CN103058953B - Tetrahydrobenzothiazole derivatives for the treatment of neurological diseases - Google Patents

Abstract

The invention discloses a tetrahydrobenzothiazole derivative for treating neurological diseases. Specifically, the compounds disclosed in the present invention include the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole represented by the following formula I: or Their pharmaceutically acceptable salts, or their solvates. The compounds and compositions of the present invention can be used to treat neurological disorders. <CNIPR:IMG <CNIPR:IMG file="DDA00002696263700011.GIF" wi="64" he="20" img-format="tif"

Description

Tetrahydrobenzothiazole derivatives for the treatment of neurological diseases

technical field

The present invention relates to a tetrahydrobenzothiazole derivative such as pramipexole and its dihydrochloride monohydrate for treating neurological diseases.

Background technique

Pramipexole is used in early and advanced Parkinson's disease as a dopamine agonist that stimulates dopamine receptors in the brain. In practice, pramipexole dihydrochloride monohydrate is preferred as the compound for treating Parkinson's disease. The chemical name of pramipexole dihydrochloride monohydrate is (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole dihydrochloride Monohydrate, wherein (S) means that pramipexole hydrochloride is in S configuration, and (-) means that pramipexole hydrochloride is left-handed. It is known that pramipexole hydrochloride with S configuration and left-handedness can be used as a pharmaceutical raw material for preparing a drug for treating Parkinson's disease. Specifically, the following left formula S (-) pramipexole ( In the form of its dihydrochloride monohydrate) has been used clinically, but the following right formula R (+) pramipexole is usually considered as an impurity and does not want to appear in the marketed pramipexole preparations.

The pramipexole molecule contains one chiral carbon atom, and the content of its optical isomers needs to be controlled during the directional synthesis of the target compound pramipexole hydrochloride. For the optical isomer impurities of pramipexole hydrochloride, quality control is required during the drug synthesis process. The separation of optical isomers containing chiral carbon atoms has always been a difficult point in quality control during the synthesis and preparation of chiral drugs. Realizing the separation of pramipexole hydrochloride and its optical isomers plays an important role in the synthesis and preparation of pramipexole hydrochloride. The quality control aspect of the process has practical significance.

At present, there have been many reports on the synthesis methods of pramipexole and its dihydrochloride monohydrate. J． Med.Chem.1987,30,494-498 discloses a kind of preparation method of pramipexole hydrochloride, this method uses (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzene And thiazole as raw material, under the protection of _N2 in THF (tetrahydrofuran), react with THF borane solution to obtain (S)-(-)-2-amino-6-(propylamino)-4,5,6 , 7-tetrahydrobenzothiazine, and then converted into dihydrochloride; the specific content of the preparation method is, at room temperature and under the protection of N ₂ , to contain (-) 2-amino-6-propionylamino- 4,5,6,7-Tetrahydrobenzothiazole in THF was added dropwise with borane solution in THF, then the reaction was stirred at 50°C for 1 hour and cooled, then water and concentrated hydrochloric acid were added; THF was evaporated and poured into water 25% sodium hydroxide solution was added to the phase, and then filtered to obtain a precipitate ((S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole), the The obtained precipitate was washed with water and dissolved in hot ethyl acetate; the water (Mg ₂ SO ₄ ) in the solution was removed and concentrated, and the obtained precipitate was filtered, washed with ethyl acetate, and converted into a di-salt salt and recrystallization from methanol to give (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole dihydrochloride; disadvantages of this method The production method of borane solution in THF is complicated, not suitable for industrial production, and because borane is colorless and highly toxic, flammable, explosive, easy to hydrolyze, poor in stability, difficult to store and transport, so the reaction safety is low. Chinese patent CN1834092 has improved above-mentioned method, with NaBH ₄ and BF ₃ generate borane in situ, but boron trifluoride ether solution meets water decomposition, has pungent smell, and ether is highly flammable, harsh reaction conditions and to The equipment requirements are very high, and it is not suitable for industrialized production. Chinese patent CN101676272 uses sodium borohydride and lithium aluminum hydride as reducing agent for reduction, and the conditions are relatively mild, but it needs to be reacted in a reflux state, and the reaction time is very long. Components are highly corrosive, and are likely to cause running, popping, dripping, and leaking. There is a danger of explosion in tetrahydrofuran in a reflux state, so the requirements for equipment and workshops are very high; and lithium aluminum hydride is expensive and sensitive to water and air. The danger of combustion and explosion; so it is also not easy to carry out industrialized production. Chinese patent CN101585818A discloses a method for preparing an intermediate of pramipexole hydrochloride, the steps are: in a solvent, 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzene and thiazole in the presence of Zn (BH ₄ ) ₂ , carry out the reduction reaction, and then collect 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole from the reaction product; If carried out in an environment, tetrahydrofuran as a solvent has a low boiling point and is flammable and explosive; it will damage the reaction equipment and have high requirements on the plant and equipment; and Zn(BH ₄ ) ₂ is difficult to prepare and difficult to store. In addition, CN101622235A also discloses a new method for synthesizing pramipexole.

