CN109776359A - A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine - Google Patents
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine Download PDFInfo
- Publication number
- CN109776359A CN109776359A CN201910173565.2A CN201910173565A CN109776359A CN 109776359 A CN109776359 A CN 109776359A CN 201910173565 A CN201910173565 A CN 201910173565A CN 109776359 A CN109776359 A CN 109776359A
- Authority
- CN
- China
- Prior art keywords
- octamethylenediamine
- dioxa
- boc
- amino
- synthesis technology
- 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.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine preparation technical fields, and in particular to a kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine.The synthesis technology includes the following steps: with 3,6- dioxa -1,8- octamethylenediamine and tertiary fourth oxygen acyl chlorides are that raw material generation one step of substitution reaction is made, wherein any two kind of mixed solvent of the solvent in acetonitrile, toluene, ether, cyclohexane, hexane and chloroform used by reacting.The synthesis technology reaction route of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine provided by the invention is simple, and the reaction time is short；It can be obtained the target product of high yield, high-purity without complicated purifies and separates process, it is easy to operate, it is suitble to industrial amplification production.
Description
Technical field
The invention belongs to Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine preparation technical fields, and in particular to a kind of
The synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine.
Background technique
Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine is answered extensively due to its architectural characteristic and characteristics of functional groups
For medical (chemical industry) industry.As patent WO2018129557 Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine synthesizes one
Serial tetrahydro isoquinoline derivative, the sodium ion and hydrionic reversed transport which can inhibit NHE to mediate, is being controlled
Treating has positive effect in disorder relevant to fluid retention or salt excess load, can be used for treating enterogastric diseases, including treatment
Or mitigate pain relevant to enterogastric diseases.Patent WO2006133144 is then pungent by Boc-1- amino -3,6- dioxa -1,8-
Diamines is used to synthesize the peptide compounds of EPO Receipter (EPO-R) agonist.Such peptide compounds is to treatment β-ground
Middle sea anaemia, cystic fibrosis, gestation and menstrual disorders, it is special that there is low or defective erythrocyte to generate for acute blood loss etc.
The hematologic disease of sign is effective.According to statistics, Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine existing market demand tons up to a hundred.
Currently, the synthesis thinking of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine is mainly from dioxa -1 3,6-,
8- octamethylenediamine (DODA) sets out, list Boc in selectivity.But since 3,6- dioxa -1,8- octamethylenediamine is full symmetric structure,
Two nitrogen will a selectively upper Boc there is larger challenge.
In fact, symmetrical diamine compounds, selectivity upper Boc on a nitrogen, are always one in organic synthesis
Technical problem.By retrieval it can be found that symmetrically mainly there are several types of thinkings: thinking one by the selectively upper Boc of diamine compound:
Use the slightly lower Boc reagent of activity；The yield and purity of the thinking products therefrom are lower, and high production cost is unfavorable for industrial life
It produces；Thinking two: the Boc acid anhydrides of less equivalent is used；Such as there is the Boc acid anhydrides of document report 0.15eq to react with DODA, with
Reduce the generation of double Boc.Although this method has a certain effect to selectivity is improved, since Boc acid anhydrides dosage is too low, cause
The DODA ratio for participating in reaction every time is seldom, if all DODA converted, the number for needing to apply increases, time-consuming and laborious
And influence efficiency；In addition the production capacity of this method is obviously insufficient.Such as document Mono-acylation ofsymmetric diamines
in the presence of water.Wei Tang,Shiyue Fang.Tetrahedron Letters.,2008(49),
6003-6006. is disclosed using phenol and the slightly weak Boc phenol of Boc elder generation synthesizing activity, is then reacted with DODA.The reaction
Yield it is lower (it is repeated, this method synthesize Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine total recovery be 38-40%) and
The product of acquisition needs to be not suitable for industrialized production using column chromatographic purifying.Thinking three: first by DODA and hydrochloric acid or hydrogen chloride gas
Body at salt, formed after balance again with Boc anhydride reaction.By DODA and hydrochloric acid or hydrogen chloride gas at salt, formed after balance again with
The technique of Boc anhydride reaction synthesis Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine has not been reported.But we are referring to other
Symmetrical diamine compounds, with hydrochloric acid, the methods of trim,ethylchlorosilane is first at salt, then the document of upper Boc has carried out technique trial
It is as a result undesirable with optimization.The yield of DODA synthesis Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine is below 42%.
