CN109879780B - Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate - Google Patents
Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate Download PDFInfo
- Publication number
- CN109879780B CN109879780B CN201910147681.7A CN201910147681A CN109879780B CN 109879780 B CN109879780 B CN 109879780B CN 201910147681 A CN201910147681 A CN 201910147681A CN 109879780 B CN109879780 B CN 109879780B
- Authority
- CN
- China
- Prior art keywords
- ethyl
- tert
- methylamine
- dichloromethane
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (2-methylamine-ethyl) -tert-butyl carbamate, belonging to the technical field of organic chemical synthesis, and the technical key points of the preparation method comprise the steps of dissolving imidazole in dichloromethane, adding di-tert-butyl dicarbonate at room temperature, reacting for 2-3 hours at room temperature, washing with water and drying to obtain an intermediate; and step two, dissolving the intermediate in toluene, adding N-methyl ethylenediamine, heating to 60-70 ℃, reacting for 2-4 hours, then evaporating toluene under reduced pressure, and purifying to obtain (2-methylamine-ethyl) -carbamic acid tert-butyl ester. The method has the advantages of few operation steps during preparation of the final product, capability of reducing the content of byproducts on the basis of ensuring the synthesis yield of the (2-methylamine-ethyl) -tert-butyl carbamate, low cost and accordance with the requirements of batch production.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of (2-methylamine-ethyl) -tert-butyl carbamate.
Background
tert-Butyl (2-methylamine-ethyl) -carbamate, also known as N-Boc-N' -methylethylenediamine or written as tert-Butyl 2- (methylamino) ethylcarbamate, known by the english name tert-Butyl 2- (methyiamino) ethyllcarbamate, has the CAS number: 122734-32-1, and its molecular formula is C8H18N2O2The chemical structural formula is
The molar mass is 174 g/mol.
The synthesis of (2-methylamine-ethyl) -carbamic acid tert-butyl ester is common on the market at present in many ways, and the following are common:
1. WO2013/67597A 1; as known from Page column 100,
2. references US2011/262355a 1; as known from the Page/Page column 136,
3. reference the synthetic route using 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile and N-methylethylenediamine as starting materials is known from Farmaco, vol.59, #12 p.987-992:
4. reference EP1864968A 1; the Page/Page column 18-19 shows that the synthesis route using di-tert-butyl dicarbonate and N-methylethylenediamine directly as the direct raw materials is:
5. reference Journal of Medicinal Chemistry, vol.33, #1p.97-101 the synthetic route using di-tert-butyl dicarbonate and N-methylethylenediamine as the direct starting materials is:
analysis shows that the raw materials adopted in the first and second synthesis are not sold in the market, synthesis is needed, the synthesis process has two steps of reaction, and noble metal is used as a catalyst for hydrogenation to remove a protecting group in the last step, so that the operation difficulty is high, the cost is high, and the method is not suitable for industrial production; the third to fifth types adopt N-methyl ethylenediamine as a raw material, but the yield of the fourth and fifth types is too low to be suitable for mass production, and byproducts are produced to influence the quality of products; in addition, the yield of the third preparation method is high, but the molecular structure of another raw material is complex, the cost for purchasing the raw material is relatively high, and the cost is high, so that a new synthetic route and a new scheme for synthesizing the (2-methylamine-ethyl) -carbamic acid tert-butyl ester need to be proposed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of (2-methylamine-ethyl) -tert-butyl carbamate, which can reduce the content of byproducts on the basis of ensuring the synthesis yield of the (2-methylamine-ethyl) -tert-butyl carbamate, has low cost and meets the requirement of batch production.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of (2-methylamine-ethyl) -carbamic acid tert-butyl ester comprises the following operation steps:
dissolving imidazole in dichloromethane, adding di-tert-butyl dicarbonate at room temperature, reacting at room temperature for 2-3 hours, washing with water and drying to obtain an intermediate;
and step two, dissolving the intermediate in toluene, adding N-methyl ethylenediamine, heating to 60-70 ℃, reacting for 2-4 hours, then evaporating toluene under reduced pressure, and purifying to obtain (2-methylamine-ethyl) -carbamic acid tert-butyl ester.
