Crystalline 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine with a bulk density between 220-360 g/l

 

(57) Abstract:

The inventive crystalline 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine F.-ly (I) with a bulk density of 220 - 360 g/l table 4. The structure of f-crystals 1:

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and the method of its production. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine can be used as a cardiotonic means simultaneously with vasodilator properties.

Known to produce 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine by reacting 3-cyan-2-chloro-5-(pyrid-4-yl)- pyridine with an excess amount of research and recrystallization of the crude product from ethanol [1,2] While the recrystallized product precipitates in the form of a thin, "stringy" needles, which have only a small apparent density of 150 g/l and creating galenical significant processing difficulties.

Therefore there is an urgent need in a compact, crystalline 3-cyan-2-morpholino-5-(pyrid-4-yl)-Piri dine with high apparent density and in a manner that allows it to receive.

The basis of the invention p is high apparent density and how it is received.

This is because 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine or:

a) is dissolved in acid and the obtained solution it is precipitated by using reason, either:

b) is dissolved in the chlorohydrocarbons and precipitated from its solution by adding aliphatic hydrocarbons, either:

b) recrystallized from aliphatic esters of carboxylic acids.

You can use 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine in the form of the crude product and purified condition.

A special variant of the invention consists in the fact that the solutions of 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine before precipitation or crystallization is subjected to treatment with adsorbents as activated carbon or silica gel, which especially has the advantage of using the crude 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine.

If 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine need to besiege of its acidic solutions using bases, respectively, of the present invention, it is preferable to carry it out at temperatures 15-40aboutWith, preferably, however, at the 30aboutC.

For implementing the method according to the variant: a) suitable Neorganicheskie is full of metals, solutions of ammonia or a solution of carbonates of alkali metals.

A special variant of the invention, in the case of the method according to variant a) is that of solutions of 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine in inorganic acids by adding another inorganic acid, is separated, dissolved in water and, if necessary, after treatment with adsorbents precipitated with reason.

If 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine need to besiege of chlorinated hydrocarbons with aliphatic hydrocarbons by way of option b), then for this purpose, suitable as a chlorinated hydrocarbon, e.g. chloroform or dichloromethane, at the same time as aliphatic hydrocarbons are preferably used with any of 5-10 C-atoms, or mixtures thereof, for example, hexane or petroleum ether.

If 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine according to the method according to option b), you need to be recrystallized, the particular variant embodiment of the invention is that the deposition is carried out by rapid and intensive cooling, especially when mixing. As aliphatic esters of carboxylic acids suitable pH is mi with one to four carbon atoms, preferably butyl acetate.

Obtained accordingly to the method of the present invention is compact, crystalline 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine, depending on the selected reaction conditions, precipitates three, still unknown crystal modifications, which are here referred to as-and-form.

While none of the three modifications cannot be included in the methods a), b) or C). Moreover, even minor changes in these mentioned methods, such as replacement of the acid and/or base option a), or the replacement of chlorinated hydrocarbon and/or an aliphatic hydrocarbon in option b), or even changes during cooling and crystallization rate lead to the occurrence of different crystalline modifications or mixtures thereof.

It is important that whatever is received, according to the invention, the crystalline modifications, or their mixtures, it is always possible to obtain a compact crystalline 3-cyano-2-morpholino-5-(pyrid-4-yl)-pyridine high in comparison with the prior art bulk density of about 220-360 g/l, which in combination with pharmaceutical carriers and excipients are well and high quality processed into pharmaceuti forms, such as, for example, tablets or pills, as this can be ensured by a large number of biologically active substances in these solid forms.

When a certain quantity per tablet or per core drops can significantly increase the amount of active substance due to the higher bulk density of the latter.

In table. 1-4 describes important to identify data, and modification of 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine.

In table. 1 presents some of the studies of x-ray diffraction data for crystals and modifications to this connection.

Below shows the molecule 1 with atom numbering scheme:

< / BR>
Table. 2 and 3 contain the coordinates of the atoms 1 and 1-.

In table. 4 presents calculated from the data of a single crystal powder chart values and relative intensity) 1 - 1- , as well as some using the Guinier method experimental powder chart 1-.

P R I m e R 1. a) 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine - hydrochloride-monohydrate.

5,0 kg 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine is mixed with 25 l of water and 2.0 l technical hydrochloric acid and heated to approximately the 50aboutC. To the yellow solution on the 20aboutC. Centrifuged and washed with a mixture of 5.4 liters of water and 0.6 l of hydrochloric acid.

