JPS60105651A - Manufacture of 2-hydroxy-5-(1-hydroxy-2-(4-phenyl-2-butyl) aminoethyl)benzamide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention is directed to the use of 2-hydroxy-5-[1-hydroxy-2-(4-phenyl-2-butyl)aminoamides having the following general formula, known as 2-bechlor. /ethyl] benzamide.

(Conventional Technique*j) Labetalol is a pharmaceutically active ingredient that has α- and β-blocking effects on adrenergic receptors.
Several methods for synthesizing 6-junmei and 2-petalol, which are important compounds in the treatment of hypertension because they have the same effect in one molecule, are known from the literature (1) E, HoGold and W,
Chang (Luntsy L.

HoCo and T, Co11in = German patent application no. 2032642 and European patent no. 9702)
(2) J, E, C11fton, I, Co11ins
* P. Hallett.

HarLley, D., Lunts, L.H.C., and P.D.

Wiks (J, Med, CI+em, 25.670
-679*1982) However, the nitrogen atom is
There was no literature describing the alkylation of red-11-phenyl-3-aminobutane with 4-hydroxy-3-carbamoyl-7enacylnolide.

On page 6 of DE 2032642, such an alkylation was described only as a hypothesis, but in the experimental section only benzylated amines were used as intermediates to be alkylated. Many attempts at alkylation of unbenzylated or protected amines have been made by the applicant.
The desired labetalol could be obtained in high yield and purity only in the 9th winter of age.

(Problems to be Solved by the Invention) An object of the present invention is to provide a method for synthesizing labetalol in a short process.

Another object of the present invention is to provide a method for synthesizing a mixture of RR and SR isomers of labetalol in a mixing ratio of about 1:1 through simple steps.

(Means for Solving the Problems) The present invention is characterized in that 1-phenyl-3-aminobutane is directly alkylated with 4-hydroxy-3-carbamoyl-7-enacylhala-f and then reduced. 2-hydroxy-5-[1-hydroxy-2 of the formula %
The present invention relates to a method for producing -(4-phenyl-2-butyl)aminoethyl]benzamide.

The adrenergic receptor blocking action of labetalol and its optical enantiomer is known [J a
pan, J, Pharmacol, 30+
743 (October 1980, J, Med, CheIm, 2
5. Table 1 on page 676 shows the remarkable effects of the pharmaceutical composition of the present invention comprising a mixture of the RR and SR isomers of two petalol in a mixing ratio of about 1:1, i.e. more active than the conventional product. Yes, there is no point suggesting the effect of reducing the dose.

In the present invention, 4-hydroxy-3-carbamoyl-
Excess of 7 enacyl halide, preferably 1 to 6
It is desirable to react a molar excess of 1-72-3-amino/butane. The above rides are CI, Br
2 I etc. can be exemplified. 2-hydroxy-5-[tN-(1-methyl-3-
722propyl)amino)acetyl]benzamide is obtained. The desired labeclol can be obtained by reducing this intermediate with a reducing agent such as NaBH+.

A typical example of the production method of the present invention is shown in the following reaction formula.

In the above, alkylation of 1-722-3-aminobutane is preferably carried out at a temperature of -15°C to +30°C, more preferably 0 to 5°C. The reduction reaction can be carried out in the same manner as known methods.

The target product of the present invention can be purified by known methods such as filtration, concentration, distillation, recrystallization, chromatography, and TLC. , the alkylation reaction is (R)-(-)-1-722-3-
When carried out using aminobutane as a starting material, (R
)-(+)-2-Hydroxy-5-[(N-(1-methyl-3-phenylp-a-pyrunamino)7cetyl-1-benzamide is obtained, which is further reduced with a reducing agent such as NaBH4 to give the general formula ( A mixture of the RR and SR isomers of the compound of 1) is obtained in a mixing ratio of approximately 1:1.

A feature of the 1-722-3-7mi/butane alkylation reaction of the present invention is that gupuru alkylation of the amine does not occur.

If the alkylation reaction is not carefully controlled, the main product will be the dimer shown below (NMR%
(confirmed by physicochemical analysis such as MSS IR and elemental analysis).

