JP4596804B2 - Method for producing cilazapril - Google Patents

Description

The present invention relates to a method for producing a therapeutically useful cilazapril characterized by an angiotensin converting enzyme (ACE) inhibitory action.

As a manufacturing method of cilazapril, (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate represented by the following formula V in dichloromethane and (1S, 9S) -9-amino- represented by the following formula IIa: tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate is condensed and (1S, 9S) -tert-butyl represented by the following formula IIIa After obtaining 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate, tert Production methods for deprotecting butyl groups are known. (Non-Patent Document 1)

Cilazapril obtained by this method is represented by the following formula VI in which an asymmetric carbon derived from ethyl (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate is represented by (1S, 9S) -9- [ (1R) -1-ethoxycarbonyl-3-phenylpropylamino] -10-oxooctahydro-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid monohydrate (hereinafter R, (Referred to as S, S-isomer).

  In a drug substance such as cilazapril, diastereomers are compounds with different pharmacological properties and are nothing but organic impurities. In order to remove organic impurities, refining operations such as recrystallization and chromatography are required, but it is a well-known fact that organic impurity suppression at the reaction stage is effective in order to suppress the economic burden.

Further, ethyl (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate is represented by the following formula VII: (R) -2-hydroxy-4-phenylbutyric acid ethyl and trifluoromethanesulfonic acid represented by the following formula VIII: Although it is produced from an anhydride, trifluoromethanesulfonic anhydride is a very expensive raw material and has a large economic burden.

On the other hand, the following formula X produced from ethyl (R) -2-hydroxy-4-phenylbutyrate and 4-nitrobenzenesulfonyl chloride represented by the following formula IX as an intermediate for adjusting the ACE inhibitor or its precursor A production method using ethyl (R) -2-[(4-nitrophenyl) sulfonyloxy] -4-phenylbutyrate represented by the formula is known.
(Patent Document 1)

Nitro-substituted benzene derivatives have a high explosion risk, and 4-nitrobenzenesulfonyl chloride corresponds to dangerous substances 5 in the Fire Service Law. Since the manufacturing method using these compounds has a problem in safety, a manufacturing method excellent in safety is desired for the manufacture of cilazapril.
J. et al. Chem. Soc. Perkin Trans. I, 1986, 1011. JP-B-5-67140

  An object of the present invention is to provide an inexpensive and safe industrial method for producing cilazapril with less organic impurities.

When the present inventors used ethyl (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate represented by the following formula V as a substrate, the following formula XI (where R is a byproduct of the condensation reaction) Represents an alkyl or aralkyl group having up to 18 carbon atoms), and a large amount of a compound having the R, S, S configuration represented by R, S, S-isomer contained in cilazapril is produced. I found out that it was converted. In order to produce high-quality cilazapril, the following formula III having a low content of the following formula XI , that is, an excellent diastereomeric excess ratio, wherein R is an alkyl or aralkyl group having up to 18 carbon atoms It is necessary to produce a compound represented by: The present inventors generated the following formula XI because of the high electron withdrawing property of the trifluoromethanesulfonyloxy group, which is the leaving group of ethyl (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate. As a result of intensive investigation of substituents having appropriate electron withdrawing ability and leaving ability, it was found that the methanesulfonyloxy group is superior.

  The production method of the present invention is advantageous in that ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate is used as an intermediate, which is excellent in safety and can produce highly pure cilazapril at low cost.

  Ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate can be produced by sulfonating commercially available ethyl (R) -2-hydroxy-4-phenylbutyrate by the method described in JP-T-2002-521369. (1S, 9S) -9-amino-tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate is a compound described in J. Am. Chem. Soc. Perkin Trans. I, 1986, 1011. It is a compound which can be manufactured by the method as described in.

The condensation reaction is represented by the following formula I: (R) -2-methylsulfonyloxy-4-phenylbutyrate and the following formula II (where R represents an alkyl or aralkyl group having up to 18 carbon atoms) in in a compound represented by a compound represented by the following formula III performs, if necessary adding a solvent and base reaction (wherein, R represents an alkyl or aralkyl group having up to 18 carbon atoms) and Obtainable. The resulting condensate is deprotected to give cilazapril hydrochloride and then dissolved in water. If necessary, excess ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate is extracted with an organic solvent and removed. The extracted ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate can be reused. The separated aqueous solution of silazapril is neutralized and the precipitated crystals are filtered, or the aqueous solution of silazapril is neutralized and extracted with a non-aqueous solvent, and after concentration, recrystallized with various solvents to obtain silazapril.

