KR101725983B1 - A New method of Tri-tert-butyl 2,2`,2``-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate synthesis - Google Patents

A New method of Tri-tert-butyl 2,2`,2``-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate synthesis Download PDF

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KR101725983B1
KR101725983B1 KR1020160018417A KR20160018417A KR101725983B1 KR 101725983 B1 KR101725983 B1 KR 101725983B1 KR 1020160018417 A KR1020160018417 A KR 1020160018417A KR 20160018417 A KR20160018417 A KR 20160018417A KR 101725983 B1 KR101725983 B1 KR 101725983B1
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tetraazacyclododecane
formula
present
butyl
compound
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KR1020160018417A
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Korean (ko)
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김태정
장용민
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경북대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Abstract

The present invention relates to a novel method for preparing tri-tert-butyl-2,2,2-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate. More particularly, the present invention relates to a method for preparing tri-tert-butyl-2,2,2-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate in a short time at room temperature by adding/reacting 1,4,7,10-tetraazacyclododecane and t-Butylbromoacetate to/with dimethylformamide in the presence of a base. According to the present invention, although the reaction is carried out under a mild temperature condition, it is possible to obtain tri-tert-butyl-2,2,2-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate in a short time with high yield. Thus, the method according to the present invention shows higher cost efficiency and industrial applicability as compared to the known methods.

Description

A novel process for producing tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate {A New method of Tri-tert-butyl 2,2 ', 2' '- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate synthesis}

The present invention relates to a novel process for the production of tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate More specifically, the present invention relates to a process for producing 1,4,7,10-tetraazacyclododecane and t-butyl bromoacetate in dimethylfromamide in the presence of a base, butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic anhydride) in a short time at room temperature by adding (t-Butylbromoacetate) , 7-triyl) triacetate.

Magnetic Resonance Imaging (MRI) is a method of obtaining anatomical, physiological, and biochemical information images of a body using the phenomenon of spin relaxation of hydrogen atoms in a magnetic field, It is one of the excellent imaging devices that can be invasive and can be imaged in real time.

In life sciences and medical fields, in order to make various and precise use of MRI, materials are injected from outside to increase image contrast, and the substance used at this time is called a contrast agent. The contrast between tissues on the MRI image is due to the different tissues' different relaxations of the water molecule nuclear spin in the tissue to equilibrium, and the contrast agent affects this relaxation And the difference in the degree of relaxation between the tissues is opened to cause a change in the MRI signal, thereby making the contrast between the tissues clearer. Contrast agents have a difference in utilization and precision depending on the features, functions, and targets to be injected. Augmented contrasts using contrast agents can enhance or diminish the visualization of the perimeter and imaging signals of specific organs and tissues. The contrast agent which makes the image signal of the body part which wants to obtain the MRI image relatively high is referred to as a 'positive contrast agent,' while the contrast agent which makes it relatively lower than the surrounding is called a 'negative contrast agent'.

Meanwhile, tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (hereinafter referred to as' DO3A- tBuO) 3 ') is known as a basic platform for the synthesis of gadolinium contrast agents.

For the synthesis of DO3A- ( t BuO) 3 , see European Journal of Medicinal Chemistry, 65, 12-20; 2013, Molecular Pharmaceutics, 11 (2), 445-456; 2014, Angewandte Chemie, International Edition, 54 (3), 1007-1010; 2015, Dalton Transactions, 42 (14), 4994-5003; 2013, etc. However, the synthesis methods disclosed in the above documents are disadvantageous in that they are not economically synthesized because they react at relatively high temperature conditions or consume a long reaction time, and the yield of the desired compound is low.

Therefore, the present inventors have found that when dimethylformamide is used as a solvent in the synthesis of DO3A- ( t BuO) 3 , even when the reaction is carried out at room temperature for a short time, the desired compound can be synthesized in an excellent yield, ( T BuO) 3 crystals synthesized by the method of the present invention can be obtained, and the present invention has been completed.

Accordingly, it is an object of the present invention to provide a process for the preparation of 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) of the following formula (I) in dimethylfromamide in the presence of a base, Butyl bromoacetate (t-Butyl bromoacetate) and reacting the compound of formula (III).

(I)

Figure 112016015714504-pat00001

≪ RTI ID = 0.0 &

Figure 112016015714504-pat00002

(III)

Figure 112016015714504-pat00003

In order to accomplish the above object of the present invention, the present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane (1,4,7,10,10-tetraazacyclododecane) of the following formula (I) in dimethylfromamide in the presence of a base: -tetraazacyclododecane) and t-butyl bromoacetate of formula (II) and reacting the compound of formula (III).

(I)

Figure 112016015714504-pat00004

≪ RTI ID = 0.0 &

Figure 112016015714504-pat00005

(III)

Figure 112016015714504-pat00006

Hereinafter, the present invention will be described in detail.

