CN116143713A - 1, 4-diazacycloheptane series derivatives and preparation method thereof - Google Patents

1, 4-diazacycloheptane series derivatives and preparation method thereof Download PDF

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CN116143713A
CN116143713A CN202310141232.8A CN202310141232A CN116143713A CN 116143713 A CN116143713 A CN 116143713A CN 202310141232 A CN202310141232 A CN 202310141232A CN 116143713 A CN116143713 A CN 116143713A
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diazacycloheptane
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吴晓明
仲晨昊
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Jiaxing Heji Pharmaceutical Co ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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Abstract

The invention relates to the field of organic synthesis, in particular to a 1, 4-diazacycloheptane derivative and a preparation method thereof. The synthesis reaction was performed with reference to the following synthetic route:
Figure DDA0004087577220000011
wherein R is selected from alkyl or aromatic groups, R 1 、R 2 And R is 3 Each independently selected from hydrogen or alkyl, ar represents an aromatic group. The finished product prepared by the method has low impurity content and stable quality index, and can obtain 1, 4-diazacycloheptane derivatives.

Description

1, 4-diazacycloheptane series derivatives and preparation method thereof
Technical Field
The invention relates to the field of organic synthesis, in particular to a 1, 4-diazacycloheptane derivative and a preparation method thereof.
Background
1, 4-diazacycloheptane structures are found in a number of drug substances, such as rosuvastatin (Ripasudil, K-115), fasudil (Fasudil) and Suvorexant (Suvorexant), and the like, and 1, 4-diazacycloheptane structures have specific biological activities, wherein the structural formulas of rosuvastatin and Suvorexant are as follows:
Figure SMS_1
as an example, rosudil is a Rho kinase (Rho-associated coiled-coil-forming protein kinase) specific inhibitor, developed and sold by japan, and approved by the japan medical equipment and device complex (PMDA) at 9, 26, 2014, and is suitable for use in the two-wire treatment of glaucoma and ocular hypertension. There are two main synthetic routes reported in the literature. One synthetic route is as follows:
Figure SMS_2
the route takes 4-fluoroisoquinoline-5-sulfonyl chloride as a starting material, and a seven-membered ring is directly synthesized on a substrate through a linear process to obtain rosuvastatin. However, in actual production, the expensive 4-fluoroisoquinoline-5-sulfonyl chloride is directly used as the starting material of the route, so that the yield loss is larger after multi-step reaction, and the final cost is higher; secondly, the linear process is not beneficial to impurity control and has poor anti-interference capability.
The other synthesis path is:
Figure SMS_3
the route is changed to a convergent process, wherein S-2-amino-1-propanol is used as a starting material to synthesize a seven-membered ring intermediate, and then the seven-membered ring intermediate is condensed with 4-fluoroisoquinoline-5-sulfonyl chloride and then Boc protection is removed to obtain rosudil. Although the process has increased steps compared with the prior process, the material for preparing INT B is low in cost until the process is finally combined with 4-fluoroisoquinoline-5-sulfonyl chloride, so that the loss of high-cost raw materials is reduced, and the cost is effectively reduced. However, in this process, there are isomer impurities which are not easily removed, as follows:
Figure SMS_4
in addition, the process uses methylsulfonyl chloride, azodicarboxylic acid diester and the like, wherein the methylsulfonyl chloride belongs to a highly toxic product, and the dangerous use is limited; the azo dicarboxylic acid diester is easy to explode and has high toxicity when being impacted by heating; not very economical to atom, use equivalent amounts of azodicarbonesCarboxylic acid diesters and triphenylphosphine; the formation of equivalent amounts of hydrazino dicarboxylic acid diester and triphenylphosphine oxide is difficult to remove, and the formation of waste residues, especially triphenylphosphine oxide, is extremely difficult to remove. Therefore, the preparation method of the 1, 4-diazacycloheptane derivatives has the problems of high impurity content, unstable quality index and the like.
Disclosure of Invention
The invention provides a 1, 4-diazacycloheptane series derivative and a preparation method thereof, which aim to solve the problems in the prior art, and the prepared finished product has low impurity content and stable quality index, and can obtain the 1, 4-diazacycloheptane series derivative.