  The amount of ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate used in the condensation reaction is 1 to 10 mol equivalents, preferably 3 mol equivalents, relative to the compound represented by the above formula II.

  When an organic solvent is used, various solvents such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, alcohols, esters, amines, polar aprotic solvents, water, or mixed solvents thereof can be used.

  Among them, preferred are ethylene glycol monomethyl ether (methyl cellosolve), ethylene glycol monoethyl ether (cellosolve), ethers such as isopropyl ether, tetrahydrofuran, dioxane, ketones such as acetone, methyl ethyl ketone, cyclohexanone, methanol, ethanol, isopropanol. , Alcohols such as methyl acetate, ethyl acetate, butyl acetate, and the like, polar aprotic solvents such as dimethylformamide, dimethylacetamide, and acetonitrile, water, or a mixed solvent thereof, and particularly preferred solvents. Is acetonitrile.

  The amount of the solvent used is 1 to 50 times, preferably 2 to 20 times, and more preferably 3 times the weight of the compound represented by Formula II.

  When a base is used, inorganic bases such as alkali metal hydroxides and alkali metal carbonates, organic bases such as alkali metal acetates, triethylamine, N-methylmorpholine and pyridine are preferable, and triethylamine, N, N-diisopropyl More preferred is ethylamine. The amount of base used is 0. 0 with respect to (1S, 9S) -9-amino-tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate. 1 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents. A large excess of base is not preferred in terms of diastereomeric suppression.

  When reacting, reaction temperature is 0-120 degreeC, Preferably it is 10-90 degreeC, More preferably, it is 20-80 degreeC. The reaction time varies depending on the reaction conditions such as the amount of solvent, the amount of basic substance, and temperature, but is usually 1 to 30 hours.

If the reaction is continued excessively, a compound having the R, S, S configuration represented by the formula XI is generated, which is not preferable. The progress of the reaction is efficiently measured by liquid chromatography and can be taken out after cooling at an appropriate time.

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
In addition, the progress of the reaction and the diastereomeric excess rate in the examples were measured by liquid chromatography analysis under the following conditions.
Apparatus: LC-2000 Plus series (JASCO Corporation)
Column: Waters XTerra RP18
Moving layer: 20 mM-KH ₂ PO ₄ (adjusted to pH = 2.5 with phosphoric acid) A mixture of aqueous solution / acetonitrile = 60/40, and sodium octanesulfonate added to a concentration of 20 mM.
Detection wavelength: 210 nm

After adding 1600 mL of toluene, 330.0 g (1.58 mol) of ethyl (R) -2-hydroxy-4-phenylbutyrate, and 217.6 g (1.90 mol) of methanesulfonyl chloride to a 5 L flask equipped with a stirrer and a thermometer. While cooling with ice water, 191.9 g (1.90 mol) of triethylamine was added dropwise. After dropping, the mixture was stirred for 1 hour while cooling with ice water, then warmed to room temperature and stirred for 2 hours, and then 1000 mL of water was added. After the organic layer and the aqueous layer were separated, the organic layer was concentrated to obtain 453.7 g (colorless oil) of ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate.
¹ H-NMR (CDCL ₃ ) δ (ppm): 1.3 (3H, t), 2.3 (2H, m), 2.8 (2H, m), 3.2 (3H, s), 4 .3 (2H, q), 5.0 (1H, t), 7.2-7.4 (5H, m)

In a 1 L flask equipped with a stirrer and a thermometer, 283 mL of acetonitrile and 282.9 g (0.99 mol) of ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate obtained in Example 1 (1S, 9S) -9 -Amino-tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate 94.3 g (0.33 mol), triethylamine 33.3 g (0.33 mol) ) And stirred at 80 ° C. for 8 hours. Acetonitrile was distilled off under reduced pressure, and then extracted by adding 283 mL of toluene and 283 mL of water. After separating the organic layer and the aqueous layer, the organic layer was concentrated and (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [ 434.0 g of a yellow oil containing 1,2-a] [1,2] diazepine-1-carboxylate was obtained.
Diastereomeric surplus rate: 99.5% de
MASS m / z 474