The present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) of the general formula (I) in the presence of a base and t-butyl A process for the preparation of a compound of formula III (tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraaza- (Hereinafter referred to as DO3A- ( t BuO) 3 ).

(I)

Figure 112016015714504-pat00007

≪ RTI ID = 0.0 &

Figure 112016015714504-pat00008

(III)

Figure 112016015714504-pat00009

In the preparation method of the present invention, the compound of formula (I) is commercially available or can be obtained by a known method, for example, J. Org. Chem., 2002, 67 (12), pp 4081-4085.

In the present invention, the compound of formula (II) is commercially available or can be prepared by a known method, for example, the method described in CN 102659588B.

The DO3A- (t BuO) 3 production method of the present invention is the use of dimethylformamide (dimethylformamide) as a reaction solvent in technical features. That is, by using dimethylformamide as a solvent in the course of the synthesis of DO3A- ( t BuO) 3 , desired compounds can be obtained in a high yield in a short time under mild conditions as compared with the methods reported in the prior art.

In the present invention, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, sodium formate, potassium formate, sodium acetate, Triethylamine, and preferably sodium hydrogencarbonate, but is not limited thereto.

According to one preferred embodiment of the present invention, in a reactor, dimethylformamide is used as a solvent to dissolve sodium hydrogencarbonate and 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) Butylbromoacetate was added dropwise to the solution at 20-35 ° C for 2 hours, and then stirred at room temperature for 24 hours. As a result, a suspension of cyanogen was generated and it was confirmed that DO3A- ( t BuO) 3 was synthesized.

Accordingly, the present invention provides a process for the production of t-butyl bromoacetate, which comprises adding the t-butyl bromoacetate dropwise at 20 to 35 ° C.

If the temperature is lower than 20 ° C, the solubility of 1,4,7,10-tetraazacyclododecane in the solvent may be lowered, and if it exceeds 35 ° C (T-Butylbromoacetate) reacts with one molecule of 1,4,7,10-tetraazacyclododecane to form DO3A- ( t BuO) 3 is generated but DO4A- ( t BuO) 3 is generated.

The time for dropping the t-butyl bromoacetate may be 30 minutes to 5 hours, preferably 1 hour to 4 hours, more preferably 1 hour to 3 hours, most preferably 2 minutes Time, but is not limited thereto.

When the dropping time is shorter than 30 minutes, four molecules of t-butyl bromoacetate are added to one molecule of 1,4,7,10-tetraazacyclododecane (1,4,7, 10-tetraazacyclododecane) with reaction DO3A- (t BuO) 3 is not produced, and may cause problems that are generated 3 DO4A- (t BuO), the reaction time becomes longer does not economical in the case of more than five time points Lt; / RTI >

Further, the present invention provides a process wherein the reaction is stirred at 20 to 35 占 폚.

The stirring time may be from 10 hours to 48 hours, preferably from 15 hours to 30 hours, more preferably from 20 hours to 25 hours, and most preferably from 24 hours to 24 hours.

In the present invention, when the reaction time is less than 10 hours, t-butyl bromoacetate reacts with 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) ( T BuO) 3 but not DO4A- ( t BuO) 3 is generated when the reaction time exceeds 48 hours. On the contrary, when the reaction time exceeds 48 hours, 3 may be generated.

Since an object of the present invention will to produce the compound (DO3A- (t BuO) 3) of formula (III) by reacting Compound (3) of the reactive molecule with the same formula (II) in one molecule of the compound of Formula I, Formula II compound is of the formula The reaction proceeds at a ratio of 3: 1 without reacting with the compound of formula (I) at a ratio of 4: 1, which is the greatest technical feature of the invention.

From this point of view, the order of addition of the compound of the formula (I), the base and the compound of the formula (II) to the solvent is very important in the production process of the present invention. That is, the reaction product in that the dimethyl formamide followed by the addition of a compound of formula (I) and a base to a compound by dropwise addition of compound II hayeoyaman slowly stirred at a relatively low temperature of 20 to 35 ℃ DO3A- (t BuO) 3 can be formed The order of addition is very important.

In the method of the present invention, the molar ratio of the compound of the formula (I), the base and the compound of the formula (II) is not particularly limited, but it is most preferred that the ratio is 1: 3: 3 in order to minimize the generation of impurities.

The method of purifying the compound to obtain DO3A- ( t BuO) 3 synthesized by the above method is not particularly limited, but the DO3A- ( t BuO) 3 crystal can be obtained by simple separation and purification.

That is, according to an embodiment of the present invention, in order to obtain DO3A- ( t BuO) 3 synthesized according to the above-described production method and present in a suspension of a solvent, (i) water is added dropwise to the suspension, Stirring the mixture for a period of time, and (ii) washing the filtered precipitate with water, followed by hot-air drying to obtain crystals.