The invention is realized in the following way:
in a first aspect, embodiments of the present invention provide a method for preparing a 1, 4-diazacycloheptane series derivative, by performing a synthesis reaction with reference to the following synthetic route
Figure SMS_5
Wherein R is selected from alkyl or aromatic groups, R 1 、R 2 And R is 3 Each independently selected from hydrogen or alkyl, ar represents an aromatic group.
Further, in a preferred embodiment of the present invention, R 1 、R 2 And R is 3 Each independently selected from hydrogen or C1-C6 alkyl;
preferably, R 1 、R 2 And R is 3 Each independently selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl and n-butyl;
preferably, ar represents any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthryl group, a substituted or unsubstituted phenanthryl group, and a substituted or unsubstituted biphenyl group;
preferably, ar represents any one of phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl, and o-xylyl;
preferably, the method comprises the steps of,
Figure SMS_6
represents any one of methylsulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.
Further, in a preferred embodiment of the present invention, the operation steps of step 1 include: mixing a raw material 1, a raw material 2, a first acid binding agent and a mixed solvent for reaction, wherein the structural formula of the raw material 1 is as follows:
Figure SMS_7
the structural formula of the raw material 2 is as follows: />
Figure SMS_8
Preferably, the operation steps of step 1 include: mixing the raw material 1, the first acid binding agent and water to form a first mixed solution, and then cooling to 0-5 ℃;
mixing the raw material 2 with a first organic solvent to form a second mixed solution;
then, the first mixed solution and the second mixed solution are mixed under the condition of 0-5 ℃, and then reacted under the condition of 15-20 ℃.
Further, in a preferred embodiment of the present invention, the first acid binding agent is selected from carbonate or bicarbonate, preferably sodium bicarbonate;
preferably, the molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, wherein the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.5.
Further, in a preferred embodiment of the present invention, the operation steps of step 2 include: mixing the intermediate 1, the raw material 3, the first catalyst, the second acid binding agent and the second organic solvent for reaction; wherein, the structural formula of the raw material 3 is as follows:
Figure SMS_9
preferably, the operation steps of step 2 include: mixing the intermediate 1, the first catalyst, the second acid binding agent and the second organic solvent, heating to 50-60 ℃ in an inert gas atmosphere, mixing with the raw material 3, and completely reacting at 50-60 ℃.
Further, in a preferred embodiment of the present invention, the first catalyst comprises an ammonium iodide compound, preferably tetrabutylammonium iodide;
preferably, the second organic solvent is selected from formamide solvents, preferably N, N-dimethylformamide;
the second acid binding agent is selected from phosphates, preferably potassium phosphate;
preferably, the molar ratio of the intermediate 1 to the second acid-binding agent is 1:1.8-2.2, the molar ratio of intermediate 1 to the first catalyst being 1:0.08-0.12; the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.5.
Further, in a preferred embodiment of the present invention, the operation steps of step 3 include: intermediate 2, a third acid binding agent,
Figure SMS_10
Mixing the second catalyst and a third solvent for reaction;
preferably, the operation steps of step 3 include: mixing the intermediate 2, the third acid binding agent, the solvent, the two catalysts and the third solvent to form a third mixed solution, and cooling to 0-5 ℃;
and then is connected with
Figure SMS_11
Mixing with the mixture of the third solvent, and then, heating to 20-25 ℃ to react.
Further, in a preferred embodiment of the present invention, the third acid binding agent includes an amine, preferably triethylamine;
preferably, the second catalyst is a pyridine compound, preferably dimethylaminopyridine;
preferably, the molar ratio of intermediate 2 to the second catalyst is 1:0.08-0.12; the molar ratio of the intermediate 2 to the third acid-binding agent is 1:2.5-3.5; said intermediate 2 and
Figure SMS_12
the molar ratio of (2) is 1:2.0-2.5.
Further, in a preferred embodiment of the present invention, the operation steps of step 4 include: mixing the intermediate 3, ammonia water and a fourth solvent for reaction, and then carrying out salt formation reaction with hydrochloric acid;
preferably, the ammonia water is 15-30% ammonia water;
preferably, the temperature of the reaction is 80-100 ℃.