(1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H obtained in Example 2 was added to a 1 L flask equipped with a stirrer and a thermometer. -434.0 g of yellow oil containing pyridazino [1,2-a] [1,2] diazepine-1-carboxylate and 1200 mL of methylene chloride were added, and hydrogen chloride gas was introduced. After stirring overnight at room temperature, methylene chloride was distilled off under reduced pressure, and 500 mL of distilled water was added to dissolve the residue. Isopropyl ether (500 mL) was added and excess ethyl (R) -2-methylsulfonyloxy-4-phenylbutyrate was extracted and separated. The aqueous layer was adjusted to pH 5-7 with sodium hydroxide and stirred overnight with ice water cooling. The obtained slurry was filtered, and the crystals were dried to obtain 70.0 g (0.16 mol) of cilazapril as white crystals.
Diastereomeric surplus rate: 99.8% de
Optical rotation [α] = − 56 ° (measurement temperature 25 ° C., wavelength 589 nm of monochromatic light used for measurement, 0.2 g converted to dehydrated product, methanol, 20 mL, 100 mm)
¹ H-NMR (CD ₃ OD) δ (ppm): 1.3 (3H, t), 1.3-1.4 (1H, m), 1.6-1.9 (4H, m), 2 .4 (1H, m), 2.6 (1H, m), 2.8 (2H, m), 3.0 (1H, br, t), 3.2 (1H, m), 3.6 ( 1H, m), 3.7 (1H, t), 4.2 (2H, m), 4.8 (1H, m), 7.1-7.3 (5H, m)

In a 200 mL flask equipped with a stirrer and a thermometer, 80 mL of acetonitrile, 24.3 g (85 mmol) of (R) -2-methylsulfonyloxy-4-phenylbutyrate obtained in Example 1, (1S, 9S) -9-amino -Tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate (7.8 g, 28 mmol) and triethylamine (3.3 g, 33 mmol) were added, and the reflux temperature was increased. For 2 hours. After acetonitrile was distilled off under reduced pressure, 80 mL of toluene and 80 mL of water were added for extraction. After separating the organic layer and the aqueous layer, the organic layer was concentrated and (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [ 29.2 g of a yellow oil containing 1,2-a] [1,2] diazepine-1-carboxylate was obtained.
Diastereomeric surplus rate: 97.2% de
Mass spectrum was (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [1,2-a obtained in Example 2 ] [1,2] Diazepine-1-carboxylate.

In a 200 mL flask equipped with a stirrer and a thermometer, 80 mL of acetonitrile, 24.0 g (84 mmol) of (R) -2-methylsulfonyloxy-4-phenylbutyrate obtained in Example 1, (1S, 9S) -9-amino -Tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate 7.8 g (28 mmol), N, N-diisopropylethylamine 4.3 g (33 mmol) And stirred at reflux temperature for 5 hours. After acetonitrile was distilled off under reduced pressure, 80 mL of toluene and 80 mL of water were added for extraction. After separating the organic layer and the aqueous layer, the organic layer was concentrated and (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [ 29.0 g of a yellow oil containing 1,2-a] [1,2] diazepine-1-carboxylate was obtained.
Diastereomeric surplus rate: 97.6% de
Mass spectrum was (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [1,2-a obtained in Example 2 ] [1,2] Diazepine-1-carboxylate.

Preparation Example (1S, 9S) -tert-Butyl 9-[(1S) -Ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine -1-carboxylate, and (1S, 9S) -tert-butyl 9-[(1R) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [1,2-a] [ A diastereomer mixture of 1,2] diazepine-1-carboxylate was synthesized by the following series of steps and the liquid chromatography analysis described above was performed to confirm that the diastereomeric peaks were separated.