By adopting the technical scheme, because of imidazole
The compound is a five-membered aromatic heterocyclic compound of which the structural molecule contains two nitrogen atoms, at the moment, an unshared electron pair of a 1-site nitrogen atom in an imidazole ring participates in cyclic conjugation, the electron density of the nitrogen atom is reduced, and hydrogen on the nitrogen atom is easy to leave in a hydrogen ion form, so that dichloromethane is used as a solvent and undergoes a substitution reaction with di-tert-butyl dicarbonate to obtain an intermediate (N-Boc-imidazole); and then carrying out substitution reaction with N-methyl ethylenediamine in a toluene solvent to obtain the (2-methylamine-ethyl) -tert-butyl carbamate.
The invention is further configured to: in step one, the intermediate has the structural formula:
by adopting the technical scheme, the intermediate is named as N-Boc-imidazole, namely N-tert-butyloxycarbonyl-imidazole, and is a solid compound formed by substituting active hydrogen on an imidazole N atom by tert-butyloxycarbonyl. Its English name is N-Boc-imidazole, CAS number is 49761-82-2, molecular formula is C8H12N2O2Is a chemical intermediate.
The invention is further configured to: in the first step, after reacting for 2-3 hours at room temperature, washing with water for three times, each time using 150ml, then drying with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and distilling under reduced pressure at 30-45 ℃ and a vacuum degree of 0.08-0.1MPa to remove dichloromethane.
The invention is further configured to: the reaction equation involved in step one is:
the invention is further configured to: in step two, the specific way of purification is as follows: adding dichloromethane as organic phase, extracting with water once, cutting organic phase, extracting with saturated saline once, drying the extracted organic phase with anhydrous sodium sulfate, distilling under reduced pressure at 30-45 deg.C and 0.08-0.1MPa to remove dichloromethane, and distilling under reduced pressure at 93-95 deg.C and 5-50Pa to remove imidazole.
By adopting the technical scheme, because the final product is colorless liquid, the purification mode of the product needs to adopt a separating funnel for layering treatment, the solvent adopted by the organic phase is dichlorotoluene, the final product can be dissolved in the organic phase formed by the dichloromethane according to a similar compatibility principle, the water phase adopts pure water and saturated salt water for secondary extraction successively, some substances which are easy to dissolve in water in the reaction process can be removed, then, anhydrous sodium sulfate is adopted to further dry the residual water in the organic phase, then, the operation is carried out in a reduced pressure distillation mode, thus the removal rate of the dichloromethane in the product can be greatly improved, then, the temperature is further improved, thus, the imidazole in the product can be effectively distilled off (the boiling point of the imidazole under the normal condition is 256 ℃, and the boiling point of the tert-butyl (2-methylamine-ethyl) -carbamate is 537 ℃), the imidazole can be removed by distillation with large boiling point difference between the two, and the product is not influenced.
The invention is further configured to: the reaction equation involved in step two is:
the invention is further configured to: in the first step, the weight ratio of imidazole to di-tert-butyl dicarbonate is 1 (2.5-3.2), and 4.7-5.2ml of dichloromethane is added for every 1g of imidazole.
By adopting the technical scheme, the yield of the intermediate obtained by reaction in the above proportioning range is found to be high after optimization experiments.
The invention is further configured to: in the second step, the weight ratio of the intermediate to the N-methyl ethylenediamine is 1 (0.5-0.55), and 1.7-1.8ml of toluene is added for each 1g of the intermediate.
By adopting the technical scheme, the yield of the intermediate obtained by reaction in the above proportioning range is found to be high after optimization experiments.
The invention is further configured to: in step two, 1.8-2ml of dichloromethane are added per 1g of intermediate.
By adopting the technical scheme, the yield of the product obtained by the reaction in the above mixture ratio range is found to be higher after optimization experiments.
