CN113999142A - Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine - Google Patents
Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine Download PDFInfo
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- CN113999142A CN113999142A CN202111437236.8A CN202111437236A CN113999142A CN 113999142 A CN113999142 A CN 113999142A CN 202111437236 A CN202111437236 A CN 202111437236A CN 113999142 A CN113999142 A CN 113999142A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/26—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- C07B2200/07—Optical isomers
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
The invention discloses a preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine, belonging to the technical field of organic synthesis. Reacting 7-azabicyclo [4.1.0] heptane as raw material with dicarbonyl di-tert-butyl ester under alkaline condition to generate N-Boc-7-azabicyclo [4.1.0] heptane 2; then carrying out ring opening with ammonia water at high temperature and high pressure to obtain N-Boc-trans-1, 2-cyclohexanediamine 3; salifying and resolving (S) -3-cyclohexene carboxylic acid, and dissociating to obtain N-Boc- (1S,2S) -1, 2-cyclohexanediamine. The method has the advantages of simple reaction operation, relatively simple steps, recoverability of the resolving agent, and potential industrial amplification prospect.
Description
Technical Field
The invention relates to a preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine, belonging to the technical field of organic synthesis.
Background
The trans-1, 2-cyclohexanediamine has C2 symmetry, is used as chiral organic amine with a heterocyclic structure symmetry, is widely applied to the field of medicine, is an important medical intermediate, plays an important role in chemical linkage, and has been proved to be capable of combining with biologically important molecules.
The N-Boc-trans-1, 2-cyclohexanediamine well solves the problem of reaction selection of one amino group. The N-Boc-trans-1, 2-cyclohexanediamine is further classified into N-Boc-1S,2S-1, 2-cyclohexanediamine and N-Boc-1R,2R-1, 2-cyclohexanediamine. Wherein, N-Boc- (1S,2S) -1, 2-cyclohexanediamine can also be applied to synthesizing steric hindrance type antitumor platinum (II) complexes, and N-Boc-trans-1, 2-cyclohexanediamine can be coordinated with a transition metal center to form corresponding ligands.
Currently, the synthesis method of the compounds is synthesized by searching the existing published patents and documents, and most of WO2019/180628a1, Synlett,2017,28,1278, j.chem.soc., Dalton trans.,2001,2188, eur.j.org.chem.,2018,2018 and 99 adopt large excess of (1S,2S) -1, 2-cyclohexanediamine/(1R, 2R) -1, 2-cyclohexanediamine and di-tert-butyl dicarbonate under alkaline conditions. The literature reports yields as high as 53.6-94% using this method, but the yields are calculated as molar equivalents of di-tert-butyl dicarbonate. This is clearly disadvantageous for the efficient reaction of the expensive starting materials (1R,2R) -1, 2-cyclohexanediamine or (1S,2S) -1, 2-cyclohexanediamine.
Therefore, it is necessary to deeply research the process of N-Boc-trans-1, 2-cyclohexanediamine, and avoid the reaction between di-tert-butyl dicarbonate and diamino, thereby avoiding the selectivity problem, and research from the source provides a reaction route which has easily available raw materials, high reaction yield and stable production, so as to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine. Reacting 7-azabicyclo [4.1.0] heptane as raw material with dicarbonyl di-tert-butyl ester under alkaline condition to generate N-Boc-7-azabicyclo [4.1.0] heptane 2; then carrying out ring opening with ammonia water at high temperature and high pressure to obtain N-Boc-trans-1, 2-cyclohexanediamine 3; salifying and resolving (S) -3-cyclohexene carboxylic acid, and dissociating to obtain N-Boc- (1S,2S) -1, 2-cyclohexanediamine. The method has the advantages of simple reaction operation, relatively simple steps, recoverability of the resolving agent, and potential industrial amplification prospect.
The invention relates to a preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine, which comprises the following steps:
the first step is as follows: carrying out DMAP (dimethyl formamide) catalytic reaction on 7-azabicyclo [4.1.0] heptane and di-tert-butyl dicarbonate in a dichloromethane solvent to obtain N-Boc-7-azabicyclo [4.1.0] heptane 2;
the second step is that: mixing the intermediate 2 with ammonia water and a catalyst, and carrying out ring opening reaction at high temperature and high pressure to obtain N-Boc-trans-1, 2-cyclohexanediamine 3;
the third step: dissolving N-Boc-trans-1, 2-cyclohexanediamine 3 and (S) -3-cyclohexenecarboxylic acid in an organic solvent, heating to generate diastereoisomer salt, salifying, cooling, filtering, and adding alkali to dissociate to obtain N-Boc- (1S,2S) -1, 2-cyclohexanediamine.
Further, in the first step, the molar ratio of 7-azabicyclo [4.1.0] heptane, di-tert-butyl dicarbonate and triethylamine is 1: 1.0-1.5: 1.2-1.5.
Further, in the second step, the ammonia water is 25-28% ammonia water, the high temperature and high pressure are 95-100 deg.C, 0.6-1.0 Mpa.
