CN109776359B - Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process - Google Patents
Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process Download PDFInfo
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Abstract
The invention belongs to the technical field of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine preparation, and particularly relates to a synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine. The synthesis process comprises the following steps: the method is characterized in that 3, 6-dioxa-1, 8-octanediamine and tert-butoxy acyl chloride are used as raw materials to perform substitution reaction, wherein a solvent used in the reaction is a mixed solvent of any two of acetonitrile, toluene, diethyl ether, cyclohexane, n-ethane and chloroform. The Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process provided by the invention has the advantages of simple reaction route and short reaction time; the target product with high yield and high purity can be obtained without a complicated purification and separation process, the operation is simple, and the method is suitable for industrial amplification production.
Description
Technical Field
The invention belongs to the technical field of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine preparation, and particularly relates to a synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine.
Background
Boc-1-amino-3, 6-dioxa-1, 8-octanediamine is widely applied to the pharmaceutical (chemical) industry due to the structural characteristics and functional group characteristics of the Boc-1-amino-3, 6-dioxa-1, 8-octanediamine. For example, patent WO2018129557 uses Boc-1-amino-3, 6-dioxa-1, 8-octanediamine to synthesize a series of tetrahydroisoquinoline derivatives, which can inhibit NHE-mediated reverse transport of sodium ions and hydrogen ions, have positive effects in treating disorders related to fluid retention or salt overload, and can be used for treating gastrointestinal diseases, including treating or relieving pain related to gastrointestinal diseases. Patent WO2006133144 uses Boc-1-amino-3, 6-dioxa-1, 8-octanediamine for the synthesis of peptide compounds of erythropoietin receptor (EPO-R) agonists. The peptidic compounds are useful for the treatment of blood diseases characterized by low or defective red blood cell production, such as beta-thalassemia, cystic fibrosis, pregnancy and menstrual disorders, acute blood loss, and the like. Statistically, Boc-1-amino-3, 6-dioxa-1, 8-octanediamine currently requires hundreds of tons in the market.
At present, the synthesis idea of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine is to start from 3, 6-dioxa-1, 8-octanediamine (DODA) and selectively use single Boc. However, since 3, 6-dioxa-1, 8-octanediamine is a completely symmetrical structure, it is more challenging to have two nitrogens to be selective for one Boc.
In fact, symmetric diamines, selective for Boc on one nitrogen, have been a technical challenge in organic synthesis. Through search, the selectivity of the symmetric diamine compound for Boc mainly has the following ideas: the first idea is as follows: using a slightly less reactive Boc reagent; the yield and purity of the product obtained by the idea are low, the production cost is high, and the industrial production is not facilitated; and a second idea: using a smaller equivalent of Boc anhydride; for example, it has been reported in the literature to react DODA with 0.15eq of Boc anhydride to reduce the generation of di-Boc. Although the method has a certain effect on improving the selectivity, the DODA proportion participating in the reaction each time is small due to the excessively low consumption of the Boc anhydride, and if all the DODA is converted, the number of times of applying is increased, so that time and labor are wasted, and the efficiency is influenced; in addition, the productivity of the method is obviously insufficient. Such as Mono-acylation of synthetic diamines in the presence of water, Wei Tang, Shiyue Fan tetrahedron letters, 2008(49),6003-6006, which discloses the synthesis of Boc phenol, which is less reactive than Boc, followed by reaction with DODA. The reaction yield is low (the total yield of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesized by the method is 38-40 percent after repetition) and the obtained product needs to be purified by column chromatography and is not suitable for industrial production. And (3) the third idea: firstly, salifying DODA and hydrochloric acid or hydrogen chloride gas to form a balance, and then reacting with Boc anhydride. The technology of synthesizing Boc-1-amino-3, 6-dioxa-1, 8-octanediamine by salifying DODA and hydrochloric acid or hydrogen chloride gas to form equilibrium and then reacting with Boc anhydride is not reported. However, referring to other symmetric diamine compounds, the salt is firstly formed by using hydrochloric acid, trimethylchlorosilane and the like, and then the process is tried and optimized in Boc literature, and the result is not ideal. The yield of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesized by DODA is lower than 42 percent.