In conclusion, the invention has the following beneficial effects:
1. the method has the advantages that the operation steps are few when the final product is prepared, the content of the by-product can be reduced on the basis of ensuring the synthesis yield of the (2-methylamine-ethyl) -tert-butyl carbamate, the cost is low, and the requirement of batch production is met;
2. the optimization is realized, after the boiling point of the liquid is reduced by adopting the pressure distillation, the difficulty of purification is reduced, the energy is saved, the environment is protected, the purification efficiency is accelerated, and the method is very practical;
3. after the proportion of each substance is optimized, the consumption of raw materials can be reduced on the basis of improving the yield of products, and the method is energy-saving and environment-friendly.
Drawings
FIG. 1 is an H-NMR spectrum of an intermediate of step one in example 1;
FIG. 2 is an H-NMR spectrum of the product obtained in step two of example 1.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
Example 1: a preparation method of (2-methylamine-ethyl) -carbamic acid tert-butyl ester comprises the following operation steps:
step one, dissolving 75g of imidazole in 370ml of dichloromethane, adding 228.7g of di-tert-butyl dicarbonate at room temperature, reacting for 2 hours at room temperature, and washing with water for three times, wherein the dosage of each time is 150 ml; then drying by adopting anhydrous sodium sulfate; then, the anhydrous sodium sulfate is removed by filtration through a Buchner funnel, and 140g of intermediate (solid) can be obtained after removing dichloromethane by adopting a reduced pressure distillation mode under the conditions of 30 ℃ and 0.08MPa of vacuum degree, and the reaction equation is as follows:
step two, dissolving 51.6g of the intermediate in 90ml of toluene, adding 27.2g of N-methyl ethylenediamine, heating to 60 ℃, reacting for 2.5 hours, and then evaporating the toluene under reduced pressure; then 100ml of dichloromethane is added as an organic phase, 100ml of pure water is added for extraction once, the organic phase is intercepted and extracted once by 100ml of saturated saline, and the organic phase obtained by extraction is dried by anhydrous sodium sulfate; then carrying out reduced pressure distillation at 30 ℃ and the vacuum degree of 0.08MPa to remove dichloromethane; then the temperature was raised to 92 ℃ and imidazole was distilled off under reduced pressure under vacuum conditions of 5Pa to obtain 52g of (2-methylamine-ethyl) -carbamic acid tert-butyl ester (colorless liquid) with a yield of the final product (2-methylamine-ethyl) -carbamic acid tert-butyl ester of 81%; the reaction equation is as follows:
example 2: a process for the preparation of tert-butyl (2-methylaminoethyl) -carbamate which differs from example 1 in that: the method is characterized in that the raw materials are different in dosage, reaction temperature, vacuum degree and reaction time, and the method comprises the following operation steps:
step one, 75g of imidazole is dissolved in 352.5ml of dichloromethane, 210g of di-tert-butyl dicarbonate is added at room temperature, the mixture is washed three times with 150ml of anhydrous sodium sulfate after 2 hours of room temperature reaction, then the anhydrous sodium sulfate is removed by filtration through a Buchner funnel, and 135g of intermediate (solid) can be obtained after dichloromethane is removed by reduced pressure distillation at 35 ℃ and 0.08MPa of vacuum degree.
Step two, dissolving 51.6g of the intermediate into 87.72ml of toluene, then adding 25.8g of N-methyl ethylenediamine, heating to 70 ℃, reacting for 2 hours, then, toluene was distilled off under reduced pressure, and then 92.88ml of methylene chloride was added as an organic phase, then 100ml of pure water is added for primary extraction, the organic phase is intercepted and extracted once by 100ml of saturated saline, then the organic phase obtained by extraction is dried by anhydrous sodium sulfate, then carrying out reduced pressure distillation at 30 ℃ and the vacuum degree of 0.08MPa to remove dichloromethane, then the temperature is raised to 95 ℃, the imidazole is removed by reduced pressure distillation under the condition that the vacuum degree is 50Pa, 50g of (2-methylamine-ethyl) -carbamic acid tert-butyl ester (colorless liquid) were obtained, the yield of the final product (2-methylamine-ethyl) -carbamic acid tert-butyl ester being 75.2%.
