JPH042598B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a process for the preparation of esters of amino acid boron analogues as biologically active substances having antitumor or hypolipidemic activity. [Prior Art] Boron analogs of amino acids are widely known in the art. For example, Journal of Pharmaceutical Science.
Antihyperlipidemic Activity of Aminocyanoborane, Aminocarboxyborane and Related Compounds, March 1981, No. 3, V.70.
Activity of Amino Cyanoboranes, Amino
Carboxyboranes and Related Compounds) discusses the antihyperlipidemic activity of aminocyanoboranes. U.S. patents issued regarding boron analogs of amino acids include No. 4209510; No. 4312989;
No. 4368194 is mentioned. Boron analogs of amino acids can be prepared by condensation of the corresponding acids and alcohols in dichloromethane at room temperature in the presence of dicyclohexylcarbodiimide (DCC) or by the method using chloroformates disclosed below. Preparation of Representative Ester Substances 1 Trimethylamine-carboethoxyborane ( _CH3 ) _{3NBH2COOC2H5 is prepared by dehydrating a solution of (CH3)3NBH2COOH and absolute ethanol with} DCC at room _{temperature for} 6 days. did.
The yield with this method was 45%. This sweet-smelling ester has relatively high volatility and water solubility;
This is believed to be the cause of the low yield of this method. Trimethylamine- _{carbomethoxyborane} ( _CH3 ) _3NBH2COOCH3 was prepared in 82% yield by condensing ₂ (CH3) _3NBH2COOH and CH3 _- OH _with DCC for one week at room _temperature . The yield also increased to 98% when the reaction time was extended to 2 weeks. 3 (CH ₃ ) ₃ NBH ₂ COOH ₃ and an 8-fold excess (by weight) of (CH ₃ ) ₂ NH to conduct the transamination reaction in a glass pressure-resistant reaction vessel at room temperature for 2 weeks to form dimethylamine-carbohydrate. Methoxyborane _{(CH3)2NHBH2COOCH3 was produced} in 67% _yield . Washing with H ₂ O and vacuum pumping removed 8% of the unreacted starting ester in the product mixture. Ester bonds in the starting material and product were not cleaved by excess amine. As a variant (CH ₃ ) ₂ NHBH ₂ COOCH and CH ₃ OH
It was also possible to carry out a condensation reaction between DCC and DCC at room temperature for 4 days. This reaction method gave a very low yield (8%). 4 Methylamine _- carbomethoxyborane by condensing _{CH3NH2BH2COOH} and _CH3OH with DCC at room _temperature for 6 days,
_{CH3NH2BH2COOCH3 was produced .} The yield from this reaction was 21%. 5 Using the same method as for compound 4, (CH ₃ ) ₃ NBH ₂ COOH and HOCH ₂ CH ₂ Cl were
Trimethylamine-(carbo _- 2-chloroethoxy)borane (( _CH3 ) _{3NBH2COOCH2CH2Cl} (5)) by condensation with DCC for ₁ week at room _temperature
was manufactured. The yield from this reaction was 61%. 6 Ammonia-carbomethoxyborane, _H3 - _NBH2 , was produced by a transamination reaction between ( _CH3 ) _3NBH2COOCH3 and excess liquid _NH3 at room temperature for 2 weeks in a _{stainless steel} pressure vessel. COOCH ₃ was manufactured. 7 Lithiation _of ( _CH3 ) _3NBH2COOH with n- _C4H9Li in the presence of dry _N2 in ether, then lithiation of the lithium salt ( _unisolated ) at room temperature for 16 h (CH3 ₎ ) ₃ trimethylamine-(carbotrimethylsiloxy)borane by reacting with SiCl,
( _CH3 ) _{3NBH2COOSi ( CH3} ) ₃ was produced. After the operation, vacuum distillation yielded 58% of the silyl ester as a clear, moisture-sensitive liquid. This solidified when left alone. All of these compounds were analyzed by elemental analysis, IR,
The properties were investigated by HNMR and BNMR spectroscopy. The physical and spectral data of these esters are shown in the table. The IR spectrum showed characteristic absorptions of B-H and C=0. Proton and boron NMR spectral data were consistent with the formulas shown in the table for these compounds. IR spectra were recorded on a Perkin-Elmer 297 spectrometer. Solid samples were prepared as KBr disks, as Nujol mulls between NaCl disks, or as solutions in appropriate solvents. Oils were clearly recorded. Proton and boron NMR spectra were obtained on a Varian EM360A spectrometer and a JEOL FX90Q spectrometer, respectively. Elemental analysis was performed by Galbraith Laboratory, Knoxville, Tennessee.
Laboratories, Inc.) or Schwarzkopf Microanalytical Laboratories, Woodside, New York.
Microanalytical Laboratory Inc.).

