JPS5911589B2 - Method for producing benzodiazepine derivatives - Google Patents

Description

Detailed Description of the Invention 35 The present invention relates to a method for producing benzodiazepine derivatives of the general formula: [wherein R represents halogen, R2 represents hydrogen, and R3 represents phenyl or 27-pyridyl] be.

The production method of the present invention comprises preparing a compound of the general formula, wherein R1, R2 and R3 have the same meanings as above, and x represents chlorine, bromine or iodine, preferably chlorine, in an inert organic solvent. with hexamethylenetetramine and isolating or not isolating the intermediate formed, in which R1, R2, R3 and x have the same meanings as above, and adding ammonia to the reaction. It is characterized by its use.

[Halogen] as used herein refers to the four forms of chlorine, bromine, fluorine and iodine, unless otherwise specified.

Rl. When is a halogen, chlorine and bromine are preferred halogens, with chlorine being particularly preferred. In a preferred embodiment of the present invention, the following compounds are produced:
J me[chlor-1,3-dihythro-5-phenyl-2H-
1●4-benzodiazepine-2-one and 7-prom-1,3-dihythro-5-(2-pyridyl)-2H-1
-4-Benzodiazepine-2-one.

The prior art discloses inter alia the preparation of benzodiazepines of formula (1) using hexamethylenetetramine and compounds of formula ().

However, such conventional methods do not always provide good yields. If ammonia is the formula (
) with hexamethylenetetramine, or if this reaction is followed by treatment with ammonia, it is present in the Journal of Heterocyclic Chemistry (J. HeterOcyclic Chemistry).
m. ) Vol. 7, p. 1173 (1970), it has been found that the compound of formula (1) can be obtained in a better yield than the so-called conventional method.

Therefore, the present invention provides a method for preparing a compound of formula (1) using a compound of formula () and hexamethylenetetramine as indicated in the above description of the prior art, which method comprises: It is simple and easy and gives higher yields than the prior art methods described above. Furthermore, when the technique described in Section X is used, a highly pure compound of formula (1) can be obtained. In one aspect of the invention, namely the reaction of a compound of formula () with hexamethylenetetramine in the presence of ammonia, the reaction is accomplished in the presence of any inert organic solvent suitable for the purposes of the invention. Among the many such inert organic solvents that are highly suitable are lower alkanols such as methanol, ethanol, n-butanol and the like, dimethylformamide and similar inert organic solvents, as well as their aqueous counterparts. It includes a mixture of ethanol aqueous solution (95%) and butanol aqueous solution. What is required of the solvent is that the starting materials dissolve therein and do not interfere with the subsequent reaction. Preferred are lower alkanols such as methanol or ethanol. Moreover, the nature of the solvent must be such that it tends to solubilize the ammonia in such a way that it enters the reaction zone. Although temperature and pressure are not critical for the successful implementation of aspects of this process, it is preferred to carry out the reaction at a temperature between about room temperature and about the reflux temperature of the reaction medium. Most preferably, high temperatures are used, most preferably at about reflux temperature of the reaction medium. Additionally, in some embodiments, the reaction is conducted under pressure to increase the concentration of ammonia in the reaction zone. Preference is given to adding ammonia to the reaction medium in such an amount as to saturate the inert organic solvent.

As mentioned above, it is preferred to carry out this reaction at the reflux temperature of the solvent because it will generally require less ammonia to saturate the solvent if higher temperatures are used. Usually only a small molar amount of ammonia is required to successfully complete the desired reaction of the compound of formula () above with hexamethylenetetramine. Although the starting material is dissolved in this way, it is a preferred aspect that a solvent is chosen that is saturated with ammonia when a relatively small molar amount of ammonia is added thereto. For example, ethanol is used in one preferred embodiment. Saturation occurs when about 1% molar amount of ammonia is present in the reaction zone. Such percentages are the ratio of the numerator of the molar amount of ammonia required to supersaturate the solvent medium to the denominator, which is the sum of the molar amounts of hexamethylenetetramine, the compound of formula (), and ammonia present in the reaction zone. It can be determined by
The solubility of ammonia in any inert organic solvent that can be used for the purposes of this invention can be readily determined by reference to common texts. From this determination, suitable inert organic solvents can be easily identified. As stated above, the use of pressure will increase the concentration of ammonia present in the reaction zone above that required for the inert organic solvent to be normally saturated. Thus, in one embodiment, the reaction is carried out under about 1 to 2 atmospheres. Larger amounts of ammonia can be fed to the reaction zone by the simple expedient of using a suitable aqueous inert solvent. It has been observed that when carrying out the process of the invention intermediates of the above formula () are obtained.

This intermediate can be isolated from the reaction medium or reacted without isolation with ammonia to produce the desired compound of formula (1) above. In this way the expression ()
A compound corresponding to formula (1) can be obtained by isolating the compound from the reaction medium and treating it with ammonia.

Alternatively, the compound of formula () above and hexamethylenetetramine can be added to the reaction zone to provide ammonia therein without isolating the compound of formula ().
In a preferred embodiment, the intermediate of formula () is not isolated and is reacted with ammonia without being isolated from the reaction medium in which it was prepared. Compounds of formula () can be prepared by techniques other than those described here.

For example, in a manner similar to that described in the aforementioned Journal of Heterocyclic Chemistry, the compound of formula () above and hexamethylenetetramine are added to a low polarity solvent such as acetonitrile at room temperature with stirring, and thus Intermediates of formula () can be generated. The compound of formula () so obtained is isolated from the solvent in which it was prepared and then reacted with ammonia to obtain the compound of formula (1) above in good yield and high purity. be able to. The reaction of a compound of formula () with ammonia is carried out by treatment of a compound of formula (1) as described above with hexamethylenetetramine and ammonia, as should be obvious to one of ordinary skill in the art. The reaction proceeds under the same reaction conditions as the method for producing the same. In this way, using hexamethylenetetramine, the formula (1
) All of the reaction conditions and solvents detailed above in connection with the preparation of formula () apply to the treatment of the intermediate of formula () with ammonia, except that hexamethylenetetramine is not added to the reaction zone. It is equally effective. As should be clear from the above, the invention consists in adding ammonia to the reaction medium in which hexamethylenetetramine and a compound of formula () or an intermediate of formula () are present. The method of adding ammonia to the reaction zone is not critical. For example, hexamethylenetetramine can be added to an inert organic solvent of the type shown above, and then ammonia can be added to the reaction zone before the compound of formula () above is added. . Alternatively, ammonia can be dissolved in an inert organic solvent, followed by the addition of a compound of formula () above and hexamethylenetetramine or an intermediate of formula () above to the reaction zone. Furthermore, the manner in which ammonia is introduced into the reaction zone is not critical.

One preferred process aspect is to provide the ammonia as gaseous ammonia by simply bubbling it into the reaction zone.
Ammonia can also be used in less preferred embodiments by using an ammonia-generating agent in the reaction zone, such as ammonium carbonate, which dissociates to ammonia when present in a solvent medium such as ethanol that is heated to reflux temperature. It can also be supplied as Yields are not always good when ammonia-generating chemicals are used instead of ammonia itself. One particularly noteworthy feature of the process aspect of the present invention is that large molar excesses of hexamethylenetetramine are not required for the success of this invention.

For example, from this point of view, if one of the compounds of formula () is used
0.1 mole of hexamethylenetetramine per mole is
Most preferably small amounts, such as 0.5 mole, are used to obtain the desired compound of formula 5(1) above. The present invention thus achieves the additional and particularly surprising and noteworthy object of minimizing the amount of hexamethylenetetramine used, and as a result of which the method described in The price of the raw material used in surutakome was reduced without correspondingly decreasing the yield. A particularly noteworthy aspect of the present invention therefore further provides a process that is particularly industrially viable. It must be noted that the yield begins to decrease if less than 0.5 mol of hexamethylenetetramine is used. However, if 0.5 mol of hexamethylenetetramine is used, the compound of formula (1) is obtained in very good yields and in high quality. It has been observed that formaldehyde is evolved as a result of the reaction of hexamethylenetetramine with the above compound of formula () according to the above method of preparation.

The ammonia present reacts with the formaldehyde thus formed to regenerate hexamethylenetetramine. It has further been found that the desired compounds of formula (1) can be prepared by treating compounds of formula () with formaldehyde in the presence of excess ammonia.

In the last mentioned reaction, anhydrous formaldehyde (bara formaldehyde) or an aqueous formaldehyde solution (38
% formalin) can be used.

Although the temperature and pressure are not critical for successfully accomplishing this aspect of the process, it is preferred to carry out the process at elevated temperatures, such as from about reflux to the temperature of the reaction medium. The reaction is preferably accomplished in the presence of an inert organic solvent, among which are a number of suitable organic solvents, including the formation of a compound of formula (1) from a compound of formula () with hexamethylenetetramine and ammonia. You can include things that you have previously reviewed that are relevant to what you are doing. As such, among the many inert organic solvents suitable for the purpose of this aspect of the invention are methanol, ethanol, n-butanol and the like, dimethylformamide and similar inert organic solvents, as well as methanol, ethanol, n-butanol and the like. Mixtures with water such as ethanol or aqueous methanol solutions are included. Again in X, all that is required of the solvent is that the starting materials dissolve therein and that the solvent does not interfere with the subsequent reaction.
Preferred is methanol and/or ethanol. In this aspect of the process, formaldehyde is reacted with ammonia present in molar excess to form hexamethylenetetramine, resulting in a compound of formula (), which is isolated or isolated. It is preferably converted to the compound of formula (1) without being isolated.

The method of introducing ammonia and the amount introduced are the same as described when the compound of formula (1) is prepared using hexamethylenetetramine and ammonia. Thus, in a preferred version, the reaction solvent in this process variant is preferably saturated with ammonia by constantly bubbling ammonia through the reaction solvent. Although the following examples specifically illustrate the invention:
It does not limit it. All temperatures are expressed in degrees Centigrade (°C). Example 1 7.21 parts of ethanol and 470.4 parts of hexamethylenetetramine are added to a 121 three-necked flask with a condenser and an ammonia inlet tube.

Ammonia is bubbled through the resulting reaction medium with stirring until the medium is supersaturated. 2- while refluxing
Chlor-acetamido-5-chlorobenzophenone 480
．． Add 0y carefully over 4 hours. Heat to reflux for an additional 2 hours while bubbling in ammonia. The resulting medium is left overnight and then concentrated to dryness in vacuo. Toluene 2.41 in the concentrate? and the resulting medium is heated to reflux. Then p-toluenesulfonic acid 0.5
Add y. Reflux is continued for 1 hour. Cool the medium to 70° C. and then add 1.51 g of boiling water. The separated product was cooled to 20°C, isolated by filtration, washed, and dried under vacuum to obtain 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine with a melting point of 213-214.
- Get on. Yield: 80.3% 7-prom-1,3-dihythro-5-(2-pyridyl )-2H-1
- 4-benzodiazepine-2-one can be produced. Example 2 A 121 three-necked flask with a sealed stirrer, countercurrent condenser, and ammonia inlet tube is charged with 7.21 volumes of ethanol.

Heat on a steam bath to reflux the alcohol. The solvent is then saturated with ammonia to a concentration of about 0.6 to 0.7% by weight. While the heating bath is being removed, hexamethylenetetramine 4937 is added. The mixture is heated again and 2-chloroacetamido-5-chlorobenzophenone 4807 is gradually added little by little. Ammonia is bubbled into the constantly refluxing solution. The addition of the chloracetamide compound is carried out over a period of 3 to 4 hours. The reaction mixture is then heated to reflux for a further 2 hours. Stop the ammonia injection and remove the alcohol by vacuum distillation.

Transfer the reaction flask to a heating mantle and slurry the residue in 2.4 ml of toluene and heat to reflux.

At reflux temperature, 0.57 g of p-toluenesulfonic acid is added twice, 15 minutes apart. A small amount of water (approximately 1 to 2 mO) separates. The slurry of crystals is cooled to 70 °C and the water-soluble substances are dissolved in 700 °C of warm water. The heterogeneous mixture is brought to room temperature while stirring overnight. Cool to 250 ml of water from a cold tap.
ml and once with 250 ml of cold (0° C.) toluene. The product is dried to constant weight at 80 DEG C. to give 7-chlor-1,3-dihythro-5-phenyl-2H-1,4-benzodiazepine-2-one with a melting point of 213-214. Yield 80.7% Example 3 2-Chloracetamide 5-chlorobenzophenone 907 and hexamethylenetetramine 92 in 50 ml of ethanol 13
．． Add 5V.

The resulting medium is blown with ammonia under pressure. The resulting medium is heated to reflux. The medium obtained is evaporated to dryness in vacuo. It is then ground twice with 250 ml of boiling water on a steam bath. Decant the aqueous phase. The crystalline residue is heated on a steam bath with 250 ml of toluene for 30 minutes and then cooled to room temperature. The formed crystals were filtered, washed twice with 25 ml of toluene and twice with 25 ml of petroleum ether, and dried to a constant weight to give 7-chlor-1,3-dihydro-5-phenyl-2H-1 with a melting point of 213-215°C. 4
- Obtain benzodiazepine-2-one. Yield 78% Example 4 95% ethanol 1 in a pressurized container with stirring
3.5112-Chloracetamide-5-chlorobenzophenone 900y and hexamethylenetetramine 925
Prepare y.

The medium is saturated with ammonia gas while stirring. Discontinue ammonia supply. The obtained medium is 78~
Heat at 80°C for 3 hours. After cooling and expelling the ammonia, one batch is taken out of the pressure cooker and placed in a vacuum distillation kettle. Concentrate the batch to dryness in vacuo on a steam bath. Toluene 21/21 and p-toluenesulfonic acid 5
．． 0V is applied and the resulting medium is heated to reflux. Approximately 5 ml of water is removed by azeotropic distillation. After cooling to 70° C., add 3 liters of water at 70 m.

The slurry of crystals so obtained is cooled to +10 to +15 degrees for 1 hour. After filtration, the product was washed twice with 250 mj of water from the faucet and 250 mj of cold (10°C) toluene.
After washing once with
13.5 7-chloro-1,3-dihythro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained. Yield 66% Example 5 Ethanol 1100ml 11 Hexamethylenetetramine 7
0.0f (0.5 mol), 26% ammonium hydroxide solution 58WL1 and 2-quilacetamido-5-chlorobenzophenone 308.2? (1 mol) is stirred and heated to gradual reflux while bubbling ammonia.

After continuing reflux for 5 hours, the ammonia flow was stopped,
The reaction mixture is distilled to dryness in vacuo. The residue is heated to reflux for 30 minutes in a mixture of 500 ml of toluene and 500 ml of water and then allowed to cool slowly to room temperature. Filter the crystalline substance and add toluene 1007F
! After washing twice with 250 ml of boiling water and once with 250 ml of boiling water, dry to constant weight. The product, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, melts at 210°C. Yield 83.5% Example 6 Ethanol 11001111 Hexamethylenetetramine 35f (0.25 mol), 26% ammonium hydroxide solution 58mj and 2-chloroacetamido-5-chlorobenzophenone 308.2V (1.0 mol) The mixture is reacted as described in Example 5 except that the reflux time is increased to 5 hours to 7 hours.

The reaction product 7-chlor-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one, isolated in the same manner as in Example 5, melts at 208.5-209 ton. Yield 81.6% Example 7 Methanol 550ml 11 Hexamethylenetetramine 14
．． 1y (0.1 mol) and 2-chloroacetamide-5-
A mixture of 308.2y of chlorobenzophenone is saturated with ammonia at room temperature with stirring.

The solution is gradually heated to reflux while constantly bubbling ammonia into the solution. Reflux is continued for 24 hours. The ammonia blowing is stopped and the resulting crystal slurry is cooled to room temperature. The product was filtered and diluted with methanol 125W11.
Washed 4 times with 500 Tn1 of boiling water and dried at 213 Tn1.
-7-chlor-1,3-dihythro-5-phenyl-2H-1●4-benzodiazepine-2-
Get on. Yield: 62.3% Example 8: 275 ml of methanol and 5 ml of 2-chloroacetamide
- A mixture of 154.27 (0.5 mol) of chlorobenzophenone is heated to reflux with constant ammonia bubbling.

237ml of 37% formaldehyde solution under reflux
Prepare for about 40 minutes. The reaction mixture is then heated under reflux for 5 hours. The ammonia flow was stopped, the crystal slurry was cooled to room temperature, filtered and then diluted with 125 ml of methanol.
Wash with 500ml of boiling water 4 times and dry. 7-chloro-1,3-dihythro-5-phenyl-2H-1,4-benzodiazepine-2-one having a melting point of 211.5-214.5°C is obtained. Yield 77.3% Example 9 Paraformaldehyde 14762f and methanol 5501!
The mixture in step 11 was heated to reflux while stirring and constantly bubbling ammonia.

The resulting slurry of hexamethylenetetramine crystals is cooled to room temperature and then 308.2f (1.0 mole) of 2-chloroacetamido-5-chlorobenzophenone is added in one portion. The reaction mixture is heated to reflux for 10 hours while bubbling ammonia. After stopping the ammonia blowing, the reaction mixture was cooled to room temperature, filtered, and washed twice with 125 ml of methanol and 4 times with 500 ml of hot water.
dry. 7-chlor-1.3 with melting point 2.5-215℃
-Dihydro-5-phenyl-2H-1.4-benzodiazepine-2-one is obtained. Yield 81.4% Example 10 51 equipped with a stirrer and calcium chloride drying tube
Add 250 y of 2-chloroacetamido-5-chlorobenzophenone and 122,57 y of hexamethylenetetramine to 2.5 ml of acetonitrile in a three-necked flask.

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [R_ in the formula
1 represents halogen, R_2 represents hydrogen, and R_3 represents phenyl or 2-pyridyl], the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (II) [in the formula , R_
1, R_2 and R_3 are the same as above, and X represents chlorine, bromine or iodine] with hexamethylenetetramine in an inert organic solvent, resulting in the formation of the general formula ▲ , chemical formulas, tables, etc. ▼ (III) [In the formula, R_1, R_2, R_3 and How to become.