Further, in the second step, the catalyst is B (C)6H5)3(ii) a The amount of catalyst added is 2-5 wt% of compound 2.
Further, in the third step, the organic solvent is selected from 2-methyltetrahydrofuran, acetic acid/isopropanol mixed solvent; wherein the ethyl acetate/isopropanol ratio is 10: 1 volume ratio.
Further, in the third step, the molar ratio of compound 3 to (S) -3-cyclohexenecarboxylic acid was 1: 0.98-1.02.
Further, in the third step, mother liquor obtained by salt formation filtration is mainly N-Boc- (1R,2R) -1, 2-cyclohexanediamine, and the mother liquor is concentrated, dissociated and further purified with (R) -3-cyclohexenecarboxylic acid salt formation dissociation.
Advantageous effects of the invention
1. By Boc protection of the source, subsequent selectivity problems are avoided. The enantiomers of a single chirality are further separated by a crystallization resolution method. The resolving agent can be recycled. The mother liquid of crystallization can be recovered, and then the enantiomer of another chirality can be resolved.
2. The chiral purity of the N-Boc- (1S,2S) -1, 2-cyclohexanediamine and the chiral purity of the N-Boc- (1R,2R) -1, 2-cyclohexanediamine obtained by the method can reach more than 99.0% ee.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1:
adding 7-azabicyclo [4.1.0] into a reaction bottle]Heptane (97.2g,1.0mol), DMAP2.2g, di-tert-butyl dicarbonate (261.9g,1.2mol) were dissolved in 600mL of dichloromethane. Controlling the temperature to be 0-5 ℃, dropwise adding triethylamine (126.5g,1.25mol), naturally heating to room temperature for reacting for 8 hours after dropwise adding, detecting by TLC that the reaction is complete, adjusting the pH value to be 7-8 by 1M hydrochloric acid for layering, extracting by 400mL of dichloromethane, combining organic phases, washing by 200mL of 20% potassium bisulfate aqueous solution, washing by saturated sodium carbonate aqueous solution, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and distilling under reduced pressure at 55-60 ℃ to obtain 7-azabicyclo [4.1.0] after reduced pressure distillation]182.1g of tert-butyl heptane-7-carboxylate in 92.2% yield and 99.4% chemical purity.1HNMR(400MHz,CDCl3):4.12-4.10(m,2H),1.74-1.46(m,4H),1.44(s,9H),1.21-1.10(m,4H).
Example 2:
adding 7-azabicyclo [4.1.0] into a high-pressure reaction kettle]98.7g (0.5mol,1eq) of tert-butyl heptane-7-carboxylate, 500mL of 25% ammonia water, and 4.4g of triphenylboron were mixed and stirred uniformlyAnd (4) homogenizing. Heating to 95-100 deg.c and reaction at 0.8MPa for 5 hr. Cooling to room temperature, concentrating under reduced pressure to dryness, adding 400mL of dichloromethane and 200mL of 20% ammonium chloride solution for washing, extracting 200mL of aqueous phase dichloromethane, combining organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure, adding N-heptane, cooling to 10 ℃, separating out solids, and filtering to obtain 96.9g of N-Boc-trans-1, 2-cyclohexanediamine, wherein the yield is 90.4%, and the chemical purity is 99.0%.1H NMR (400MHz, CDCl3):4.51(s,1H),3.12(dt, J ═ 4.0,10.8Hz,1H),2.33(dt, J ═ 4.0and J ═ 10.8Hz,1H),1.84-2.02(m,2H),1.68-1.72(m,2H),1.51(s,2H),1.44(s,9H),1.02-1.33(m,4H), under the same conditions, in the absence of a catalyst, the starting material remained 73% after 48 hours of reaction.
Example 3:
adding N-Boc-trans-1, 2-cyclohexanediamine (85.7g,0.4mol), (S) -3-cyclohexenecarboxylic acid (49.5g,0.392mol) and 600mL 2-methyltetrahydrofuran into a reaction bottle, uniformly mixing, heating to 70-75 ℃, reacting for 3-5 hours after reaction liquid is clear, cooling to 10-15 ℃ in a gradient (10 ℃/30min), filtering, leaching a filter cake with 2-methyltetrahydrofuran to obtain (S) -3-cyclohexenecarboxylic acid/N-Boc- (1S,2S) -1, 2-cyclohexanediamine salt, and recovering the filtrate. Then putting the mixture into the kettle again, adding 300mL of dichloromethane, dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 11-12, separating layers, extracting 150mL of aqueous phase dichloromethane for 3 times, combining organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, adding N-heptane, cooling to 10 ℃ to separate out a solid, and filtering the solid to obtain 36.7g of N-Boc- (1S,2S) -1, 2-cyclohexanediamine, wherein the yield is 85.6%, GC 99.7% and 99.5% ee.
