ in an ice water bath, and dropwise adding trimethylchlorosilane, wherein the dropwise adding is finished; after stirring for a period of time, cbzCl benzyl chloroformate is added dropwise, after the dripping is completed, stirring for a period of time, TLC monitors complete reaction of raw materials, concentrated HCl is added to adjust the pH of the system to 1, water is added for layering, saturated saline water is used for washing, an organic layer is separated, anhydrous magnesium sulfate is dried, filtered, evaporated to dryness and spun-dried to obtain an intermediate A.
Further, as described above for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate, the reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:
Figure BDA0004085840290000022
。
further, as described above, the preparation method of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester comprises the following specific steps of the second reaction: adding the intermediate A into a reaction bottle, adding dichloromethane, stirring to dissolve, adding triethylamine, cooling to below 0 ℃, dropwise adding ethyl sulfonyl chloride, stirring for a period of time after the dropwise adding is finished, monitoring the raw materials by TLC to react completely, adding a proper amount of water, layering, washing with saturated salt water, filtering, and evaporating to obtain an intermediate B.
Further, as described above for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate, the reaction in the third step is shown in formula (III), and intermediate C is obtained after the reaction:
Figure BDA0004085840290000031
。
further, as described above, the preparation method of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester comprises the following specific steps: adding the intermediate B into a reaction bottle, adding acetonitrile, stirring uniformly, adding cesium fluoride and trimethylcyanosilane, stirring at room temperature overnight, monitoring the complete reaction of the raw materials by TLC, adding a proper amount of saturated sodium bicarbonate aqueous solution, layering, washing with saturated salt water, filtering, and evaporating to dryness to obtain an intermediate C.
Further, the preparation method of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester comprises the following steps:
Figure BDA0004085840290000032
。
further, as described above, the preparation method of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester comprises the following specific steps: adding the intermediate C and ethyl acetate into a reaction bottle, uniformly stirring, adding concentrated HCl, stirring at room temperature for a period of time, completely reacting TLC raw materials, adding a proper amount of water, adding NaOH to adjust the pH of a system to 10-11, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, filtering, evaporating to dryness to obtain a crude product, and purifying by column chromatography to obtain a finished product.
The beneficial effects of the invention are as follows:
the preparation method provided by the invention has scientific and reasonable design, avoids the use of dangerous reagents, highly toxic reagents and valuable reagents in the preparation process, and can realize the safe preparation of the (R) -2- (cyanomethyl) piperazine-1-benzyl carboxylate with lower cost.
Of course, it is not necessary for any one product to practice the invention to achieve all of the advantages set forth above at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of the inspection of the finished product of the present invention;
FIG. 2 is a second schematic diagram of the inspection of the finished product of the present invention;
FIG. 3 is a schematic diagram of the inspection of the finished product of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The concrete terms of the embodiment are as follows:
SM: (S) -1-BOC-3-hydroxymethylpiperazine
TEA: triethylamine
CbzCl: benzoic acid benzyl ester
TMSCl trimethylchlorosilane
EsCl: ethylsulfonyl chloride
TMSCN: trimethylcyanosilane
CsF: cesium fluoride
DCM: dichloromethane (dichloromethane)
MeCN: acetonitrile
HCl: hydrochloric acid
EA: acetic acid ethyl ester
The specific embodiment of the invention is as follows:
example 1
The preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is characterized in that (S) -1-BOC-3-hydroxymethyl piperazine is used as a starting material, and the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is subjected to Cbz protection, hydroxyl activation, cyanation and hydrochloric acid Boc removal to obtain a finished product.
The reaction in the first step is shown in a formula (I), and an intermediate A is obtained after the reaction:
Figure BDA0004085840290000051
。
the reaction in the first step comprises the following specific steps: SM (90.0 g,1.0 eq.) and DCM (900 mL) were added to a reaction flask and stirred, TEA (231 mL,4.0 eq.) was added, the ice water bath was cooled to 0deg.C, TMSCL (148 mL,2.8 eq.) was added dropwise, after stirring for 0.5 hours, cbzCl (76 mL,1.3 eq.) was added dropwise, after stirring for 3 hours, TLC monitored the starting materials to react completely, concentrated HCl was added to adjust pH to 1, water was added to separate layers, saturated brine was used to separate out an organic layer, anhydrous magnesium sulfate was dried, filtered, evaporated to dryness and spun-dried to give 159.2g of yellow oil, yield: 109%.
The reaction in the second step is shown in a formula (II), and an intermediate B is obtained after the reaction:
Figure BDA0004085840290000052
the second step of reaction comprises the following specific steps: intermediate a (159.2 g,1.0 eq.) was added to a reaction flask, DCM (900 mL) was added and dissolved by stirring, TEA (86 mL,1.5 eq.) was added, esCl (48 mL) was added dropwise after cooling to below 0 ℃, stirring was completed for 4 hours, TLC monitored complete reaction of starting materials, 3L of water was added, delamination, 3L of saturated brine wash, filtration, and evaporation to dryness gave 195.0g of intermediate B as a black oil in 106% yield.
The reaction in the third step is shown in a formula (III), and an intermediate C is obtained after the reaction:
Figure BDA0004085840290000061
the reaction in the third step comprises the following specific steps: intermediate B (190.0 g,1.0 eq.) was added to the reaction flask, meCN (1.2L) was added and stirred well, csF (168.0 g,2.6 eq.) and TMSCN (144 ml,2.6 eq.) were added, stirred overnight at room temperature, TLC monitored the starting material reacted well, saturated aqueous sodium bicarbonate solution 2L was added, the layers were separated, saturated brine 2L washed, filtered, evaporated to dryness to give crude intermediate C, column chromatography gave 63.1g, yield: 40%.
The fourth step of reaction is shown as a formula (IV), and a finished product is obtained after the reaction:
Figure BDA0004085840290000062
the reaction in the fourth step comprises the following specific steps: intermediate C (63.1 g,1.0 eq.) and EA (200 mL) were added to a reaction flask, stirred well, concentrated HCl (120 mL) was added, stirred at room temperature for 4 hours, TLC starting material was reacted completely, water (1L) was added, pH was adjusted to 10-11 by NaOH, EA (1L. Times.4) was extracted, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness to give crude oil, 30.4g was purified by column chromatography, yield: 65%.
The results of the product related tests are shown in fig. 1 to 3.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.