In addition to the above synthesis thinking, there are also the texts of other synthesis Boc-1- amino -3,6- dioxa -1,8- octamethylenediamines
Offer report.Such as document Preparation and biological assessment of hydroxycinnamic acid
amides of polyamines.Fixon-Owoo,Solomon et al.,Phytochemistry,2003(63),315-
334. disclose first by trifluoroacetyl group on DODA, then upper Boc, and the method for finally taking off trifluoroacetyl group synthesizes Boc-1- ammonia
Base -3,6- dioxa -1,8- octamethylenediamine, this method step is long, and total recovery is less than 50%.To avoid the selectively upper Boc of diamine, text
Offer Development of target protein-selective degradation inducer for protein
knockdown.Itoh,Yukihiro et al.,Bioorganic&Medicinal Chemistry,2011(19),3229-
3241. have reported the variation route of a synthesis Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine.The route is with 2- [2-
(2-T-BOC- amino ethoxy) ethyoxyl] ethyl alcohol has been raw material, it is reacted with TsCl and converts TsO for hydroxyl, then use nitrine
Compound is replaced, and is finally restored nitrine and is obtained Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine.The process route
It is long, it needs to use dangerous azido compound, is not suitable for amplification and carries out industrialized production.
Summary of the invention
In order to solve the above problem in the prior art, present invention is designed to provide a kind of easy to operate, nothing
Complicated purification is needed to can be obtained the synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine of high yield.
In order to achieve the above-mentioned object of the invention, the invention provides the following technical scheme:
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps: with 3,6-
Dioxa -1,8- octamethylenediamine (DODA) He Shuding oxygen acyl chlorides is that raw material generation one step of substitution reaction is made,
Wherein, react used by solvent be selected from acetonitrile, toluene, methyl tertiary butyl ether(MTBE), ether, cyclohexane, hexane and
Any two kinds of mixed solvent in chloroform.
Preferably, the solvent selects any two kinds of mixed solvent in acetonitrile, toluene and methyl tertiary butyl ether(MTBE).
It is further preferred that the solvent is any two kinds of mixing in acetonitrile, toluene and methyl tertiary butyl ether(MTBE).
It is further preferred that the solvent is the mixed solvent of acetonitrile and toluene, the volume ratio of the two is 10-3:3-5；
It is still more preferably 6-3:3-5；As optimum embodiment, the volume ratio of the two is 5:3.
Preferably, the molar ratio of the tertiary fourth oxygen acyl chlorides and DODA are 0.5-2.5, further preferably 0.8-1.2.
Preferably, the reaction temperature of the substitution reaction be 0-80 DEG C, further preferably 0-25 DEG C, still more preferably
It is 0-10 DEG C, most preferably 0-5 DEG C.
Preferably, the raw material 3,6- dioxa -1,8- octamethylenediamine stir under the conditions of before substitution reaction occurs at 0-55 DEG C
Mix dissolution；It is further preferred that above-mentioned temperature is 0-10 DEG C, it is still more preferably 0-5 DEG C.
A preferred embodiment provided by the invention comprising following steps:
Tertiary fourth oxygen solution of acid chloride is added dropwise into 3,6- dioxa -1,8- octamethylenediamine (DODA) solution, it is anti-that process control is added dropwise
Answer temperature to 0-80 DEG C, stirring is filtered, filter cake is drenched with mixed solvent identical with reaction system to fully reacting after being added dropwise
It washes, is then extracted with organic solvent after water dissolution with lye pH adjustment to 10-11 in the filter cake after elution, after organic phase concentration i.e.
Obtain target compound Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine (Boc-DODA).