In these existing synthetic methods, the isomers in the product have various synthetic methods to avoid, for example, use chiral raw materials to prepare, or for example prepare first to obtain the isomer mixture, and then the pramipexole isomer The mixture is subjected to isomer resolution, for example, using L-(+)-tartaric acid for resolution, for example, refer to the details disclosed in the literature disclosed by Wang Wenting, etc. (Wang Wenting, etc., the synthesis of pramipexole hydrochloride, Chinese Journal of Pharmaceutical Industry, 2012, 43(7):524). Another example is CN101429173A which discloses a method for preparing pramipexole intermediate 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole. Those skilled in the art can obtain (S)-(-)pramipexole or (R)-(+)pramipexole and their salts and solvates by referring to these known methods and combining existing experience.

Contents of the invention

The object of the present invention is to provide a substantially pure (S)-(-)pramipexole or a pharmaceutically acceptable salt or solvate thereof.

The object of the invention is achieved by the following invention scheme:

Invention Scheme 1. A compound comprising the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole represented by the following formula I:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Invention Scheme 2. The compound according to Invention Scheme 1, wherein the pharmaceutically acceptable salt of the compound of formula I is its hydrochloride.

Invention Scheme 3. The compound according to Invention Scheme 1-2, wherein the pharmaceutically acceptable salt of the compound of formula I is its dihydrochloride.

Invention Scheme 4. The compound according to Invention Scheme 1-3, wherein the solvate of the compound of formula I or its salt is a hydrate.

Inventive Scheme 5. The compound according to Inventive Scheme 4, wherein the hydrate is a monohydrate.

Invention scheme 6. The compound according to invention scheme 1-5, wherein the compound of formula I is dihydrochloride monohydrate, namely (S)-(-)-2-amino-6-(propylamino)-4, 5,6,7-Tetrahydrobenzothiazole dihydrochloride monohydrate.

Invention Scheme 7. The compound according to Invention Scheme 1-6, which also includes (R)-(+)-2-amino-6-(propylamino)-4,5,6,7-tetrahydro as shown in the following formula II Benzothiazole:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Invention scheme 8. The compound according to invention scheme 1-7, wherein the molar ratio of the compound of formula I to the compound of formula II is greater than 200:1 (for example, between 200 and 3000:1).

Invention scheme 9. The compound according to invention scheme 1-7, wherein the molar ratio of the compound of formula I to the compound of formula II is greater than 250:1 (for example, between 250 and 3000:1).

Invention scheme 10. The compound according to invention scheme 1-7, wherein the molar ratio of the compound of formula I to the compound of formula II is greater than 300:1 (for example, between 300 and 3000:1).

Invention scheme 11. The compound according to invention scheme 1-7, wherein the molar ratio of the compound of formula I to the compound of formula II is greater than 350:1 (for example, between 350 and 3000:1).