Output: 5.3 kg (88% of theory).

b) 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine ( -option).

5,3 kg 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine-hydrochloride-monohydrate are suspended in 40 l of water, the suspension is heated to 50aboutWith add 0.5 kg of activated charcoal, after stirring for 15 min sucked off and washed with water. The filtrate is cooled to 30aboutC and under stirring for one hour at this temperature, poured about 2.7 l of concentrated solution of hydroxyl sodium until pH 8-9. Centrifuged and washed in the whole 30 l of water.

Output: 4.1 kg (93,2% of theory).

So pl. 126-128aboutC.

The apparent density of the crushed in a mortar samples: approximately 360 g/l

P R I m m e R 2. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine ( -option).

1 g of purified 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine any modification dissolved in 4 ml 1A HCl by heating at about 50aboutC and under stirring at 30-40aboutWith precipitated by mixing with about 4 ml 1A NaOH. Sucked off, washed with water and dried at 110aboutC.

Yield: 0.95 g (95% of theory>P R I m e R 3. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine ( -option).

4.0 kg pre-purified 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine are suspended in 40 l of water and add 5.5 kg of lactic acid. Heated to 50aboutWith add 0.2 kg of activated charcoal and after stirring for 15 minutes and filtered. Washed with warm water, cooled to 30aboutWith and added dropwise to about 1.25 l of concentrated sodium hydroxide solution until pH 8-9. Stirred for further 1 h, centrifuged, washed in General, 30 l of water and dried.

Output: 3,74 kg (93,5% of theory), slightly yellowish crystals.

So pl. 127-129aboutC. the Apparent density of the crushed in a mortar samples: approximately 230 g/l

P R I m e R 4. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine ( and modifications).

100 g of pre-purified 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine are suspended in 1.2 l of water, add 39 ml technical hydrochloric acid and 5 g of activated charcoal. Heated to 50aboutC and filtered. To the filtrate was added dropwise 26 ml of concentrated ammonia solution at about 30aboutC, stirred for further 1 h, sucked off and washed 6 times with 50 ml water.

Output: 96,2 g 00 g/L.

P R I m e R 5. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine ( -option).

3 g of purified 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine any modification dissolved in 5 ml SIST3with light heating and under stirring precipitated by mixing with 10 ml of hexane. Sucked off and dried.

Output: 2,82 g (94% of theory).

So pl. 127-128aboutC. the Apparent density of the pulverized with stupke samples: approximately 230 g/l

P R I m e R 6. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine (-option).

1 g of purified 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine any modification when heated, dissolved in 4 ml of CH2CL2and under stirring precipitated by mixing with 5 ml of hexane. Sucked off and dried.

Yield: 0.97 g (97% of theory).

So pl. (124) 127-130aboutC. the Apparent density of the crushed in a mortar samples: about 220 g/l

P R I m e R 7. 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine (a mixture of - and-modification).

125 g of the crude product 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine with 1 l of butyl acetate is refluxed until dissolution. Filter the hot solution, when heated, stirred for 10 min with 10 g of activated charcoal. Suck goracinova dissolved in 900 ml of butyl acetate when heated, treated with 7 g of activated charcoal, filtered and heated to approximately 70aboutWith the solution with vigorous stirring and cooling is brought to crystallization. Then further stirred for 2 hours at room temperature, left to stand overnight in the refrigerator, sucked off, washed with methanol and dried at 110aboutC.

Output: 80 g (67% of theory).

So pl. (124) 128-130aboutC.

Apparent density pounded in a mortar samples: approximately 245 g/L.

By concentrating the mother liquor and recrystallization of the resulting product in the manner described it is possible to increase the output.

P R I m e R 8. 3-Cyan-2-morpholino-5-(pyrid-4-yl)-pyridine (a mixture of - and-modifications).

The example is carried out analogously to example 5, however, the deposition is carried out by addition of 60 ml of 45% potassium carbonate solution at 30aboutC.

Output: 46.6 g (93.2% of theory).

So pl. 121-123aboutand 126-128aboutC.

Apparent density pounded in a mortar samples approximately 330 g/L.

Crystalline 3-cyan-2-morpholino-5-(pyrid-4-yl)-pyridine of the formula

< / BR>
with a bulk density of 220 - 360 g/L.

 

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