[Table] a (C ₂ H ₅ ) ₂ O.BF ₃ was used as an external standard.
All chemical shifts shown in this table are (negatively) upfield from the standard. Serum Lipid Screening CF ₁ male mice (30 g) were fed rodent laboratory food and had water ad libitum during the experiment. The compound of the present invention was suspended in 1% carboxymethylcellulose-water and homogenized. Doses were calculated based on the weekly weight of these mice. Test compounds were administered intraperitoneally (ip) at a rate of 20 mg/Kg/day. On days 9 and 16, blood was collected by tail vein exsanguination into alkali-free, non-heparinized capillary tubules and centrifuged for 3 minutes to obtain serum. Using a pair of 30 ml samples of non-hemolyzed serum, the procedure was performed by Ness et al., Clin, Chem, Acta, Vol. 10, p. 229.
Serum cholesterol level (percent milligrams) using a modification of the Liebermann-Burchard reaction described in (1964).
I looked into it. Another group of mice was exsanguinated on day 14, and 25 ml samples were used to measure serum triglyceride levels (percent milligrams). Serum test results are shown in Table 2. Values shown are percentages of control.
The percentage inhibition, or effect of the compound, is determined by subtracting the percentage relative to the control from 100.

TABLE All these compounds exhibit some degree of regulatory activity with respect to serum cholesterol and triglycerides. In particular, trimethylaminecarbomethoxyborane showed a 77% inhibitory effect on serum triglycerides. Journal of Pharmaceutical Sciences (J.Pharm.Sci.), Volume 70, No. 339
This effect is remarkable when compared to the corresponding ethyl ester, which showed only 43% inhibition at a dose of 20 mg/Kg, as reported by Page (1981). The production of esters of boron analogs of amino acids as described above provided a technique for producing sufficient quantities of test materials. However, the conventional method of preparing said compounds by condensing the corresponding acids and alcohols in CH ₂ Cl ₂ at room temperature in the presence of DCC requires very long reaction times. The yield of this reaction is usually good to moderate, but it takes a week or more. Additionally, this ester contains dicyclohexylurea as a by-product that must be removed. Isolation of the desired product by fractional crystallization and solvent extraction is time consuming and difficult because the desired ester and the by-product have similar solubility characteristics. Another synthetic technique for making the esters is the treatment of trialkylamine carboxyborane with a tetrafluoroborate compound as described in US Pat. No. 4,368,194. This method was effective for compounds where the starting carboxyborane had a triamine substituent, but not for diamine, monoamine or ammonia carboxyboranes. This is because hydrogen on boron in borane is hydrolyzed. Process for Preparing Ester of the Invention A new, more effective and more commonly used synthetic method is described below. This new synthetic method can be used to prepare esters with or without a hydrogen atom on the nitrogen of the amine carboxyborane. The desired ester is usually prepared by reacting mixed carboxylic acid-carbonic anhydrides under mild conditions. In this improved synthesis method, decarboxylation occurs rapidly by mixing equimolar amounts of amine carboxyborane, alkyl chloroformate, and trialkyl amine in methylene chloride at low temperatures, i.e., between -10 and +10°C. to obtain the desired ester product. [Example] Amine carboxyborane in 100ml of methylene chloride