In a second aspect, embodiments of the present invention provide a 1, 4-diazepane series derivative prepared by the method of preparing the 1, 4-diazepane series derivative.
The beneficial effects of the invention are as follows: the invention provides a brand-new preparation process of 1, 4-diazacycloheptane derivatives, which can avoid the problems existing in the prior art, has low impurity content, high purity and stable quality index, can prepare 1, 4-diazacycloheptane intermediates with various substituents, does not use virulent drugs such as methylsulfonyl chloride, azo dicarboxylic acid diester and the like, is easy to operate, has conventional materials as raw materials, and has low raw material cost. Meanwhile, the intermediates in the step 2 and the step 3 in the preparation process provided by the embodiment of the invention do not need to be subjected to independent purification post-treatment, can be directly subjected to the next reaction, and can be crystallized and purified until the final reaction is finished, and even so, a high-purity product can be obtained.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some examples of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product INTA provided in example 1 of the present invention;
fig. 2 is an HPLC diagram of the product INTA provided in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The following provides a specific description of a 1, 4-diazacycloheptane series derivative and a preparation method thereof.
The embodiment of the invention provides a preparation method of a 1, 4-diazacycloheptane series derivative, wherein the structural formula of the 1, 4-diazacycloheptane series derivative is shown as follows:
Figure SMS_13
wherein R is 1 、R 2 And R is 3 Each independently selected from hydrogen or alkyl groups, such as C1-C6 alkyl groups, specifically any of methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, and n-butyl groups may be selected, but it is understood that the above alkyl groups are merely illustrative of embodiments of the present invention, alkyl groups such as n-pentyl, isopentyl, etc., or substituted alkyl groups such as benzyl, monochloromethyl, dichloromethyl, etc., may be selected.
Ar represents an aromatic group which may be selected from any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthryl group, a substituted or unsubstituted phenanthryl group and a substituted or unsubstituted biphenyl group; specifically, aromatic groups including, but not limited to, phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl, and o-xylyl, and methyl-substituted naphthyl groups may be selected.
Specifically, the synthesis is performed with reference to the following synthesis route:
Figure SMS_14
the specific process is as follows,
step 1: mixing a raw material 1, a raw material 2, a first acid binding agent and a mixed solvent for reaction, wherein the structural formula of the raw material 1 is as follows:
Figure SMS_15
the structural formula of the raw material 2 is as follows: />
Figure SMS_16
Specifically, the raw material 1, the first acid binding agent and water are mixed to form a first mixed solution, and then the temperature is reduced to 0-5 ℃; mixing the raw material 2 with a first organic solvent to form a second mixed solution; and then, mixing the first mixed solution and the second mixed solution at the temperature of 0-5 ℃, then reacting at the temperature of 15-20 ℃, detecting the reaction by HPLC, controlling the o-nitrobenzenesulfonyl chloride to be less than or equal to 1.0% in the HPLC, stopping the reaction, and then performing post-treatment.
Specifically, the post-treatment comprises adding water into a reaction bottle for stirring after the central control is qualified, extracting by adopting ethyl acetate, combining organic phases, drying by adopting anhydrous sodium sulfate, concentrating under reduced pressure, steaming for 4 times by using methyl tertiary butyl ether, adding methyl tertiary butyl ether for steaming and stirring, filtering and drying under reduced pressure, and obtaining white to off-white solid.
Further, the first acid binding agent is selected from carbonate or bicarbonate, preferably sodium bicarbonate; the molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, for example 1:0.8, 1:0.9, 1:1. 1:1.1 and 1:1.2, etc. 1: any number between 0.8 and 1.2; the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.5, for example 1:1.2, 1:1.3, 1:1.4 and 1:1.2-1.5.
Step 2: mixing the intermediate 1, the raw material 3, the first catalyst, the second acid binding agent and the second organic solvent for reaction; wherein, the structural formula of the raw material 3 is as follows:
Figure SMS_17
specifically, the intermediate 1Mixing the first catalyst, the second acid binding agent and the second organic solvent, heating to 50-60 ℃ in an inert gas atmosphere, mixing with the raw material 3, and completely reacting at 50-60 ℃.