Example 3: a process for the preparation of tert-butyl (2-methylaminoethyl) -carbamate which differs from example 1 in that: the method is characterized in that the raw materials are different in dosage, reaction temperature, vacuum degree and reaction time, and the method comprises the following operation steps:
step one, 75g of imidazole is dissolved in 390ml of dichloromethane, 240g of di-tert-butyl dicarbonate is added at room temperature, after reaction is carried out for 3 hours at room temperature, the mixture is washed three times with water, the dosage is 200ml each time, then, anhydrous sodium sulfate is used for drying, then, a Buchner funnel is used for filtering and removing the anhydrous sodium sulfate, and under the condition of 45 ℃ and the vacuum degree of 0.1MPa, the dichloromethane is removed by adopting a reduced pressure distillation mode to obtain 142g of intermediate (solid).
Step two, dissolving 51.6g of the intermediate into 103.2ml of toluene, then adding 28.38g of N-methyl ethylenediamine, heating to 60 ℃, reacting for 4 hours, then, toluene was distilled off under reduced pressure, and then 92.88ml of methylene chloride was added as an organic phase, then adding 100ml pure water to extract once, intercepting organic phase to extract once by using 100ml saturated saline, then drying the organic phase obtained by extraction by using anhydrous sodium sulfate, then carrying out reduced pressure distillation at 30-45 ℃ and the vacuum degree of 0.08-0.1MPa to remove dichloromethane, then the temperature is raised to 92 ℃, the imidazole is removed by reduced pressure distillation under the condition that the vacuum degree is 5Pa, 55g of (2-methylamine-ethyl) -carbamic acid tert-butyl ester (colorless liquid) were obtained, with a yield of the final product (2-methylamine-ethyl) -carbamic acid tert-butyl ester of 87%.
The specific embodiments are only for explaining the present invention, and the present invention is not limited thereto, and those skilled in the art can make modifications without inventive contribution to the present embodiments as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.
Claims (7)
1. A preparation method of (2-methylamine-ethyl) -carbamic acid tert-butyl ester is characterized by comprising the following operation steps:
dissolving imidazole in dichloromethane, adding di-tert-butyl dicarbonate at room temperature, reacting at room temperature for 2-3 hours, washing with water and drying to obtain an intermediate;
dissolving the intermediate in toluene, adding N-methyl ethylenediamine, heating to 60-70 ℃, reacting for 2-4 hours, then decompressing and steaming off the toluene, and then purifying to obtain (2-methylamine-ethyl) -carbamic acid tert-butyl ester; in the second step, the weight ratio of the intermediate to the N-methyl ethylenediamine is 1 (0.5-0.55), and 1.7-1.8ml of toluene is added into each 1g of the intermediate;
in step two, the specific way of purification is as follows: adding dichloromethane as organic phase, extracting with water once, cutting organic phase, extracting with saturated saline once, drying the extracted organic phase with anhydrous sodium sulfate, distilling under reduced pressure at 30-45 deg.C and 0.08-0.1MPa to remove dichloromethane, and distilling under reduced pressure at 93-95 deg.C and 5-50Pa to remove imidazole.
2. The process of claim 1, wherein in step one, the intermediate has the formula:
3. the method for preparing (2-methylamine-ethyl) -carbamic acid tert-butyl ester according to claim 2, characterized in that, in the step one, after reacting for 2-3 hours at room temperature, it is washed three times with water, each time using 150ml, then dried with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and distilled under reduced pressure at 30-45 ℃ and 0.08-0.1MPa vacuum degree to remove dichloromethane.