0.01 mole of alkyl chloroformate and 0.001 mole of dimethylaminopyridine were added to a solution containing 0.01 mole of triethylamine and 0.011 mole of triethylamine.
The mixture was maintained at 0° C. for 1 hour with constant stirring. The reaction proceeded smoothly with the production of carbon dioxide. After 1 hour, the solution was diluted with 20 ml of water.
It was washed twice and dried using magnesium sulfate.
The resulting material was concentrated to the pure ester. Various starting materials were used to prepare esters of basic structure (R) ₃ NBH ₂ COOR' using various starting compounds. Esters were prepared where R represents methyl or ethyl. The number of organic groups bonded to the amino nitrogen was 1-3. Esters were prepared where R' represents methyl, ethyl, cholesteryl, benzyl, phenyl, ethyl bromide and ethyl chloride. Examples of the present invention will be described below with reference to more specific experimental examples. Production of trimethylamine-methoxycarbonylborane (3a) Trimethylamine-carboxyborane (1.1696
g, 0.01 mol) and triethylamine (1.1131 g,
0.011 mol) in dichloromethane solution (100 ml, 0
C) and to this was added methyl chloroformate (0.945 g, 0.01 mol) followed by 4-dimethylaminopyridine (0.1222 g, 0.001 mol). The resulting mixture was stirred at 0 °C for 1 h, then washed with water (2 x 20 ml), dried over magnesium sulfate, and concentrated to give the following Table 3:
In the process, the pure ester designated 3a was obtained. yield
1.1g (84%). mp = 90-92℃. Analysis data C ₅ H ₁₄ BNO ₂ (76.0) Calculated value C45.85 H10.77 N10.69 Actual value C45.95 H10.99 N10.56 IR (CDCl ₃ ); ν = 2950 (CH); 2385 (BH) ;
1660 (CO) cm ^-1 , ¹ H-NMR (CDCl ₃ ); δ=2.72
[s, (CH ₃ ) ₃ N] 3.48 ppm (s, OCH ₃ ), ¹¹ B−
NMR [ _CDCl3 /( _C2H5 ) _2OBF3 ]: _δ = _-9.09ppm
(t, J _BH = 99Hz). Other compounds in Table 3 were prepared in a similar manner. However, for Compounds 5a and 7a, the same molar amounts of dimethylamine carboxyborane and methylamine carboxyborane were used instead of trimethylamine carboxyborane, respectively. Regarding 3e, the reaction was carried out at room temperature for one day.

[Table] Using this method, a variety of ester materials can be obtained rapidly and in high yields. Having described above a new and improved method for producing esters of boron analogs of amino acids,
Esters of this type exhibit a reducing effect on serum cholesterol and triglycerides.

Claims (1)

[Claims] 1 General formula: R ₁ R ₂ R ₃ NBH ₂ COOR' [In the formula, R ₁ , R ₂ and R ₃ each independently represent hydrogen, methyl or ethyl (provided that at least R ₁ ,
One of R ₂ and R ₃ is methyl or ethyl. ), R' represents methyl, ethyl, cholesteryl, phenyl, benzyl or haloethyl. ] A method for producing an amine borane ester having an equimolar amount of an amine carboxyborane and a compound of the general formula: ClCOOR′ (wherein R′ is as defined above) and at least an equimolar amount of a compound of the general formula: A trialkylamine of R ₁ R ₂ R ₃ N (wherein R ₁ , R ₂ and R ₃ are as defined above) is mixed in a compatible solvent, and the amine borane ester is isolated from the reaction mixture. The method comprises the steps of: 2. Process according to claim 1, characterized in that a catalytic amount of dimethylaminopyridine is added to the reaction mixture. 3. The method according to claim 1, wherein the trialkylamine is trimethylamine or triethylamine. 4. The method according to claim 1, wherein the solvent is methylene chloride. 5. The method according to claim 1, characterized in that the reaction is carried out at a temperature of -10°C to +10°C.