KR0134565B1 - Method of preparation of bisoxime derivatives - Google Patents

Abstract

The present invention relates to (RR / SS) -4, 8-diaza-3, 6, 6, 9-tetramethyl undecane-3, 8-diene-2, 10, which are medical diagnostic reagents by one-step or two-step reactions. It relates to a method for producing Dion bis oxime. By the present invention, d, 1-HM-PAO can be effectively obtained.

Description

Method for preparing bis oxime derivative

The present invention relates to (RR, SS) -4, 8-diaza-3, 6, 6, 9-tetramethylundecane-2, 10-dione bisoxime [(RR, SS) -4, 8-Diaza-3, 6, 6, 9-tetra-methylundecane-2, 10-dione bisoxime (d, l-HM-PAO)].

The development of single photon emission computed tomography (SPECT) has led to the urgent need for radiopharmaceuticals for localized cerebral blood flow. However, since the use of ¹²³ I has a disadvantage that the price is expensive, there are many restrictions on use, especially in the domestic it was more difficult to use.

As with other radiopharmaceuticals, radiopharmaceuticals for local cerebral blood flow measurement have made great efforts to synthesize compounds capable of labeling ^99m Tc. Radiopharmaceuticals for localized cerebral blood flow should be well distributed in the brain, in proportion to the brain blood flow, and should be difficult to get out of the bloodstream once it enters the brain. Many compounds have been synthesized to satisfy these conditions. Most of them have a good ability to pass through the blood barrier, but many of them fall back into the bloodstream due to lack of ability to remain in the brain. However, many derivatives of the PnAO family have been synthesized in view of the fact that the Tc-99m complex of propyleneamine oxime (PnAO) is neutral, fat-soluble, and absorbed by the brain in proportion to the bloodstream. Hexamethyl propyleamineoxime (HM-PAO) was developed, and the results and clinical results in experimental animals have been reported to be excellent in absorption and storage by the brain following local cerebral blood flow.

Conventional manufacturing method of HM-PAO is heated to reflux using Dean and Stark apparatus, reduced to obtain HM-PAO, where both meso and d, l-HM-PAO is obtained Lose. Therefore, the yield (33%) was greatly reduced due to recrystallization using several ethyl acetate to obtain d, l-HM-PAO (J. Nucl. Med. 28 191-202, 1987).

The present inventors have just stirred at room temperature for 2, 3-butanedione monooxime and 2, 2-dimethyl-1, 3-propane diamine without using a chadine and a stark device, which have been studied to solve the above disadvantages. And then reduced the compound to obtain d, l-HM-PAO without meso-HM-PAO, and also as a one-stage reaction in the presence of a 2, 3-butanedione monooxime and 2, 2 The present invention has been completed based on the fact that d, l-HM-PAO can be obtained by reacting -dimethyl-1,3-propane diamine.

Accordingly, an object of the present invention is to prepare a method for preparing d, l-HM-PAO from 2, 3-butanedione monooxime and 2, 2-dimethyl-1, 3-propane diamine by one-step or two-step reaction. To provide.

More specifically, the one-step preparation method of the present invention consists of reducing amination reaction of 2, 3-butanedione monooxime with 2, 2-dimethyl-1, 3-propane diamine in the presence of a reducing agent, and the present invention. The two-step preparation method of the 2, 3-dibutanedione monooxime solution in anhydrous ethyl alcohol was added 2, 2-dimethyl-1, 3-propane diamine and stirred at room temperature to 4, 8-diaza-3, 6 , 6, 9-tetra methyl undegan-3, 8-diene-2, 10-dione bis oxime, followed by reduction.

In the preparation method, sodium cyano borohydride (NaBH ₃ CN), HC1, hydrogen, sodium triacetoxy borohydride, pentacarbonyl iron-alcoholic KOH, BH ₃ -pyridine and the like may be used as the reducing agent.

In particular, the first step of the method of the present invention is a method of producing an amine by the reaction of the amine and the carbonyl functional group at pH = 6 through a reductive amination reaction with a reducing agent (eg, NaBH ₃ CN) of the monooxime carbonyl group to be. The desired product can be obtained by appropriately adjusting the pH of the reaction solution.

An example of the preparation method of the present invention is as follows.

One step manufacturing method of the present invention

Two step manufacturing method of the present invention

If described in detail as an example to help understand the present invention.