The present invention also provides a pharmaceutical composition containing as an active ingredient a mixture of the RR and SR isomers of the compound of general formula (1) in a mixing ratio of about 1:1. The pharmaceutical composition of the present invention has the same medicinal efficacy as conventional labetalol, but its efficacy is superior, so that the dosage can be reduced.

The pharmaceutical composition of the present invention can be manufactured using known excipients, carriers, solvents, etc. according to known methods. The pharmaceutical composition of the present invention may take the form of an oral preparation such as a capsule or a tablet, or an injection preparation such as an ampoule for parenteral, intramuscular or intravenous administration.

Although the dosage of the pharmaceutical composition of the present invention can be selected from a wide range, it is usually about 0.1 to 100 mg per day as the active ingredient.
/kg, preferably 1 to 50+H/kg.

(Example) The present invention will be described below with reference to Examples, but the present invention is not limited thereto.

Example 1 Synthesis of 2-hydroxy-5-[+N-(1-meth/thyl-3-phenylpropyl)amino)acetyl]benzamide hydrochloride Into a 2-liter seven flask equipped with stirring conditions and a thermometer, 10,100 O of ethanol and 98% 1-phenyl-3-7
Add Minobutane 30011 (1,970 moles). Cool the temperature of the solution to 0°C. Then 4-hydroxy-3
-Carbamoyl-7-Nacyl Bromide 100g (0,
387 mmol) and reacted for 4 hours at a temperature of 0-5°C. The reaction mixture is then left stirring overnight at 0-5°C.

When concentrated hydrochloric acid 1001 is added and stirred, crystals are precipitated. The white crystals were separated by filtration and washed with ethanol.
Dry at 50°C under vacuum for 10 hours. Melting point 220-22
120 g (yield 85.3%) of a 2° C. dry product was obtained. By making the oral solution alkaline, unreacted phenylaminobutane was recovered.

Confirmation elemental analysis of product (C+sH2□N2O5・HCI) analysis value
Calculated value C62,7562,88 H6,216,11 N 7.55 7.72 IR (Nujol) 3Z95.3150.1670.1625.1585.
1!550cm-'NMR (D, -DMSO, δ) 1.33 (3H+ dy j=31111111)1
．． 63-2.33 (2H, river), 2.55-3.33
(5H, m).

5.43 (4H and St can all be deuterated).

6.76 (I He +J+ j=4-5ppmmL
7.41 (5Hv 5)t7.96 (I H,d,
d, j = 1 ~ 4 p9)? s, ea (I Hs
dy J = 1 pp Tsuru) TLC (Developing agent: toluene/ethyl acetate/methanol/nol/triethylamine = 50/30/20/1
Capacity ratio) A main spot appeared at the same location as the standard material Rf (0,36).

Example 2 2-hydroxy-5-El-hydroxy-2
Synthesis of -(4-72-2-2-butyl)aminoethyl]benzamide In a 2 liter flask equipped with a stirrer and a thermostat, 1200 ml of water and 11,200 liters of 30% NaOH solution were added.
(2 mol) and 350 g (0.90 mol) of 2-hydroxy-5-[(N-(1-methyl-3-phenylpropyl)amino l-acetyl 1-benzamide hydrochloride) were added at room temperature. Stir until completely dissolved.

Then 30 g (0.75 mol) of 95% Na B H4 was added portionwise over about 4 hours. After the addition was complete, the mixture was stirred at room temperature overnight and the "rL C (expansion angle 1:
Chloroform/methanol/ammonia = 7!5/2
The end point of the reaction was carefully checked by 5/2.5 volume ratio). The reaction mixture was decolorized with activated carbon and then brought to isoelectric pH (10,5) with dilute acetic acid to obtain a precipitate of 2 bechlor.

This white precipitate was crushed and washed with distilled water until neutral.
Drying at 60'C under reduced pressure of 0+ue) (H gave 270ir (85% yield) of dry labeclol with a melting point of 139-141°C.
(HPL'C), two peaks with a peak ratio of approximately 1=1 were observed.

The obtained product was analyzed by TLC (771 initiator: chloroform/
When investigated using methanol/ammonia = 75/25/2.5 volume ratio), the same Rf as the standard material (0.63
) was observed.