Comparative Example 1
A 300 mL flask equipped with a stirrer and a thermometer was charged with 30 mL of dichloromethane, 16.0 g (80 mmol) of ethyl (R) -2-hydroxy-4-phenylbutyrate, and 6.2 mL (80 mmol) of pyridine, and cooled to 10 ° C. or lower. A solution prepared by dissolving 24.8 g (80 mmol) of trifluoromethanesulfonic anhydride in 60 mL of dichloromethane was added dropwise over 1 hour. After dropping, the mixture was warmed to room temperature and stirred for 2 hours, and 10 mL of water was added. The organic layer and the aqueous layer were separated, and the organic layer was concentrated to obtain 26.4 g (colorless oil) of (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate.
¹ H-NMR (CDCL ₃ ) δ (ppm): 1.3 (3H, t), 2.3 (2H, m), 2.8 (2H, m), 4.3 (2H, q), 5 .1 (1H, t), 7.2-7.4 (5H, m)

Comparative Example 2
In a 200 mL flask equipped with a stirrer and a thermometer, 100 mL of dichloromethane, 112 g of 10% aqueous sodium hydrogen carbonate solution, 19.8 g (58 mmol) of ethyl (R) -2-trifluoromethanesulfonyloxy-4-phenylbutyrate obtained in Comparative Example 1, Add (1S, 9S) -9-amino-tertbutyloctahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate 15 g (53 mmol) at room temperature. Stir for 5 hours. The organic and aqueous layers are separated and the organic layer is concentrated (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H-pyridazino [ There were obtained 21.3 g (45 mmol) of 1,2-a] [1,2] diazepine-1-carboxylate as a brown oil.
Diastereomeric surplus rate: 76.2% de
MASS m / z 474

Comparative Example 3
(1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H obtained in Comparative Example 2 was added to a 1 L flask equipped with a stirrer and a thermometer. -Pyridazino [1,2-a] [1,2] diazepine-1-carboxylate (21.3 g, 45 mmol) and methylene chloride (150 mL) were added, and hydrogen chloride gas was introduced. After stirring overnight at room temperature, methylene chloride was distilled off under reduced pressure, and 500 mL of distilled water was added to dissolve the residue. 100 mL of isopropyl ether was added for extraction and liquid separation. The aqueous layer was adjusted to pH 5-7 with sodium hydroxide and stirred overnight with ice water cooling. The obtained slurry was filtered, and the crystals were dried to obtain 7.6 g (17 mmol) of cilazapril as white crystals.
Diastereomeric surplus rate: 95.9% de
As a result of quantifying the filtrate, it contained 8.4 g of cilazapril, and its diastereomer excess rate was 53.4%. Since the R, S, S-isomer is contained in the reaction crude product, the yield is low, and it can be seen that it remains in the obtained crystal.

Comparative Example 4
The result of experimental evaluation of explosion risk is shown below.
(R) -2-[(4-Nitrophenyl) sulfonyloxy] -4-phenylbutyrate Exothermic starting temperature 248.8 ° C
Calorific value 1.50kJ / g
There is a possibility that it corresponds to the dangerous goods class 5 by the Fire Service Act.
(R) -2-Methylsulfonyloxy-4-phenylbutyrate ethyl exothermic starting temperature 287.5 ° C
Calorific value 0.66 kJ / g
Compared with nitro-substituted benzene derivatives, the exothermic onset temperature is low, the calorific value is small and the risk of explosion is low.
Equipment: DSC50 (Shimadzu Corporation)
Heating rate: 10 ° C / min
Hold temperature: 500 ° C

  According to the method of the present invention, (1S, 9S) -tert-butyl 9-[(1S) -ethoxycarbonyl-3-phenylpropylamino] -octahydro-10-oxo-6H- having excellent diastereomeric excess ratio By passing through pyridazino [1,2-a] [1,2] diazepine-1-carboxylate, it is possible to produce high-quality cilazapril with few organic impurities at low cost. In addition, since it is excellent in safety, its value in the manufacturing process is great.

Claims (3)

(R) -2-methylsulfonyloxy-4-phenylbutyrate represented by the following formula and a compound represented by the following formula II (wherein R represents an alkyl or aralkyl group having up to 18 carbon atoms) Of the silazapril represented by the following formula IV, wherein the compound is represented by the following formula III, wherein R represents an alkyl or aralkyl group having up to 18 carbon atoms: Production method.

The production method according to claim 1, wherein a base is added during the production of the compound represented by formula III .   The production method according to claim 2, wherein triethylamine or N, N-diisopropylethylamine is used as a base.