Example 1

4, 8-diaza-3, 6, 6, 9-tetramethyl undecane-3, 8-diene-2 10-dione bisoxime

2, 3-butanedione monooxime (10 g, 98.9 mmol) is dissolved in 80 ml of anhydrous ethyl alcohol, and the solution is heated to 60 ° C. Slowly add 2, 2-dimethyl-1, 3-protane diamine (4.55g, 44.5mmol) to this solution. After stirring for 16 hours at room temperature, all solvents are removed and cold acetonitrile (-40 ° C) is added. The white solid produced at this time is filtered to obtain 4, 8-diaza-3, 6, 6, 9-tetra methyl undecane-3, 8-diene-2, 10-dione bis oxime.

Yield: 10.7 g (91%)

mp: 132-134 ° C

NMR: (DMSO); (δ1.0, 6H, s, Me); (δ1.9, 12H, s, MeC); (δ3.2, 4H, s, CH ₂ N); (δ11.2, s, 2H, NOH)

Example 2

(RR / SS) -4, 8-diaza-3, 6, 6, 9-tetra methyl undecane-2, 10-dione bis oxime (d, l-HM-PAO) 4, 8-diaza-3 , 6, 6, 9-tetra methyl undecane-3, 8-diene-2, 10-dione bisoxime (10 g, 37.3 mmol) was dissolved in 100 ml of anhydrous ethyl alcohol, and the temperature of the solution was reduced from -5 to -10. Adjust the temperature to ℃. Sodium borohydride (NaBH ₄ ) (1.4 g, 37.3 mmol) was slowly added to the solution for 20 minutes. Stir at this temperature for 1 hour and add 20 ml of water. After reacting for another 1 hour, reduce the volume of solution by 1/3 and add 50 ml of water again. After adjusting the solution pH to about 11, the resulting white solid was obtained by filtration and recrystallized using ethyl acetate solution to prepare d, l-HM-PAO, the desired (RR / SS) isomer.

Yield: 8.2 g (81%)

mp: 128-130 degreeC

NMR: (DMSO); (δ0.78, 6H, s, Me); (δ1.07, 6H, d, Me); (δ 1.64, 6H, s, Me); (δ2.12, 4H, q, CH ₂ ); (δ 3.12, 2H, q, CH); (δ 3.3, 2H, s, NH); (δ10.5, s, 2H, NOH)

Example 3

(RR / SS) -4, 8-diaza-3, 6, 6, 9-tetra methyl undecane-2, 10-dione bis oxime 2, 2-dimethyl-1, 3-propane diamine (1.0 g, 9.9 mmol), sodium cyano borohydride (2.49 g, 39.6 mmol) and 2, 3-butanedione monooxime (5.0 g, 49.5 mmol) were slowly added to 5 ml of anhydrous methanol. The color of the solution changes from colorless to pale yellowish green with a slight exotherm. After stirring at room temperature for 72 hours, the solvent was removed, water was added, and the resulting solid was filtered (RS / SR, RR / SS) -4, 8-diaza-3, 6, 6, 9- Tetramethyl undecane-2, 10-dione bis oxime is obtained and recrystallized from ethyl acetate to prepare the desired (RR / SS) isomer d, l-HM-PAO.

Yield: 2.35 g (87%)

mp: 128-130 degreeC

NMR: (DMSO); (δ0.78, 6H, s, Me); (δ1.07, 6H, d, Me); (δ 1.64, 6H, s, Me); (δ2.12, 4H, q, CH ₂ ); (δ 3.12, 2H, q, CH); (δ 3.3, 2H, s, NH); (δ10.5, s, 2H, NOH)

Claims (4)

2,2-dimethyl-1,3-propanediamine was added to a 2,3-dibutanedione monooxime solution in anhydrous ethyl alcohol and stirred at room temperature to give 4,8-diaza-3, 6, 6, 9-tetra (RR / SS) -4, 8-diaza-3, 6, 6, 9-tetra methyl unde consisting of the steps of obtaining and then reducing methyl undecane-3, 8-diene-2, 10-dione bis oxime Can-2, 10-dione bis oxime (d, l-HM-PAO) manufacturing method. The method according to claim 1, wherein sodium borohydride is used as the reducing agent. (RR / SS) -4, 8-diaza-3, 6, consisting of reductive amination reactions of 2, 3-butanedione monooxime with 2, 2-dimethyl-1, 3-propane diamine in the presence of a reducing agent 6, 9-tetra methyl undecane-2, 10-dione bis oxime (d, l-HM-PAO). The preparation according to claim 3, wherein the reducing agent is selected from the group consisting of sodium cyano borohydride and HCl, hydrogen, sodium triacetoxy borohydride, pentacarbonyl iron-alcoholic KOH, BH ₃ -pyridine Way.