Reaction route of the invention is as follows:
The present invention utilizes 3,6- dioxa -1,8- octamethylenediamine hydrochloride (DODA) and tertiary fourth oxygen acyl chloride reaction, upper Boc base
HCl gas is released simultaneously, reacts with the amido in reaction system and generates hydrochloride, since 3,6- dioxa -1,8- is pungent
Diamine hydrochloride (DODA.2HCl), Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine hydrochloride (Boc-DODA.HCl), with
And N, N- bis--Boc--3,6- dioxa -1,8- octamethylenediamine solubility difference in different solvents are very big, provided by the invention
Under reaction condition, Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine preferential salt formation is simultaneously precipitated, to obtain higher yields
Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine hydrochloride (Boc-DODA.HCl).
Compared with prior art, the synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine provided by the invention
It has the following beneficial effects:
(1) the synthesis technology reaction route letter of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine provided by the invention
Single, the reaction time is short；It can be obtained the target product of high yield, high-purity without complicated purifies and separates process, it is easy to operate,
It is suitble to industrial amplification production.
(2) the present invention solves symmetrical two using dissolubility difference of the compound in different solvents similar in structure
The purifies and separates problem of product after asymmetric reaction occurs for aminated compounds, provides reaction thinking for similar reaction.
Specific embodiment
To keep purpose and the technical solution of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention, to this
The technical solution of invention is clearly and completely described.
Embodiment 1
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
With 70mL acetonitrile: toluene=5:3 mixed solvent elutes, with sodium hydroxide solution tune pH after the 1L water dissolution of the filter cake after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 183.7g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 99.3%, yield 74%.
Embodiment 2
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring,
136.6g (1.0 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL acetonitrile, then at 0-5 DEG C of temperature control, by tertiary fourth oxygen acyl
The acetonitrile solution of chlorine is slowly added dropwise into the acetonitrile solution of DODA, and time for adding was controlled at 1-2 hours, is stirred for after being added dropwise
30min, filtering, filter cake 70mL acetonitrile: the elution of methyl tertiary butyl ether(MTBE)=5:3 mixed solvent, the filter cake 1L water after elution
It with sodium hydroxide solution tune pH to 10 after dissolution, then is extracted twice with methyl tertiary butyl ether(MTBE), each 750mL, after merging organic phase
It is washed, is concentrated with 250mL, dried to get 131.6g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 99.3%,
Yield 53%.
Embodiment 3
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL toluene is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring.By 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the toluene solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
Eluted with 70mL toluene, filter cake after elution dissolved with 1L water after with sodium hydroxide solution tune pH to 10, then use methyl tertbutyl
Ether is extracted twice, each 750mL, is washed after merging organic phase with 250mL, is concentrated, dry to get 74.5g Boc-1- amino-
3,6- dioxa -1,8- octamethylenediamines, purity 95.3%, yield 30%.
Embodiment 4
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL methyl tertiary butyl ether(MTBE), then at 0-5 DEG C of temperature control, by the methyl of tertiary fourth oxygen acyl chlorides
Tertbutyl ether solution is slowly added dropwise into the acetonitrile solution of DODA, and time for adding was controlled at 1-2 hours, is stirred for after being added dropwise
30min, filtering, filter cake 70mL acetonitrile: the elution of methyl tertiary butyl ether(MTBE)=5:3 mixed solvent, the filter cake 1L water after elution
It with sodium hydroxide solution tune pH to 10 after dissolution, then is extracted twice with methyl tertiary butyl ether(MTBE), each 750mL, after merging organic phase
It is washed, is concentrated with 250mL, dried to get 101.8g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 97.2%,
Yield 41%.
Embodiment 5
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 163.9g
(1.2 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 176.3g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 99.2%, yield 71%.
Embodiment 6
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 136.6g
(1.0 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 171.3g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 99.3%, yield 69%.
Embodiment 7
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 122.9g
(0.9 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 153.9g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 99.0%, yield 62%.
Embodiment 8
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 20-25 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, and then at 20-25 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is delayed
Slowly it is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter
Cake 70mL acetonitrile: toluene=5:3 mixed solvent elution；With sodium hydroxide solution tune after filter cake 1L water dissolution after elution
PH to 10, then be extracted twice with methyl tertiary butyl ether(MTBE), each 750mL, it is washed, is concentrated with 250mL after merging organic phase, it is dry,
Up to 161.4g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.2%, yield 65%.