Example 4:
into the reaction flask were charged N-Boc-trans-1, 2-cyclohexanediamine (85.7g,0.4mol), (S) -3-cyclohexenecarboxylic acid (49.5g,0.392mol), 500mL ethyl acetate and 50mL isopropanol. Heating to reflux, reacting for 3-5 hours after the reaction solution is clear, reducing the temperature to 15-20 ℃ in a gradient manner (10 ℃/30min), filtering, leaching a filter cake by using a mixed solution of ethyl acetate and isopropanol to obtain (S) -3-cyclohexenecarboxylic acid/N-Boc- (1S,2S) -1, 2-cyclohexanediamine salt, and recovering the filtrate. Then putting the mixture into the kettle again, adding 300mL of dichloromethane, dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 11-12, separating layers, extracting 150mL of aqueous phase dichloromethane for 3 times, combining organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, adding N-heptane, cooling to 10 ℃ to separate out a solid, and filtering the solid to obtain 31.2g of N-Boc- (1S,2S) -1, 2-cyclohexanediamine, wherein the molar yield is 72.7%, GC 99.8% and 98.4% ee.
Example 5
The mother liquor obtained in example 3 was added to a four-necked flask, a 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 11-12, and the mixture was subjected to layer separation and 150mL extraction with dichloromethane, and extracted 3 times (the aqueous phase was adjusted to 1.0-1.5 with hydrochloric acid, and extracted with ethyl acetate, and S-3-cyclohexenecarboxylic acid was recovered), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to a non-flowing liquid, and N-heptane was added thereto, and the temperature was reduced to 10 ℃ to precipitate a solid, which was then filtered and dried to obtain 45.1g of N-Boc-trans-1, 2-cyclohexanediamine and 77.2% ee (1R, 2R-configuration is predominant).
The filter cake was charged into the reaction flask again and (R) -3-cyclohexenecarboxylic acid (25.2g,0.2mol) and 315mL of 2-methyltetrahydrofuran were added. Heating to 70-75 ℃, reacting for 3-5 hours after the reaction solution is clear, reducing the temperature to 10-15 ℃ in a gradient manner (10 ℃/30min), filtering, leaching a filter cake with 2-methyltetrahydrofuran to obtain (R) -3-cyclohexenecarboxylic acid/N-Boc- (1R,2R) -1, 2-cyclohexanediamine salt, and recovering the filtrate. And then putting the mixture into the kettle again, adding 300mL of dichloromethane, dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 11-12, separating layers, extracting 150mL of aqueous-phase dichloromethane for 3 times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, adding N-heptane, cooling to 10-15 ℃, separating out a solid, and filtering the solid to obtain 36.4g of N-Boc- (1R,2R) -1, 2-cyclohexanediamine. Yield 80.7%, GC 99.7%, 99.5% ee.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. A preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine is characterized by comprising the following steps:
the first step is as follows: carrying out DMAP (dimethyl formamide) catalytic reaction on 7-azabicyclo [4.1.0] heptane and di-tert-butyl dicarbonate in a dichloromethane solvent to obtain N-Boc-7-azabicyclo [4.1.0] heptane 2;
the second step is that: mixing the intermediate 2 with ammonia water and a catalyst, and carrying out ring opening reaction at high temperature and high pressure to obtain N-Boc-trans-1, 2-cyclohexanediamine 3;
the third step: dissolving N-Boc-trans-1, 2-cyclohexanediamine 3 and (S) -3-cyclohexenecarboxylic acid in an organic solvent, heating to generate diastereoisomer salt, salifying, cooling, filtering, and adding alkali to dissociate to obtain N-Boc- (1S,2S) -1, 2-cyclohexanediamine.
2. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the first step, the molar ratio of 7-azabicyclo [4.1.0] heptane, di-tert-butyl dicarbonate and triethylamine is 1: 1.0-1.5: 1.2-1.5.
3. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the second step, the ammonia water is 25-28% ammonia water, the high temperature and high pressure are 95-100 deg.C, 0.6-1.0 Mpa.
4. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the second step, the catalyst is B (C)6H5)3(ii) a The amount of catalyst added is 2-5 wt% of compound 2.
5. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the third step, the organic solvent is selected from 2-methyltetrahydrofuran, acetic acid/isopropanol mixed solvent; wherein the ethyl acetate/isopropanol ratio is 10: 1 volume ratio.
6. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the third step, the molar ratio of the compound 3 to the (S) -3-cyclohexenecarboxylic acid is 1: 0.98-1.02.
7. The method of preparing chiral N-Boc-trans-1, 2-cyclohexanediamine of claim 1, wherein: in the third step, mother liquor obtained by salifying and filtering is mainly N-Boc- (1R,2R) -1, 2-cyclohexanediamine, and the mother liquor is concentrated, dissociated and further purified with (R) -3-cyclohexenecarboxylic acid salifying and dissociating.
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| CN115819251A (en) * | 2022-12-20 | 2023-03-21 | 沧州普瑞东方科技有限公司 | Preparation method of (1R) -1- [3- (difluoromethyl) -2-fluorophenyl ] ethylamine |
| CN116102465A (en) * | 2023-02-17 | 2023-05-12 | 珠海市海瑞德生物科技有限公司 | Process for producing optically active diamine compound |
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| CN116102465A (en) * | 2023-02-17 | 2023-05-12 | 珠海市海瑞德生物科技有限公司 | Process for producing optically active diamine compound |
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