Next, the hydrochloride of labeclol was obtained as follows.

400 ml of acetone and 50 g of labetal were placed in 1 liter of 72ml, and 15 ml of concentrated hydrochloric acid was added while stirring. The suspension was heated to 30 molar reflux and cooled to 15°C. The solid was sipped, washed on a filter with acetone and dried at 50°C under a vacuum of 20111111HFl to give pure veclol hydrochloride 52 with a melting point of 180-181°C.
g (yield 94%) was obtained.

Confirmation elemental analysis of product (C, sH24N 20-・HCI) Analysis value Calculated value C62,6562,54 H6,486,63 N 7,73 7.78 IR (Nushor) 3200+ 1655-162L 1582+ 149
0c+a-'NMR (D, -DMSO, δ) 1.46 (3Hl dt j= 3 ppia) 1.
76-2.43 (2H, theory), 2.56-3.06 (
2H, export).

3.06-3.76 (3H, mL 4.80-5.2
0 (I H, m).

6.26 (2,H, disappeared by deuteration).

7.08 (I Ht d, j=4.5ppm)t
7,4B (5Ht 5at7.6B (I H= d
-dy J= 1~4 ppmL8.16 (I Hl
dl j= i ptl teacher).

8.76 (2f (, disappeared by deuteration) MS
(m/e) 310 (3%M”-18), 292 (3%310-
17).

162 (70%310-148), 91 (100
%M”-237).

Example 3 (R)-(+)-2-hydroxy-5-[+
Synthesis of N-(1-methyl-3-phenylpropyl)ami/)acetyl 1-benzamide hydrochloride In a 2-liter 7 flask equipped with a stirrer and a thermometer, 1000 a+l of ethanol and 98% (1'1(R)-( −
)-1-phenyl-3-aminobutane 300+r(1,
970 mol) was added. The temperature of the solution was cooled to (1°C). Then, 100 g (0,387 mol) of 4-hydroxy-3-carbamoyl-7-hydroxyl bromide was added,
React for 4 hours at a temperature of ~5°C. The reaction mixture is then left stirring overnight at 0-5°C.

Add 100 ml of concentrated hydrochloric acid, evaporate the ethanol, add water to the residue, and stir to precipitate crystals. White crystals are separated by filtration, washed with ethanol and dried at 50° C. under a vacuum of 20 mtsHg. 120 g (yield 85.3%) of a dry product with a melting point of 220-221° C. was obtained.

[1:' = +14.7° (c = 5%, methanol medium Example 4 (RR-3R) 2-hydroxy-5-11-
Synthesis of hydro-2-(4-phenyl-2-butyl)aminoethyl 1-benzamide In a 2-liter flask equipped with a stirrer and a thermometer, add 1 liter of water.
200ml 1.30% NaOH solution 200ml (2 moles)
and R-(+)-2-hydroxy-5-[IN-(1-
350 g (0.96 mol) of methyl-3-phenylpropyl)amino)acetyl 1-benzamide hydrochloride was added at room temperature. The mixture was stirred until the hydrochloride was completely dissolved.

Then 30 g of 95% NaBH4 (0.75 mo/I,
) was added little by little over about 4 hours. After the addition was complete, the mixture was stirred at room temperature overnight and analyzed by TLC (I open cut: chloroform/methanol/ammonia = 75/25/2.
The end point of the reaction was carefully checked (5 volume ratio).

After decolorizing the reaction mixture with activated carbon, the isoelectric p
The reaction mixture was heated to H(10,5) to obtain a precipitate of labeclol.

Separate this white precipitate and wash it with distilled water until neutral.
When dried at 60°C under a vacuum of 0 mm Hg, the melting point is 15
9-160℃ dry product is 27011 (yield 85%)
Obtained.

HPLC: RR/SR isomer ratio = 48.37151
．． 63 RR-8R labetalol obtained above was converted to the corresponding hydrochloride salt in the same manner as described above.

Yield: 94% Melting point: 191-192°C [aJ″) = +107° (c = 5% in methanol)D
!・HPLC: RR/SR isomer ratio = 49,92150
,0B Example 5 2 petalol (RR/SR) 1 kg, lactose 600
170 g of polyvinylpyrrolidone aqueous solution was added and kneaded, and the resulting powder was passed through a sieve of 6 meshes/(!A2) and dried at 45°C.