Embodiment 9
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is warming up to 50-55 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, and then at 20-25 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is delayed
Slowly it is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter
Cake 70mL acetonitrile: toluene=5:3 mixed solvent elution；With sodium hydroxide solution tune after filter cake 1L water dissolution after elution
PH to 10, then be extracted twice with methyl tertiary butyl ether(MTBE), each 750mL, it is washed, is concentrated with 250mL after merging organic phase, it is dry,
Up to 144.0g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 95.2%, yield 58%.
Embodiment 10
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 600mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 600mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=1:1 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 168.8g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.7%, yield 68%.
Embodiment 11
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 1.48L acetonitrile is added in 3L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 890mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 158.9g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.8%, yield 64%.
Embodiment 12
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 68.3g
(0.5 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 139.0g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.3.0%, yield 56%.
Embodiment 13
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 341.4g
(2.5 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 136.6g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.1.0%, yield 55%.
Embodiment 14
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 409.7g
(3.0 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 114.2g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 96.20%, yield 46%.
Embodiment 15
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 409.7g
(3.0 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 0-5 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
It is eluted with 70mL acetonitrile: toluene=5:3 mixed solvent；With sodium hydroxide solution tune pH after filter cake 1L water dissolution after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 149.0g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 98.67%, yield 60%.
Embodiment 16
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL acetonitrile is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 80 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
With 70mL acetonitrile: toluene=5:3 mixed solvent elutes, with sodium hydroxide solution tune pH after the 1L water dissolution of the filter cake after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 117.7g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 94.63%, yield 45%.
Embodiment 17
A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps:
148.2g DODA and 740mL ether is added in 2L reaction flask, is cooled to 0-5 DEG C under stirring, by 150.3g
(1.1 equivalent) tertiary fourth oxygen acyl chlorides is dissolved in 445mL toluene, then at 80 DEG C of temperature control, the toluene solution of tertiary fourth oxygen acyl chlorides is slow
It is added dropwise in the acetonitrile solution of DODA, time for adding was controlled at 1-2 hours, and 30min is stirred for after being added dropwise, and was filtered, filter cake
With 70mL ether: toluene=5:3 mixed solvent elutes, with sodium hydroxide solution tune pH after the 1L water dissolution of the filter cake after elution
It is extracted twice to 10, then with methyl tertiary butyl ether(MTBE), each 750mL, is washed after merging organic phase with 250mL, is concentrated, it is dry, i.e.,
Obtain 104.3g Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine, purity 92.44%, yield 42%.
The above is only embodiments of the present invention, and the description thereof is more specific and detailed, and but it cannot be understood as right
The limitation of the invention patent range.It should be pointed out that for those of ordinary skill in the art, not departing from the present invention
Under the premise of design, various modifications and improvements can be made, these are all belonged to the scope of protection of the present invention.
Claims (10)
1. a kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine comprising following steps: with 3,6- bis-
Oxa- -1,8- octamethylenediamine and tertiary fourth oxygen acyl chlorides are that raw material generation one step of substitution reaction is made,
Wherein, any two kinds mixed in acetonitrile, toluene, ether, cyclohexane, hexane and chloroform of solvent used by reacting
Bonding solvent.
2. synthesis technology according to claim 1, the solvent is any two in acetonitrile, toluene and methyl tertiary butyl ether(MTBE)
The mixed solvent of kind.
3. synthesis technology according to claim 2, the solvent is any two in acetonitrile, toluene and methyl tertiary butyl ether(MTBE)
The mixed solvent of kind.
4. synthesis technology according to claim 3, the solvent is the mixed solvent of acetonitrile and toluene, the volume ratio of the two
For 10-3:3-5.
5. synthesis technology according to claim 1, the tertiary fourth oxygen acyl chlorides and 3, mole of 6- dioxa -1,8- octamethylenediamine
Than for 0.5-2.5.