In addition to the above synthetic schemes, there are also some other literature reports of synthesis of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine. For example, Preparation and biological assessment of hydroxyl acid amides of polyamides, Fixon-Owood, Solomon et al, Phytochemistry,2003(63), 315-octanediamine, was synthesized by the procedure of first trifluoroacetyl group on DODA, then Boc, and finally trifluoroacetyl group removal, which is long and gives an overall yield of less than 50%. To avoid Boc on diamine selectivity, the document Development of target protein-selective degradation indicator for protein knock down. Itoh, Yukihiro et al, Bioorganic & Medicinal Chemistry,2011(19),3229-3241 reports a new route to Boc-1-amino-3, 6-dioxa-1, 8-octanediamine. The route uses 2- [2- (2-T-BOC-aminoethoxy) ethoxy ] ethanol as a raw material, reacts with TsCl to convert hydroxyl into TsO, then uses azide compound for substitution, and finally reduces azide to obtain Boc-1-amino-3, 6-dioxa-1, 8-octanediamine. The process has long route, needs dangerous azide and is not suitable for industrial production.
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention aims to provide a synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, which is simple in operation and can obtain a high yield without complicated purification.
In order to achieve the above object, the present invention provides the following technical solutions:
a synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps: the compound is prepared by one-step substitution reaction of 3, 6-dioxa-1, 8-octanediamine (DODA) and tert-butoxy acyl chloride,
wherein the solvent adopted in the reaction is a mixed solvent of any two of acetonitrile, toluene, methyl tert-butyl ether, diethyl ether, cyclohexane, n-ethane and chloroform.
Preferably, the solvent is a mixed solvent of any two of acetonitrile, toluene and methyl tert-butyl ether.
Further preferably, the solvent is a mixture of any two of acetonitrile, toluene and methyl tert-butyl ether.
More preferably, the solvent is a mixed solvent of acetonitrile and toluene, and the volume ratio of the acetonitrile to the toluene is 10-3: 3-5; more preferably 6-3: 3-5; in a preferred embodiment, the volume ratio of the two is 5: 3.
Preferably, the molar ratio of tert-butoxy chloride to DODA is 0.5 to 2.5, more preferably 0.8 to 1.2.
Preferably, the reaction temperature of the substitution reaction is 0 to 80 ℃, more preferably 0 to 25 ℃, even more preferably 0 to 10 ℃, and most preferably 0 to 5 ℃.
Preferably, the raw material 3, 6-dioxa-1, 8-octanediamine is dissolved by stirring at the temperature of 0-55 ℃ before the substitution reaction; more preferably, the temperature is 0 to 10 ℃ and still more preferably 0 to 5 ℃.
The invention provides a preferred embodiment, which comprises the following steps:
dropwise adding a tert-butoxy acyl chloride solution into a 3, 6-dioxa-1, 8-octanediamine (DODA) solution, controlling the reaction temperature to 0-80 ℃ in the dropwise adding process, stirring until the reaction is complete after the dropwise adding is finished, filtering, leaching a filter cake by using a mixed solvent which is the same as a reaction system, dissolving the leached filter cake in water, adjusting the pH value to 10-11 by using an alkali liquor, extracting by using an organic solvent, and concentrating an organic phase to obtain a target compound Boc-1-amino-3, 6-dioxa-1, 8-octanediamine (Boc-DODA).
The reaction route of the invention is as follows:
the invention utilizes 3, 6-dioxa-1, 8-octanediamine hydrochloride (DODA) to react with tert-butoxy chloride, HCl gas is released while the Boc group is on, and the HCl gas is generated by reacting with amine group in a reaction system, because the solubility of 3, 6-dioxa-1, 8-octanediamine hydrochloride (DODA.2HCl), Boc-1-amino-3, 6-dioxa-1, 8-octanediamine hydrochloride (Boc-DODA.HCl) and N, N-bis-Boc-3, 6-dioxa-1, 8-octanediamine in different solvents is greatly different, under the reaction conditions provided by the invention, Boc-1-amino-3, 6-dioxa-1, 8-octanediamine preferentially forms salt and precipitates, thereby obtaining Boc-1-amino-3 with higher yield, 6-dioxa-1, 8-octanediamine hydrochloride (Boc-DODA. HCl).