Conventional methods for separating and purifying DO3A- ( t BuO) 3 crystals used HPLC, recrystallization, or column chromatography methods. However, in column chromatography, separation and separation of substances by the difference in adsorption and solubility between stationary phase and mobile phase It requires a large amount of solvent as a purification method and requires a long time until the material flows through the fixed bed and flows along the mobile phase. In addition, the recrystallization method is difficult to find a solvent condition in which crystals can be formed by a method using a difference in solubility in a solvent, and it takes a long time until crystals are formed.

Therefore, the production method of the present invention may further include the step of adding water after the step of synthesizing DO3A- ( t BuO) 3 , followed by hot air drying to obtain crystals.

A novel process for producing tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate of the present invention The use of dimethylformamide as a solvent makes it possible to synthesize a desired compound in a short time in spite of the progress of the reaction under mild temperature conditions, so that it is more economical and industrially applicable than conventional methods.

1 is a view showing a process of synthesizing DO3A- ( t BuO) 3 .

Hereinafter, the present invention will be described in detail.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

≪ Example 1 >

Preparation of tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate

84 g of 1,4,7,10-tetraazacyclododecane is dissolved in 1.5 L of dimethylformamide, and 134 g of NaCO 3 is added. 306 g of t-butyl bromoacetate was added dropwise for 2 hours using a constant temperature water bath at a temperature of 20-35 ° C, followed by stirring at room temperature for 24 hours to obtain a cyan suspension. When the reaction is completed, 2.2 L of water is added dropwise for 1 hour, and the mixture is stirred for 3 hours, and the resulting white solid is filtered. The filtered solid material was washed with 1.5 L of water and hot air dried at 50 째 C to give 231.4 g (92%) of the title compound as a white.

1H NMR (400 MHz, CDCl 3 ): δ = 3.37 (s, 4H, 2CH 2 acetates), 3.29 (s, 2H, CH 2 unique acetate), 3.10 (br, 4H, -CH 2 CH 2 - ring), 2.88-2.93 (br m, 12H, -CH 2 CH 2 -ring), 1.55 (s, 27H, -C (CH 3 ) 3 ).

A novel process for producing tri-tertiary-butyl-2,2`, 2``- (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate of the present invention The use of dimethylformamide as a solvent makes it possible to synthesize the target compound with a high yield in a short time despite the progress of the reaction under mild temperature conditions, It is very likely to use the award.

Claims (6)

1,4,7,10-tetraazacyclododecane of formula (I) and t-butyl bromoacetate of formula (II) in the presence of a base in dimethylformamide (t-Butylbromoacetate) and reacting the compound of formula (III).
(I)
Figure 112016015714504-pat00010

≪ RTI ID = 0.0 &
Figure 112016015714504-pat00011

(III)
Figure 112016015714504-pat00012

 The method according to claim 1, wherein the method of adding t-butyl bromoacetate is a dropwise addition at 20 to 35 占 폚.
3. The process of claim 1 wherein the reaction is stirred at 20-35 < 0 > C.
The method of claim 1, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, sodium formate, potassium formate, Potassium acetate, and triethylamine. ≪ RTI ID = 0.0 > 11. < / RTI >
The process according to claim 1, wherein the molar ratio of the compound of formula (I), the base and the compound of formula (II) is 1: 3: 3.
The method of claim 1, further comprising the step of adding crystals after the reaction step by hot-air drying the precipitated target compound by adding water.
KR1020160018417A 2016-02-17 2016-02-17 A New method of Tri-tert-butyl 2,2`,2``-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate synthesis KR101725983B1 (en)

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PCT/KR2017/000674 WO2017142221A1 (en) 2016-02-17 2017-01-19 Novel preparation method for tri-tertiary-butyl-2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

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CN114845998A (en) * 2019-12-13 2022-08-02 伯拉考成像股份公司 Preparation of protected DO3A

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KR20140125896A (en) * 2013-04-18 2014-10-30 경북대학교 산학협력단 DO3A-diaminobiphenyl compounds and Gadolinium complex comprising the same compounds as a ligand

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US20080124270A1 (en) * 2003-12-23 2008-05-29 Bracco Imaging S.P.A. Compounds Useful as Metal Chelators
CN103463647B (en) * 2013-09-17 2015-06-17 大连理工大学 Responsive nuclear magnetic resonance contrast agent based on naphthyridine amide as recognition site and preparation method thereof

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KR20140125896A (en) * 2013-04-18 2014-10-30 경북대학교 산학협력단 DO3A-diaminobiphenyl compounds and Gadolinium complex comprising the same compounds as a ligand

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114845998A (en) * 2019-12-13 2022-08-02 伯拉考成像股份公司 Preparation of protected DO3A

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