The intermediate 1 is less than or equal to 2.0 percent of HPLC, water is dripped into the reaction bottle after the intermediate is qualified, and the internal temperature is controlled to be 15-25 ℃. The reaction solution was extracted three times with ethyl acetate, and the organic phases were combined, washed twice with hydrochloric acid and saturated brine in this order, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure.
Further, the first catalyst comprises an ammonium iodide compound, preferably tetrabutylammonium iodide; the second organic solvent is selected from formamide solvents, preferably N, N-dimethylformamide; the second acid binding agent is selected from phosphates, preferably potassium phosphate. The molar ratio of the intermediate 1 to the second acid binding agent is 1:1.8-2.2, e.g. 1:1.8, 1:1.9, 1:2.0, 1:2.1 and 1:2.2, etc. 1: any number between 1.8 and 2.2; the molar ratio of the intermediate 1 to the first catalyst is 1:0.08-0.12; for example, 1:0.08, 1:0.09, 1:0.1, 1:0.11 and 1:0.12, etc. 1: any number between 0.08 and 0.12; the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.5, for example 1:1.2, 1:1.3, 1:1.4 and 1:1.2-1.5.
Step 3: intermediate 2, a third acid binding agent,
Figure SMS_18
The second catalyst and the third solvent are mixed to react. Specifically, the intermediate 2, the third acid binding agent, the solvent, the two catalysts and the third solvent are mixed to form a third mixed solution, and the temperature is reduced to 0-5 ℃; and then go to->
Figure SMS_19
Mixing with the mixture of the third solvent, and then, heating to 20-25 ℃ to react.
And (3) dropwise adding hydrochloric acid into a reaction bottle for stirring after the intermediate 2 is less than or equal to 1.0% in the HPLC (high performance liquid chromatography), layering, adding an organic phase into a three-mouth bottle, adding a sodium carbonate aqueous solution, stirring at room temperature, layering, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure.
Further, the third acid binding agent comprises an amine substance, preferably triethylamine; the second catalyst is a pyridine compound, preferably dimethylaminopyridine; the molar ratio of the intermediate 2 to the second catalyst is 1:0.08-0.12; for example, 1:0.08, 1:0.09, 1:0.1, 1:0.11 and 1:0.12, etc. 1: any number between 0.08 and 0.12; the molar ratio of the intermediate 2 to the third acid-binding agent is 1:2.5-3.5; for example, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4 and 1:3.5, etc. 1: any number between 2.5 and 3.5; said intermediate 2 and
Figure SMS_20
the molar ratio of (2) is 1:2.0-2.5, e.g. 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4 and 1:2.5, etc. 1: any number between 2.0 and 2.5.
Figure SMS_21
Any one of methylsulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride is represented, and it is understood that other sulfonyl chloride compounds may be selected as long as the above reaction can be performed.
Step 4: mixing the intermediate 3, ammonia water and a fourth solvent for reaction, and then carrying out salt formation reaction with hydrochloric acid; specifically, the intermediate 3 ammonia water and a fourth solvent are mixed and added into a pressure-resistant kettle for reaction, the intermediate 3 is controlled to be less than or equal to 1.0 percent in HPLC, the temperature is reduced to room temperature after the intermediate is controlled to be qualified, saturated saline water is added, the ethyl acetate is used for extraction for three times, the organic phases are combined, the saturated saline water is used for washing once, anhydrous sodium sulfate is used for drying, the concentration is carried out until no fraction is basically generated, dichloromethane and water are added, the solution of hydrogen chloride-ethyl acetate is added dropwise under stirring at 0-5 ℃, the stirring is completed for 2 hours, the filtration is carried out, the pre-cooled dichloromethane is used for leaching, and the filter cake is dried under reduced pressure.
The following describes a specific method for preparing a 1, 4-diazacycloheptane series derivative according to the present invention with reference to specific examples.