Claims (9)

1. A preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester is characterized by comprising the following steps: the preparation of the (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester takes (S) -1-BOC-3-hydroxymethyl piperazine as a starting material, and the finished product is obtained through four steps of reaction of Cbz protection, hydroxyl activation, cyanation and hydrochloric acid debroc.
2. The process for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 1, wherein the reaction in the first step is represented by formula (I) to give intermediate a:
Figure FDA0004085840150000011
。
3. the process for the preparation of benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 2, wherein the reaction of the first step comprises the following specific steps: adding (S) -1-BOC-3-hydroxymethyl piperazine and methylene dichloride into a reaction bottle, stirring, adding triethylamine, cooling to 0 ℃ in an ice water bath, and dropwise adding trimethylchlorosilane, wherein the dropwise adding is finished; after stirring for a period of time, cbzCl benzyl chloroformate is added dropwise, after the dripping is completed, stirring for a period of time, TLC monitors complete reaction of raw materials, concentrated HCl is added to adjust the pH of the system to 1, water is added for layering, saturated saline water is used for washing, an organic layer is separated, anhydrous magnesium sulfate is dried, filtered, evaporated to dryness and spun-dried to obtain an intermediate A.
4. The process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 3, wherein the reaction in the second step is represented by formula (II), and the intermediate B is obtained after the reaction:
Figure FDA0004085840150000012
。
5. the process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 4, wherein the second step comprises the following steps: adding the intermediate A into a reaction bottle, adding dichloromethane, stirring to dissolve, adding triethylamine, cooling to below 0 ℃, dropwise adding ethyl sulfonyl chloride, stirring for a period of time after the dropwise adding is finished, monitoring the raw materials by TLC to react completely, adding a proper amount of water, layering, washing with saturated salt water, filtering, and evaporating to obtain an intermediate B.
6. The process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 5, wherein the reaction in the third step is represented by formula (III), and the intermediate C is obtained after the reaction:
Figure FDA0004085840150000021
。
7. the process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 6, wherein the reaction in the third step comprises the following specific steps: adding the intermediate B into a reaction bottle, adding acetonitrile, stirring uniformly, adding cesium fluoride and trimethylcyanosilane, stirring at room temperature overnight, monitoring the complete reaction of the raw materials by TLC, adding a proper amount of saturated sodium bicarbonate aqueous solution, layering, washing with saturated salt water, filtering, and evaporating to dryness to obtain an intermediate C.
8. The process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 7, wherein the fourth step is represented by the formula (IV):
Figure FDA0004085840150000022
。
9. the process for preparing benzyl (R) -2- (cyanomethyl) piperazine-1-carboxylate according to claim 8, wherein the fourth step comprises the following steps: adding the intermediate C and ethyl acetate into a reaction bottle, uniformly stirring, adding concentrated HCl, stirring at room temperature for a period of time, completely reacting TLC raw materials, adding a proper amount of water, adding NaOH to adjust the pH of a system to 10-11, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, filtering, evaporating to dryness to obtain a crude product, and purifying by column chromatography to obtain a finished product.
CN202310136393.8A 2023-02-20 2023-02-20 Preparation method of (R) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester Pending CN116041265A (en)

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