Compared with the prior art, the synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine provided by the invention has the following beneficial effects:
(1) the Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process provided by the invention has the advantages of simple reaction route and short reaction time; the target product with high yield and high purity can be obtained without a complicated purification and separation process, the operation is simple, and the method is suitable for industrial amplification production.
(2) The invention utilizes the solubility difference of compounds with similar structures in different solvents, solves the problem of purification and separation of products after asymmetric reaction of symmetric diamine compounds, and provides a reaction idea for similar reactions.
Detailed Description
In order to make the purpose and technical solution of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30 minutes after dropwise adding, filtering, leaching a filter cake with a mixed solvent of 70mL of acetonitrile and toluene-5: 3, dissolving the leached filter cake with 1L of water, adjusting the pH to 10 with a sodium hydroxide solution, extracting twice with methyl tert-butyl ether, 750mL each time, combining organic phases, washing with 250mL of water, concentrating and drying to obtain 183.7g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, the purity is 99.3%, and the yield is 74%.
Example 2
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring,
136.6g (1.0 equivalent) of tert-butoxy acyl chloride is dissolved in 445mL of acetonitrile, then the temperature is controlled to be 0-5 ℃, the acetonitrile solution of tert-butoxy acyl chloride is slowly dripped into the acetonitrile solution of DODA, the dripping time is controlled to be 1-2 hours, after the dripping is finished, the mixture is stirred for 30min, the filtration is carried out, a filter cake is leached by a mixed solvent of 70mL of acetonitrile and methyl tert-butyl ether (5: 3), the leached filter cake is dissolved by 1L of water, the pH value is adjusted to 10 by sodium hydroxide solution, the extraction is carried out twice by methyl tert-butyl ether, 750mL each time, after organic phases are combined, 250mL of water is used for washing, concentration and drying, and 131.6g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with the purity of 99.3% and.
Example 3
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
148.2g DODA and 740mL toluene were added to a 2L reaction flask and the temperature was reduced to 0-5 ℃ with stirring. Dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, then slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the toluene solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, leaching a filter cake with 70mL of toluene, dissolving the leached filter cake with 1L of water, adjusting the pH to 10 with a sodium hydroxide solution, extracting twice with 750mL of methyl tert-butyl ether each time, combining organic phases, washing with 250mL of water, concentrating, and drying to obtain 74.5g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with the purity of 95.3% and the yield of 30%.
Example 4
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 445mL of methyl tert-butyl ether, slowly dropwise adding a methyl tert-butyl ether solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after dropwise adding, filtering, leaching a filter cake with 70mL of a mixed solvent of acetonitrile and methyl tert-butyl ether (5: 3), dissolving the leached filter cake with 1L of water, adjusting the pH to 10 with a sodium hydroxide solution, extracting twice with methyl tert-butyl ether (750 mL each time), combining organic phases with 250mL of water, concentrating and drying to obtain 101.8g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with the purity of 97.2%, the yield thereof was found to be 41%.
Example 5
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 163.9g (1.2 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of acetonitrile-toluene-5: 3 mixed solvent; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 176.3g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with a purity of 99.2% and a yield of 71%.
Example 6
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 136.6g (1.0 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of acetonitrile-toluene-5: 3 mixed solvent; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 171.3g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with a purity of 99.3% and a yield of 69%.
Example 7
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 122.9g (0.9 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 153.9g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with a purity of 99.0% and a yield of 62%.
Example 8
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 20-25 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 20-25 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 161.4g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with 98.2% purity and 65% yield.
Example 9
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, heating to 50-55 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 20-25 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 144.0g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with 95.2% purity and 58% yield.
Example 10
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 600mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 600mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 1: 1; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 168.8g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with 98.7% purity and 68% yield.
Example 11
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 1.48L of acetonitrile into a 3L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy acyl chloride in 890mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile, toluene and 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to give 158.9g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, 98.8% purity, 64% yield.
Example 12
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 68.3g (0.5 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 139.0g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, purity 98.3.0%, yield 56%.
Example 13
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 341.4g (2.5 equivalents) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of acetonitrile-toluene-5: 3 mixed solvent; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 136.6g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with purity of 98.1.0% and yield of 55%.