Carboxymethyl cellulose Na salt (N
ymcel Z SD-18) 8011 and 40g of Mg stearate were added, kneaded well, passed through a sieve of 8 mesh/e1m', and then compressed with a compressor having a punch of diameter 91 to a thickness of 4.5+e111, Hardness 5
kg.

100 tablets with an average size of 1240 mg were obtained. The active ingredient in one tablet is lOO++g.

Example 6 Labetal (RR/SR) 2 kg, lactose 400
280 g of polyvinylpyrrolidone aqueous solution was added and kneaded. The resulting powder was passed through a 6 mesh/cm 2 sieve and dried at 45°C.

Carboxymethyl cellulose Na salt (N
ya+cel Z SD -16) 120 g and stearic acid M were added and kneaded well, passed through a sieve of 8 mesh/cm2, and then passed through a sieve with a diameter of 10.6 sa.
Compressed with a compressor with + bunches to a thickness of 5.4111
111. Hardness: 5 kg.

10,000 tablets with an average weight of 340 w+g were obtained. The active ingredient in one tablet is 200mg.

Example 7 Fuvetalol (RR/SR) 100+r is dissolved in 10 liters of sterile distilled water. The solution was passed through a 0.3 micron millipore (M i l l 1pore),
Then dispense 21 volumes into each ampoule and close the ampoules. It was sterilized in an autoclave on an automatic cycle and inspected for the presence of suspended impurities by light.

(Effects of the Invention) According to the method of the present invention, labetalol can be synthesized through short and simple steps.

Furthermore, by using the mixture of RR and SR isomers in a mixing ratio of approximately 1:1 obtained by the method of the present invention, as already mentioned, a better pharmaceutical composition than before is obtained. Specifically, to obtain similar therapeutic effects,
Lower 111 doses can be used.

(that's all) Agent: Patent Attorney Iwao Yamamura Continuation of page 1 @Inventor Giuseppe Seri Shiloh, Italy/2

Claims (13)

[Claims] (1) 2-hydroxy-5-[1- Hydroxy-2
A method for producing -(4-722-2-butyl)aminoethyl]benzamide. (2) The production method according to claim 1, wherein the alkylation reaction of 1-phenyl-3-7 minobutane is carried out at a temperature in the range of -15°C to +30°C. (3) The manufacturing method according to claim 2, wherein the temperature range is 0 to 5°C. (4) The production method according to claim 2, wherein the alkylation reaction is carried out under conditions of a 1 to 6 mole excess of 1-yuniru-3-7minobutane. (5) Alkylation reaction under conditions where the molar ratio of 1-phenyl-3-aminobutane and 4-hydroxy-3-carbamoyl-7enacylhydride is 5:1, that is, 3 molar excess of 1-phenyl-3-aminobutane. fII of a patent claim that makes
Manufacturing method of Paragraph 4, Paragraph 4 of Box A. (6) By alkylating (R)-(-)-1-722-3-7minobutane, (R)-(+)-2-hydroxy-5-[ (N-(
1-Methyl-3-phenylpropyl)amino)acetyl benzamide is obtained. (7) According to claim 1, obtaining a mixture of the RR and SR isomers of the compound of general formula (1) in a mixing ratio of about 1:1! ll construction method. (8) 2-hydroxy-5-[[N-(1-methyl-3
-phenylpropyl)amino)acetyl 1-benzamide hydrochloride. (9)(R)-(+)-2-hydroxy-5-[IN-
The hydrochloride according to claim 8, which is (1-methyl-3-phenylpropyl)amino)acetyl 1-pensufumide hydrochloride. (10) A pharmaceutical composition containing as an active ingredient a mixture of RR and SR isomers of the compound of general formula (1) at a mixing ratio of about 1=1. (11) The composition according to claim 10, which is in the form of a tablet and contains 10 to 1000 mg of the active ingredient. (12) The composition according to claim 11, which is in the form of a tablet and contains 100 to 200 μm of the active ingredient. (13) The composition according to claim 10 in the form of an ampoule containing IOB/+ml of the active ingredient.