4. A process for the preparation of (2-methyl-ethyl) -carbamic acid tert-butyl ester as claimed in claim 3, characterized in that the reaction equation involved in step one is:
5. a process for the preparation of (2-methyl-ethyl) -carbamic acid tert-butyl ester as claimed in claim 1, characterized in that the reaction equation involved in step two is:
6. the process of claim 1, wherein the weight ratio of imidazole to di-tert-butyl dicarbonate in step one is 1 (2.5-3.2), and 4.7-5.2ml of dichloromethane is added for 1g of imidazole.
7. A process for the preparation of (2-methyl-ethyl) -carbamic acid tert-butyl ester as claimed in claim 1, characterized in that in step two, 1.8-2ml of dichloromethane is added per 1g of intermediate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910147681.7A CN109879780B (en) | 2019-02-27 | 2019-02-27 | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910147681.7A CN109879780B (en) | 2019-02-27 | 2019-02-27 | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109879780A CN109879780A (en) | 2019-06-14 |
| CN109879780B true CN109879780B (en) | 2021-06-29 |
Family
ID=66929815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910147681.7A Active CN109879780B (en) | 2019-02-27 | 2019-02-27 | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109879780B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524732A (en) * | 2022-02-24 | 2022-05-24 | 石家庄圣泰化工有限公司 | Synthesis method of methyl carboxylic acid-2-propynyl ester |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1864968A1 (en) * | 2005-03-09 | 2007-12-12 | Japan Science and Technology Agency | Complex compound and mri probe made of same |
| WO2018200943A1 (en) * | 2017-04-28 | 2018-11-01 | Acuitas Therapeutics, Inc. | Novel carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7501526B2 (en) * | 2005-01-20 | 2009-03-10 | Taigen Biotechnology | Synthesis of polyamine compounds |
-
2019
- 2019-02-27 CN CN201910147681.7A patent/CN109879780B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1864968A1 (en) * | 2005-03-09 | 2007-12-12 | Japan Science and Technology Agency | Complex compound and mri probe made of same |
| WO2018200943A1 (en) * | 2017-04-28 | 2018-11-01 | Acuitas Therapeutics, Inc. | Novel carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109879780A (en) | 2019-06-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20110207928A1 (en) | Purification method for adefovir dipivoxil | |
| CN113999142A (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| CN109879780B (en) | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate | |
| JPS58150526A (en) | Optically active propargyl alcohol and preparation thereof | |
| CN108276296B (en) | Synthesis method of cyanide antidote | |
| CA1056388A (en) | Resolution of racemic pantolactone | |
| CN107778141B (en) | Purification method of 1, 4-butanediol | |
| CN110066240B (en) | Synthesis method of nitrendipine | |
| CN116284031A (en) | Preparation method of R-glabridin | |
| WO2007083908A1 (en) | A method for preparing decursinol from angelica gigas with high yield | |
| WO2007080470A2 (en) | A method for the purification of levetiracetam | |
| EP3666756B1 (en) | Method for preparing levetiracetam | |
| CN111848423B (en) | Preparation method of tert-butyl 3-oxocyclobutylcarbamate | |
| CN114262359A (en) | Preparation method of carfilzomib impurities | |
| CN115784990B (en) | Separation method of dextromethorphan diastereoisomers | |
| CN113461538A (en) | Preparation method of 2-chloro-3-bromoaniline | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN112430227B (en) | Preparation method of landiolol hydrochloride | |
| CN113912665B (en) | Method for synthesizing 3-methoxy-18 beta-glycyrrhetinic acid | |
| CN111233685B (en) | Preparation method of racemic D/L-tert-leucine | |
| CN111925353B (en) | Preparation method of 2-thiophenecarbonitrile | |
| CN115557914B (en) | Green synthesis method of furazan compound | |
| CN111057017B (en) | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring cyclization mother liquor | |
| CN109020816A (en) | The method of 3- hydroxyl -2,2,4- trimethyl valeric acid -2- methyl propyl ester is obtained from 12 technique waste water of alcohol ester | |
| CN109456219B (en) | Method for stably and efficiently preparing N-acrylamide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |