Method of preparing hexahydro-1,4-oxazepins or their salts

专利摘要:

公开号:SU828965A3
申请号:SU802865854
申请日:1980-01-11
公开日:1981-05-07
发明作者:Йерг Трейбер Ханс；Ленке Дитер；Вортсманн Вольфганг
申请人:Басф Аг (Фирма)；
IPC主号:

专利说明:

where p, AZ-Ag have the indicated meanings, is subjected to reduction with an aluminum hydroxide lntn in an inert solvent and obtain a compound of formula V
.
(J
n
where p, AZ-Ab have the indicated values, which is treated with an aninlining agent, such as halo-anhydride or an anhydride of an acid containing 2 to 16 carbon atoms, or a benzoic acid or phenylacetic acid and the resulting 1-acyloxazenin derivative is reduced to aluminohydrogenaceous 2. active properties.
The aim of the invention is to obtain left connections expanding the arsenal of means of influencing a living organism.
This 1; spruce tree is achieved based on the well-known solution of the proposed synthetic method of hexahydro-, 4-oxazeins of the general formula I or 1X
solei, which is a common connection
The key is that 11
CKj where R is alkyl, i;
R - R have the given values, they are dedicated to the reduction of aluminum hydride ;:, ohm linge follow, if necessary. UiMOCTi, by replacing the alkyl glue R by a hydrogen atom or acyl group and isolating the desired product in free form or as a salt.
Compounds of formula I contain 1-3. symmetric carbon atoms, therefore, can be obtained as racemates or stereoisomers. Stereoisomers can (obtained in pure form, by asymmetric synthesis, or by separation of the racemate.
D. Reduction of the compound of formula II requires strong reducing agents, and preferably lithium aluminum hydride, and in particular tetrahydrofuran, dioxane or 3i |) Hp are suitable solvents. The reduction is carried out at a peevish temperature, preferably iipii, the boiling point of the solvent.
Replacing the alkoxy group on the phenyl ring with a hydroxyl group can
to carry out, for example, the action of axial rasi1. ee mi, such as sodium methyl mercaptide in the bottled anrotonic solvent, such as hexamethylphosphoric acid triamide, dimethyl sulfoxide or dimethylformamide, at 50–200, preferably at 100–150 ° C.
For acylation of free hydroxy groups
virtually all known methods may be used, for example, reaction with an acid anhydride or acid halide or an acid at a higher temperature.
The end products of general formula 11 required for the preparation of the compounds are not yet described in the literature.
They can be obtained as follows.
By reacting ketone VI with the chloride of M-Beisyl-S - methylmethylenimone VII, the so-called Mainich VIII compound is obtained.
CH,
G
/ --V-O
1Ш
about R
i-iH-dH, -N :;
shg
Compound VIII interacts with the alkyn Grin'ra compound with the final compound IX.
// HH I I
 V-C-i Er; I -N
Uh
in
from which the benzyl residue is removed by hydrogenation.
Compound X is obtained from a debenzylated compound by reacting with chloroacetyl chloride or a-chloro-propionyl chloride in the presence of a dilute sodium hydroxide solution or triethylamine.
f.
T -S S. / Vf-JH-dH-KC - -
dH,
he
From which, when heated in the presence of a base such as gret-potassium butylonate in dimethyl sulfoxide, coy65 dinene II is obtained.
Getting the original products.
a) Hydrochloride p- (M-Beisyl-Y-tagl) i-Minio-3-methoxynpropiophenone.
60 g of 3-methoxyacetophenone (0.4 mol) are heated, without interfering, for 60 minutes to 75 ° C and for 15 minutes to 80 ° C together with 70 g of N-benzyl-N-methylmethyleneimine chloride (0.4 mol) (obtained in (l; (;- (benzylmetnlamino) methane and acetyl chloride) in 500 ml of dry acetonitrnl. Then cooled, the solution is added to 2 lff, sucked off and 88 g (69% of theory) of the product with m. nl are obtained. 134-138 ° C, which is recrystallized from isopropanol or used to react the reaction in crude form.
After recrystallization from isopropanol, m.p. is 140-142C.
In the same way, p- (N-6eHsyl-N-methyl) -amino-a-methyl-3 - methoxypropiophenone hydrochloride is obtained from 3-methoxypropiophenone with m.p. 125 ° C
b) l- (N-benzyl-N-methyl) -ampo-3-oxy-3- (3-methoxyphenyl) -pentane.
To a solution of Gripier, obtained from 218 g (0.2 mol) of ethyl bromide, 48 g (2.0 mol) of magnesium and 1.5. / G of dry ether, is added with stirring and cooling the ice bath; to it 170 g ( 0.53 mol) p- (L-benzyl-L-methyl) -amino-3-methoxy-propioiophenone hydrochloride (obtained under a), is heated to boiling point for 2-Sr under reflux, stirred overnight at room temperature and decomposed the initial mixture with a solution of ammonium chloride. The ether phase is separated, dried with sodium sulfate, the ether is distilled off, the residue is fractionated in vacuo. Output 134 g (81% of theory), t kip, (0.01 mbar) 180-190 ° C.
In the same way, 1- (L-benzyl-M-methyl) -amino-3-hydroxy-3- (3 methoxyphenyl) -hexane is obtained with m.p. (0.01 mbar) 185-195 ° C;
1- (H-benzyl-H-meth1 (l) -amino-2-methyl-3-hydroxy- (3-methoxyphenyl) -pentane with a boiling point (0.01 mbar) 180-185 ° C; l- (N-benzyl-N-methyl) -amnno-3 - hydroxy-3- (3methoxyphenyl) -butane with a bale (0.01 mbar) 175-180 ° C.
c) 1-Methylamino-3-hydroxy-3- (3-methoxy-feiyl) -pentane.
78.6 g (0.25 mol) of 1- (M-benzyl-N-methyl) amino-3-hydroxy-3- (3-methoxyphenyl) -pentane (obtained under paragraph b) are dissolved in 400 ml of methanol and hydrogenated using 8 g of a 10% catalyst (palladium-carbon) at atmospheric pressure and room temperature. At the end of the hydrogen uptake, the solution is separated from the catalyst, evaporated, and a product is obtained in which a crystalline oil is obtained.
Output 53 g (94% of theory), t. Kip. 52-54 ° C (from hexane).
In the same way, 1-methylamine () -3-hydroxy-3- (3-methoxynphenyl) butane is obtained (processed further in raw pp);
1 -methylamine 10-3-hydroxy-3- (3-methoxpfeH11l) -hexane with m. Pl. 70-72 ° C from hexane;
1-methyl: ino-2-methyl-3-hydroxy-3- (3-methoxy-1-yl) -pentane (is recycled
further raw).
d) 1- (N-chloroacetyl) -methylamino-3-oxy-3- (3-methoxyphenyl) -pentane.
To a solution of 35 g (0.16 mol) of 1-metnlamiio-3-hydroxy-3- (3-methyloxyphenyl) -pentane (obtained under c) in 250 ml of ether, add 100 .1 /. 2 n. of sodium hydroxide solution, after which 18 g (0.16 mol) of chloroacetyl chloride are added dropwise over 30 minutes with stirring over 30 minutes. The mixture is then heated for 90 minutes, the ether layer is separated, dried over sodium sulfate and the solvent is distilled off. In the same way, 1- (N-chloroacetpl) -methylaminol-3-hydroxy-3- (3-methoxyphenyl) -butane is prepared;
1 - (- Chloracytel) -methylamino-3 - hydroxy-3- (3-methoxyphenyl) -gsan;
1 - (N-chloroacetyl) methylamino-2 - methyl 3-hydroxy-3- (3-methoxyphenp, 1) -pentane.
With the addition of α-chloropropionic chloride, 1- (N-a-chloropropyl) -methylamino-3-hydroxy-3- (3-methoxyphenyl) -pentap is obtained.
e) 7-Etpl (3-methoxyphenyl) -4-methylhexahydro-1, 4-oxazepin-3-one.
41.4 g (0.14 lshl) of 1- (L-chloroacetyl) -methylamino-3-hydroxy-3- (3-methoxyphenyl) -pentane (prepared in d) is dissolved in 200 ml of dimethyl sulfoxide and with stirring and mild 33.6 g of potassium gregbutanol are added in portions by cooling at 20 ° C. Then heated for 30-120 minutes to 50 ° C, then stirring at room temperature overnight. In order to process, either the solvent is distilled off at the lowest possible temperature in a vacuum, or the initial mixture is diluted with one and a half liter of water and then extracted with methylene chloride three times, each 250 ml. The solvent is removed by drying with sodium sulfate, and a crude product is obtained which is processed directly further.
Also receive
4,7-dimethyl-7- (3-methoxyphenyl) -hexahydro-1, 4-oxazepin-3-one, crystallizes, m.p. 88-94 ° C;
7- (3-methoxpfe1P1l) -4 - metlp-7-propylhexahydro-1, 4-oxazepin-3-one;
4,6-dimethyl-7-ethyl-7- (3-methoxyphenyl) g scaxapdro-1,4-oxazep 11n-3-one;
2,4-dimethyl-7-ethyl-7- (3-methoxyphenyl) hexa hydro-1,4-oxazepin-3-one. Obtaining target and products. Example 1. 7-Ethyl-7- (3-methoxyphenyl) -4-methylhexahydro-1,4-oxazepine. 36 g (0.14 mol) of crude 7-ethnl - / - (3-methoxyphenyl) -4-meth11l-hexahydro-1,4-oxazepine (step e) is dissolved in 100 ml of absolute tetrahydrofurap and then added dropwise to the suspension 15 g of lithium aluminum hydride in 500 ml of absolute tetrahydrofuran. After that, the mixture is heated to a dark boiling point, cooled, decomposed in the usual manner with water and after suction of the inorganic residue, drying and distilling off the solvent, a crude base is obtained, which is converted into its hydrochloride with hydrochloric acid. Output 15 2 (38% of theory) of hydrochloride, so nl. 181-183 ° C. In the same way, the compounds listed in Table 2 are obtained. 1. T a G l 11 and a 1 dHjO. , Yield, Example 6. 4,7-Dimethyl-7- (3-hydroxyfepnl) -hexahydro-1,4-oxazepine. From 2.3 g (0.1 mol) of sodium, 100 ml of absolute ethanol and 6.2 g (0.1 mol of methyl mercaptan, an ethanolic solution of sodium methyl mercaptide is obtained, then the alcohol is distilled off under vacuum, 50% of dimethylformamide is added and 5 , 1 g (0.02 mol) of 4,7-dimethyl-7- (3-methoxy-feil) -hexahydro-1,4-oxaseiine (base) obtained as in Example 1, and heated to 140 ° C for 3 hours. Then diluted with 500 ml of water is neutralized with acetic acid and the solution is extracted several times with methylene chloride. After removing the solvent, it is dissolved in 100 ml of ether and the product is then precipitated as hydrochloride recited by adding hydrogen chloride, recrystallized from ethanol, 2.7 g (53% of theory), mp 248 C. A compound of Example 1 was also prepared. Example 7. 7-Ethyl-7- (3-hydroxyphenyl), 4-methylhexahydro-1,4 - oxazepine, m.p., 204-206 ° C. Example 8. 7- (3-acetoxyphenol) -ethyl 1-methyl-hexhexo-1-l, 4-oxazepine 2.7 g (0.01 mole} of noluchey by the nrpmer 2 7-ethyl-7- (3-hydroxyphenyl) -4-methylhexahydro-1, 4-oxazepine hydrochloride PG is heated to boiling together with 25 ml of anhydride of acetic acid. Then the excess acetic anhydride is distilled off in vacuo, the residue is non-recrystallized from isonropane-ether. The output of 2.4 g of hydrochloride (75% of theory), so nl. 210 ° C. Example 9. (+) -or (-) -7-ETHNL-7- (3methoxyphenyl) -4 - metlpsa-hydro-1,4-oxazepine (splitting of the rappema). From a solution of 12 g (0.05 mol) of racemic 7-ethyl-7- (3-methoxy-feil) - 4-methylhexahydro, o-1.4-oxazepine (example 1) and 17 g (0.05 mol) of the levoruscular (-) - 0,0-dibenzoylvinioic acid mopohydrate in 50 ml of isopropanol and 10 ml of diisopropanol salt of the programalgative base crystallizes out after some time. . Specific rotation ratio: -45 ° (ML1ML in ethanol). Pz salt is a well-known method m is obtained from a base which is converted to its hydrochloride. When using a right rotary (+) -0.0 - dibenzonolvic acid for decomposition of the racemate, the dibenzoyl tartrate of the left rotary base is obtained in an analogous way (D) ethanol), hydrochloride and e; |, ° C +/- 44 ° (mgmol of ethanol; t.nl. 202-203 ° C The compounds of formula I have an apalgetic effect. The so-called test with using a scorching beam but DAMOR and SMITH (I. Pharmacol. 72, 74-79, 1941). In the course of this experiment, the tested compounds 1 (aqueous solutions; injected amount of 10 ml, kg were injected intraperitoneally or orally to groups of 10 mouse masks (NMRI) weighing 19–23 g. 30 s) before the substance was introduced and to the point of 30 m (n after the injection.) As the reaction time, the time until the animal's reflex tail was removed from the irradiation zone was measured. This time was for untreated animals (670 instances). moat) 6,5 ± 0,29 s.
Substances with analgesic effects, depending on the dose, prolonged the response time of animals. There is a linear relationship between the logarithms of the doses (mg / kg) and the relative increase in the duration of the reaction, on the basis of which, using regression analysis, the dose was calculated as EDU to prolong the reaction time by half. With a treatment time of no more than 30 s, the maximum increase in the reaction time was about 360%.
The analgesic effect of the compounds of the formula I in the test with the use of a burning beam, in particular, is found in the case of clinically significant oral administration (Table 2). The efficacy is higher than that of nefopam from 2 to 28 times. The quotient of the effective dose (EDO-.) When administered intraperitoneally and orally (0.41-0.83), used as
the scale of the enteral action is very high. It shows that orally effective doses of substances are only slightly higher than those acting intraperitoneally. The epteral effect exceeds that of nefopam from 2.4 to 4.9 times.
During the test with a burning ray, when non-toxic doses of nefopam are administered (regardless of the mode of administration), only a partial analgesic effect can be achieved (192% of the extension of the reaction time for intraperitoneal administration, 93% by oral administration). At high doses, nefopam is toxic (mortality is high).
With the help of compounds of the formula I, in contrast, significantly higher maximum values (by 276-435% with intraperitoneal administration and 223-41-9% with oral administration) can be achieved without toxic effects.
In tab. 2 shows the results obtained.
table 2
) Dose (mg / kg), prolonging the response time to liOO%.
) Maximal prolongation of the dosing period.
) p-911teleral action of ED intraperitoneal / ED yo. nepopa.iibno.
) At 46.4 g / kg toxic effect (6 animals from Yu die).
) At 100 mg / kg toxic effect (6 out of 10 animals die).
The compounds of formula I are administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the usual manner,
The dosage depends on the age, condition and weight of the patient and the route of administration. As a rule, the daily dose of the active principle is approximately 0, 0 per patient, either intravenously, subcutaneously or intramuscularly, or orally. This dose is administered 1 to 3 times per day. In severe cases, you can enter more often.
The novel compounds can also be applied in the form of conventional administration forms in solid or liquid form, for example in the form of
tablets, capsules, powders, granules, dragees, solutions or suppositories. These
Preparations are made using conventional techniques. The active principles began to combine with conventional medical aids and agents (swelling agents, flow regulators, preservatives, binders, fillers, softeners, wetting agents, dispersants, emulsifiers, solvents, retarding agents, and / or antioxidants).
New substances can also be introduced in one of their salts with physiologically compatible acids. Such acids include, for example, hydrochloric, sulfuric, phosphoric, tartaric, citric, fumaric, acetic, formic, succinic, maleic, lactic and amidosulfonic.

权利要求:
Claims (2)
[1]
1. Fizer L., Fizer M. Reagents for organic synthesis. M., “Mir, 1970, Vol. 2, p. 171 - 172.
[2]
2. US patent number 3598808, cl. C 07 d 87/54, published 1971.

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引用文献:

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US3830803A|1965-05-10|1974-08-20|Riker Laboratories Inc|5-loweralkyl-1-phenyl-1,3,4,6-tetrahydro-5h-benz-2,5-oxazocines and 4-ones|

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US3391149A|1965-08-28|1968-07-02|Lilly Co Eli|Novel oxazepines and thiazepines and method for their synthesis|

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IE33382B1|1968-08-16|1974-06-12|Wyeth John & Brother Ltd|Hexahydroazepines|

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US3988448A|1974-11-25|1976-10-26|Ciba-Geigy Corporation|1,4-Oxazepines as antidepressant agents|DE3242923A1|1982-11-20|1984-05-24|Basf Ag, 6700 Ludwigshafen|7-PHENYL-7-PHENOXYMETHYL-HEXAHYDRO-1,4-OXAZEPINE, THEIR PRODUCTION AND USE|

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US4800200A|1987-12-21|1989-01-24|Hoechst-Roussel Pharmaceuticals Inc.|4,8-dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazepin-5-ones|

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DE10224624A1|2002-05-30|2003-12-11|Gruenenthal Gmbh|Metabolites and prodrugs of 1-dimethylamino-3--2-methylpentan-3-ol|

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GB0328871D0|2003-12-12|2004-01-14|Arakis Ltd|Resolution process|

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IT1401109B1|2010-07-02|2013-07-12|Archimica Srl|NEW PROCESS FOR THE PREPARATION OF TAPENTADOL AND ITS INTERMEDIATES.|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19792901180|DE2901180A1|1979-01-13|1979-01-13|HEXAHYDRO-1,4-OXAZEPINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME|

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