Example 14
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 409.7g (3.0 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 114.2g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine with a purity of 96.20% and a yield of 46%.
Example 15
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 409.7g (3.0 equivalent) of tert-butoxy acyl chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy acyl chloride into the acetonitrile solution of DODA at the temperature of 0-5 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30min after the dropwise adding is finished, filtering, and leaching a filter cake by using 70mL of a mixed solvent of acetonitrile and toluene, wherein the toluene is 5: 3; the filter cake after washing was dissolved in 1L of water, adjusted to pH 10 with sodium hydroxide solution, extracted twice with 750mL of methyl tert-butyl ether each time, combined with the organic phase and washed with 250mL of water, concentrated, and dried to obtain 149.0g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, purity 98.67%, yield 60%.
Example 16
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of acetonitrile into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy chloride in 445mL of toluene, slowly dropwise adding the toluene solution of tert-butoxy chloride into the acetonitrile solution of DODA at the temperature of 80 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30 minutes after dropwise adding, filtering, leaching the filter cake with 70mL of a mixed solvent of acetonitrile and toluene, namely 5:3, dissolving the leached filter cake with 1L of water, adjusting the pH value to 10 with a sodium hydroxide solution, extracting twice with methyl tert-butyl ether, 750mL each time, combining organic phases, washing with 250mL of water, concentrating and drying to obtain 117.7g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, wherein the purity is 94.63%, and the yield is 45%.
Example 17
A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
adding 148.2g of DODA and 740mL of diethyl ether into a 2L reaction bottle, cooling to 0-5 ℃ under stirring, dissolving 150.3g (1.1 equivalent) of tert-butoxy chloride in 445mL of toluene, slowly dropwise adding a toluene solution of tert-butoxy chloride into an acetonitrile solution of DODA at the temperature of 80 ℃, controlling the dropwise adding time to be 1-2 hours, stirring for 30 minutes after dropwise adding, filtering, leaching a filter cake with a mixed solvent of 70mL of diethyl ether and 5:3 of toluene, dissolving the leached filter cake with 1L of water, adjusting the pH to 10 with a sodium hydroxide solution, extracting twice with methyl tert-butyl ether, 750mL each time, combining organic phases, washing with 250mL of water, concentrating and drying to obtain 104.3g of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine, wherein the purity is 92.44%, and the yield is 42%.
The above are merely embodiments of the present invention, which are described in detail and with particularity, and therefore should not be construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the spirit of the present invention, and these changes and modifications are within the scope of the present invention.
Claims (8)
1. A synthesis process of Boc-1-amino-3, 6-dioxa-1, 8-octanediamine comprises the following steps:
is prepared by one-step substitution reaction of 3, 6-dioxa-1, 8-octanediamine and tert-butoxy acyl chloride,
wherein the solvent for reaction is selected from the mixed solvent of any two of acetonitrile, toluene and methyl tert-butyl ether.
2. The synthesis process of claim 1, wherein the solvent is a mixed solvent of acetonitrile and toluene, and the volume ratio of the acetonitrile to the toluene is 10-3: 3-5.
3. The process of claim 1, wherein the molar ratio of t-butoxy acid chloride to 3, 6-dioxa-1, 8-octanediamine is 0.5 to 2.5.
4. The process of claim 3, wherein the molar ratio of t-butoxy acid chloride to 3, 6-dioxa-1, 8-octanediamine is 0.8 to 1.2.
5. The process of claim 1, wherein the substitution reaction is carried out at a temperature of 0-80 ℃.
6. The process of claim 5, wherein the substitution reaction is carried out at a temperature of 0-10 ℃.
7. The process of claim 1 wherein the starting material 3, 6-dioxa-1, 8-octanediamine is dissolved by stirring at 0-55 ℃ before the substitution reaction occurs.
8. The process of claim 7 wherein the starting material 3, 6-dioxa-1, 8-octanediamine is dissolved by stirring at 0-10 ℃ before the substitution reaction occurs.
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| 1,8-二氨基-3,6-二氧辛烷的合成研究;陈建良;《广东化工》;20151231;第42卷(第17期);221-222页 * |
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