Example 1
The embodiment provides a preparation method of a 1, 4-diazacycloheptane derivative, wherein the structural formula of the 1, 4-diazacycloheptane derivative is as follows:
Figure SMS_22
the specific synthesis process is as follows: />
S1, the reaction is carried out by referring to the following synthesis route:
Figure SMS_23
20.0. 20.0g R-2-amino-1-propanol (SM 1), 100ml of water, 33.6g of sodium bicarbonate were added to a 500ml three-port reaction flask, and the temperature was lowered to 0-5℃with stirring. 57.8g of o-nitrobenzenesulfonyl chloride was dissolved in 100ml of tetrahydrofuran and added dropwise to the reaction flask at a reaction temperature of 0-5 ℃. After the dripping is finished, naturally heating to 15-20 ℃ and stirring overnight. And (3) adding 100ml of water into the reaction bottle after the control of the o-nitrobenzenesulfonyl chloride in the HPLC is less than or equal to 1.0% and stirring for 1 hour after the control is qualified. The reaction mixture was extracted with ethyl acetate (200 ml once, 100ml twice), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and steamed 4 times with 100ml of methyl tert-butyl ether, 100ml of methyl tert-butyl ether was added, stirred at 5-10℃for 4 hours, filtered and dried under reduced pressure at 40℃to give 54.6g of a white to off-white solid, yield 78.8% and HPLC purity 99.9%.
Characterization data for this product INT1 are as follows: 1 H-NMR(CDCl 3 )δ:1.14(3H,d,J＝6.8Hz),1.85(1H,br s),3.47-3.66(3H,m),5.48(1H,d,J＝6.8Hz),7.72-7.79(2H,m),7.86-7.92(1H,m),8.15-8.20(1H,m)；LC-MS:261.0[M+H + ]。
s2, the reaction is carried out by referring to the following synthesis route:
Figure SMS_24
20.0g of INT1, 32.6g of potassium phosphate, 2.64g of tetrabutylammonium iodide, 140ml of N, N-dimethylformamide were added to a 1L three-port reaction flask, the temperature was raised to 55℃under nitrogen protection with stirring, and 16.0g of 3-bromopropanol was added dropwise. After the dripping, stirring is carried out at 55 ℃ for 12 hours. HPLC (high Performance liquid chromatography) medium control INT1 is less than or equal to 2.0%, 500ml of water is dropwise added into a reaction bottle after the medium control is qualified, and the internal temperature is controlled to be 15-25 ℃. The reaction solution was extracted three times with 200ml of ethyl acetate, and the organic phases were combined, washed once with 100ml of 1m hydrochloric acid, twice with 100ml of saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure in high vacuum to give 16.1g of dark red oily liquid in 65.7% yield and 83.1% purity by HPLC.
Characterization data for this product INT2 are as follows: LC-MS 319.0[ M+H ] + ]。
S3, the reaction is carried out by referring to the following synthesis route:
Figure SMS_25
16.1g of INT2, 15.3g of triethylamine, 0.6g of 4-dimethylaminopyridine and 80ml of methylene chloride were added to a 500ml three-port reaction flask and cooled to 0℃with stirring. 21.2g of p-toluenesulfonyl chloride were dissolved in 80ml of methylene chloride and added dropwise to a reaction flask, the temperature being controlled at 0 ℃. After the dripping is completed, the temperature is naturally returned to 20-25 ℃ and the mixture is stirred overnight. HPLC central control INT2 is less than or equal to 1.0%, and 80ml of 1M hydrochloric acid is dropwise added into a reaction bottle and stirred for 30min after the central control is qualified. The layers were separated, and the organic phase was added to a 500ml three-necked flask, followed by adding 80ml of a 1M aqueous sodium carbonate solution and stirring at room temperature for 1 hour. The layers were separated, and the organic phase was washed with 80ml of saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 33.2g of a tan syrup-like liquid with a yield of 105.0% and an HPLC purity of 85.2%.
Characterization data for this product INT3 are as follows: LC-MS 626.9[ M+H ] + ]。
S4, the reaction is carried out by referring to the following synthesis route:
Figure SMS_26
10g of INT3, 100ml of 25% aqueous ammonia and 100ml of acetonitrile were added to a pressure-resistant autoclave, and reacted at a constant temperature of 90℃for 4 hours. INT3 is controlled to be less than or equal to 1.0% by HPLC, cooled to room temperature after being qualified by the control, added with 100ml of saturated saline, extracted three times with 100ml of 50ml of ethyl acetate, combined with an organic phase, washed once with 100ml of saturated saline, dried with anhydrous sodium sulfate, concentrated to be almost free of fractions, added with 30ml of dichloromethane and 0.3g of water, stirred and dropwise added with 15.7ml of 4M hydrogen chloride-ethyl acetate solution at 0-5 ℃ for 2 hours, filtered, leached with precooled dichloromethane, and dried under reduced pressure at 40 ℃ to obtain 3.7g of pale yellow solid with HPLC purity of 99.8%, yield of 65.5% and total process yield of 35.61%.
The characterization diagram of the product INTA is shown in figures 1-2, wherein figure 1 is a nuclear magnetic hydrogen spectrogram, figure 2 is an HPLC spectrogram, and specific data are as follows: 1 H NMR(400MHz,D 2 O)δ:8.00(m,1H),7.86(m,3H),4.42(m,1H),3.86(m,1H),3.61(dd,J 1 ＝14Hz,J 2 ＝6Hz,1H),3.47(m,2H),3.16(m,2H),2.03(m,2H),1.05(d,J＝8Hz,3H)；LC-MS:299.9[M+H + ]。
example 2
The embodiment provides a preparation method of a 1, 4-diazacycloheptane derivative, wherein the structural formula of the 1, 4-diazacycloheptane derivative is as follows:
Figure SMS_27
the synthesis process is as follows: the R-2-amino-1-propanol of the first step in example 1 was changed to S-2-amino-1-propanol, and the other conditions were unchanged. The product was obtained in 36.1% yield and 99.5% purity.
Example 3
The embodiment provides a preparation method of a 1, 4-diazacycloheptane derivative, wherein the structural formula of the 1, 4-diazacycloheptane derivative is as follows:
Figure SMS_28
the synthesis process is as follows: r-2-amino-1-propanol in the first step of example 1 was changed to 2-aminoethanol, and 3-bromo-1-propanol in the second step was changed to 3-bromo-1-butanol, with the other conditions unchanged. The product was obtained in 33.9% yield and 98.9% purity.
Example 4
This example provides a process for the preparation of 1, 4-diazacycloheptane derivatives, wherein the 1, 4-diazaThe structural formula of the cycloheptane derivative is as follows:
Figure SMS_29
the synthesis process is as follows: the R-2-amino-1-propanol of the first step in example 1 was changed to 1-amino-2-propanol, and the other conditions were unchanged. The product was obtained in 37.8% yield and 99.3% purity.
Example 5
The embodiment provides a preparation method of a 1, 4-diazacycloheptane derivative, wherein the structural formula of the 1, 4-diazacycloheptane derivative is as follows:
Figure SMS_30
the synthesis process is as follows: r-2-amino-1-propanol in the first step of example 1 was changed to S-2-amino-1-propanol, o-nitrobenzenesulfonyl chloride was changed to 2, 4-dinitrobenzenesulfonyl chloride, and the other conditions were unchanged. The product was obtained in 31.7% yield and 99.6% purity.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, and various modifications and variations may be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A process for producing a 1, 4-diazacycloheptane derivative, characterized in that the synthesis reaction is carried out by referring to the following synthesis route
Figure FDA0004087577160000011
Wherein R is selected from alkyl or aromatic groups, R 1 、R 2 And R is 3 Each independently selected from hydrogen or alkyl, ar represents an aromatic group.
2. The process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 1, wherein R 1 、R 2 And R is 3 Independently selected from hydrogen or C1-C6 alkanesA base;
preferably, R 1 、R 2 And R is 3 Each independently selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl and n-butyl;
preferably, ar represents any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthryl group, a substituted or unsubstituted phenanthryl group, and a substituted or unsubstituted biphenyl group;
preferably, ar represents any one of phenyl, p-tolyl, m-tolyl, o-tolyl, p-nitrobenzene, p-xylyl, m-xylyl, and o-xylyl;
preferably, the method comprises the steps of,
Figure FDA0004087577160000021
represents any one of methylsulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.