6. synthesis technology according to claim 5, the tertiary fourth oxygen acyl chlorides and 3, mole of 6- dioxa -1,8- octamethylenediamine
Than for 0.8-1.2.
7. synthesis technology according to claim 1, the reaction temperature of the substitution reaction is 0-80 DEG C.
8. synthesis technology according to claim 7, the reaction temperature of the substitution reaction is 0-10 DEG C.
9. substitution reaction is occurring for synthesis technology according to claim 1, the raw material 3,6- dioxa -1,8- octamethylenediamine
Preceding stirring and dissolving under the conditions of 0-55 DEG C.
10. synthesis technology according to claim 9, the raw material 3,6- dioxa -1,8- octamethylenediamine are occurring to replace instead
Answer preceding stirring and dissolving under the conditions of 0-10 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910173565.2A CN109776359B (en) | 2019-03-07 | 2019-03-07 | Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910173565.2A CN109776359B (en) | 2019-03-07 | 2019-03-07 | Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109776359A true CN109776359A (en) | 2019-05-21 |
| CN109776359B CN109776359B (en) | 2021-03-09 |
Family
ID=66486830
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910173565.2A Active CN109776359B (en) | 2019-03-07 | 2019-03-07 | Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776359B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823088A (en) * | 2003-05-12 | 2006-08-23 | 阿费麦克斯公司 | Novel peptides that bind to the erythropoietin receptor |
-
2019
- 2019-03-07 CN CN201910173565.2A patent/CN109776359B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823088A (en) * | 2003-05-12 | 2006-08-23 | 阿费麦克斯公司 | Novel peptides that bind to the erythropoietin receptor |
Non-Patent Citations (3)
| Title |
|---|
| RYOICHI MATSUI等: "Magnetically Alignable Bicelles with Unprecedented Stability Using Tunable Surfactants Derived from Cholic Acid", 《CHEMPHYSCHEM》 * |
| WEI TANG和SHIYUE FANG: "Mono-acylation of symmetric diamines in the presence of water", 《TETRAHEDRON LETTERS》 * |
| 陈建良: "1,8-二氨基-3,6-二氧辛烷的合成研究", 《广东化工》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109776359B (en) | 2021-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2022516932A (en) | Compounds containing diphenylmethane structure and their applications | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN107778223A (en) | A kind of preparation method of maleic acid betrixaban | |
| CN108440330A (en) | A kind of preparation method of Doxycycline Hyclate | |
| CN104860923B (en) | The preparation method of Vonoprazan fumarate | |
| CN101270074A (en) | Method for preparing high purity mitiglinide calcium | |
| CN106432032A (en) | Preparation method of levetiracetam | |
| CN109293513A (en) | A kind of preparation method of sitafloxacin intermediate | |
| CN109053479A (en) | A kind of synthetic method of quaternary amine inner salt | |
| CN109776359A (en) | A kind of synthesis technology of Boc-1- amino -3,6- dioxa -1,8- octamethylenediamine | |
| CN113651798A (en) | Preparation method of Voranolan fumarate | |
| CN106565531A (en) | Synthesis method for pharmaceutically acceptable salt of alkylhydrazine | |
| CN107216256A (en) | A kind of synthetic method of N, N diisopropyl ethylenediamine | |
| CN114369061B (en) | Preparation method of clonazepam related substance B | |
| CN106699594A (en) | Preparation method of iopromide | |
| CN109134331A (en) | The synthetic method of azithromycin genotoxicity impurity | |
| CN108164423A (en) | A kind of preparation method of naftifine hydrochloride | |
| CN107778360A (en) | A kind of method for preparing caspofungin acetate | |
| CN106748884B (en) | Preparation method of bicalutamide intermediate | |
| CN103265616A (en) | N(2)-L-alanyl-L-glutamine synthesis method | |
| CN104860946A (en) | Preparation method of CCR5 antagonist | |
| CN111825592B (en) | Synthetic method of 3-hydroxyazetidine hydrochloride | |
| CN109810052A (en) | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun | |
| CN114249703B (en) | Preparation method of medical intermediate suitable for industrial amplification | |
| CN108929236A (en) | The preparation of tomoxetine hydrochloride |
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 |