3. Process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 1 or 2, characterized in that the operating step of step 1 comprises: mixing a raw material 1, a raw material 2, a first acid binding agent and a mixed solvent for reaction, wherein the structural formula of the raw material 1 is as follows:
Figure FDA0004087577160000022
the structural formula of the raw material 2 is as follows: />
Figure FDA0004087577160000023
Preferably, the operation steps of step 1 include: mixing the raw material 1, the first acid binding agent and water to form a first mixed solution, and then cooling to 0-5 ℃;
mixing the raw material 2 with a first organic solvent to form a second mixed solution;
then, the first mixed solution and the second mixed solution are mixed under the condition of 0-5 ℃, and then reacted under the condition of 15-20 ℃.
4. A process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 3, characterized in that the first acid binding agent is selected from a carbonate or bicarbonate, preferably sodium bicarbonate;
preferably, the molar ratio of the raw material 1 to the raw material 2 is 1:0.8-1.2, wherein the molar ratio of the raw material 1 to the first acid binding agent is 1:1.2-1.5.
5. Process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 1 or 2, characterized in that the operating step of step 2 comprises: mixing the intermediate 1, the raw material 3, the first catalyst, the second acid binding agent and the second organic solvent for reaction; wherein, the structural formula of the raw material 3 is as follows:
Figure FDA0004087577160000024
preferably, the operation steps of step 2 include: mixing the intermediate 1, the first catalyst, the second acid binding agent and the second organic solvent, heating to 50-60 ℃ in an inert gas atmosphere, mixing with the raw material 3, and completely reacting at 50-60 ℃.
6. The process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 5, characterized in that the first catalyst comprises an ammonium iodide compound, preferably tetrabutylammonium iodide;
preferably, the second organic solvent is selected from formamide solvents, preferably N, N-dimethylformamide;
the second acid binding agent is selected from phosphates, preferably potassium phosphate;
preferably, the molar ratio of the intermediate 1 to the second acid-binding agent is 1:1.8-2.2, the molar ratio of intermediate 1 to the first catalyst being 1:0.08-0.12; the molar ratio of the intermediate 1 to the raw material 3 is 1:1.2-1.5.
7. 1, 4-diazacyclo ring as claimed in claim 1 or 2The preparation method of the heptane derivatives is characterized in that the operation steps of the step 3 comprise: intermediate 2, a third acid binding agent,
Figure FDA0004087577160000031
Mixing the second catalyst and a third solvent for reaction;
preferably, the operation steps of step 3 include: mixing the intermediate 2, the third acid binding agent, the solvent, the two catalysts and the third solvent to form a third mixed solution, and cooling to 0-5 ℃;
and then is connected with
Figure FDA0004087577160000032
Mixing with the mixture of the third solvent, and then, heating to 20-25 ℃ to react.
8. The process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 7, characterized in that the third acid binding agent comprises an amine species, preferably triethylamine;
preferably, the second catalyst is a pyridine compound, preferably dimethylaminopyridine;
preferably, the molar ratio of intermediate 2 to the second catalyst is 1:0.08-0.12; the molar ratio of the intermediate 2 to the third acid-binding agent is 1:2.5-3.5; said intermediate 2 and
Figure FDA0004087577160000041
the molar ratio of (2) is 1:2.0-2.5.
9. Process for the preparation of 1, 4-diazacycloheptane series derivatives as claimed in claim 1 or 2, characterized in that the operating step of step 4 comprises: mixing the intermediate 3, ammonia water and a fourth solvent for reaction, and then carrying out salt formation reaction with hydrochloric acid;
preferably, the ammonia water is 15-30 ammonia water;
preferably, the temperature of the reaction is 80-100 ℃.
10. A 1, 4-diazacycloheptane series derivative, characterized in that the 1, 4-diazacycloheptane series derivative is prepared by a process for the preparation of a 1, 4-diazacycloheptane series derivative as claimed in any one of claims 1-9.
CN202310141232.8A 2023-02-08 2023-02-08 1, 4-diazacycloheptane series derivatives and preparation method thereof Pending CN116143713A (en)

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