Invention scheme 12. The compound according to invention scheme 1-7, wherein the molar ratio of the compound of formula I to the compound of formula II is greater than 400:1 (for example, between 400 and 3000:1).

Invention scheme 13, the compound according to invention scheme 1-7, under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained by the compound, the compound of formula I and The chromatographic peak area ratio of the compound of formula II is greater than 200:1 (for example, between 200-3000:1).

Invention scheme 14, the compound according to invention scheme 1-7, under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained by the compound, the compound of formula I and the compound of formula II The chromatographic peak area ratio of the compound of formula II is greater than 250:1 (for example, between 250-3000:1).

Invention scheme 15, the compound according to invention scheme 1-7, under the HPLC chromatographic conditions that can make the resolution between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained by the compound, the compound of formula I and the compound of formula II The chromatographic peak area ratio of the compound of formula II is greater than 300:1 (for example, between 300-3000:1).

Invention scheme 16, the compound according to invention scheme 1-7, under the HPLC chromatographic conditions that can make the resolution between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained by the compound, the compound of formula I and the compound of formula II are The chromatographic peak area ratio of the compound of formula II is greater than 350:1 (for example, between 350-3000:1).

Invention scheme 17, the compound according to invention scheme 1-7, under the HPLC chromatographic conditions that can make the resolution between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained by the compound, the compound of formula I and The chromatographic peak area ratio of the compound of formula II is greater than 400:1 (for example, between 400-3000:1).

In the present invention, the above-mentioned molar ratio or peak area ratio can also be expressed by a specific value, for example, "the molar ratio is greater than 350:1" can also be expressed as "the molar ratio is greater than 350", and "the peak area ratio is greater than 350:1" can also be expressed as Expressed as "the peak area ratio is greater than 350", the molar ratio "between 350 and 3000:1" can also be expressed as the molar ratio "between 350 and 3000", and "the molar ratio is 350:1" can also be expressed as " The molar ratio is 350".

Invention Scheme 18. A pharmaceutical composition comprising the compound according to Invention Scheme 1-13 and pharmaceutically acceptable excipients.

Invention Aspect 19. The pharmaceutical composition according to Invention Aspect 18, which is in the form of tablets or capsules.

Invention Aspect 20. The pharmaceutical composition according to Invention Aspect 19, which is in the form of an immediate-release or sustained-release tablet or capsule.

Invention Scheme 21. The pharmaceutical composition according to Invention Scheme 18-20, wherein each tablet or capsule contains 0.1-5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Invention Aspect 22. The pharmaceutical composition according to Invention Aspects 18-21, wherein the pharmaceutically acceptable excipients include magnesium salts, such as but not limited to magnesium carbonate, magnesium bicarbonate, magnesium silicate, and magnesium stearate.

Invention scheme 23. The pharmaceutical composition according to invention scheme 18-22, comprising the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetra Hydrobenzothiazole:

or their pharmaceutically acceptable salts, or their solvates, and optionally (R)-(+)-2-amino-6-(propylamino)-4,5,6,7 shown in the following formula II -Tetrahydrobenzothiazole:

or their pharmaceutically acceptable salts, or their solvates;

The molar ratio of the compound of formula I to the compound of formula II in the pharmaceutical composition is greater than 200:1 (for example, between 200~3000:1), greater than 250:1 (for example, between 250~3000:1), greater than 300:1 (for example, between 300~3000:1), greater than 350:1 (for example, between 350~3000:1), or greater than 400:1 (for example, between 400~3000:1).

Invention scheme 24. The pharmaceutical composition according to invention scheme 18-22, comprising the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetra Hydrobenzothiazole:

or their pharmaceutically acceptable salts, or their solvates, and optionally (R)-(+)-2-amino-6-(propylamino)-4,5,6,7 shown in the following formula II -Tetrahydrobenzothiazole:

or their pharmaceutically acceptable salts, or their solvates;

Under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical composition, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is greater than 200:1 (for example between 200~3000:1), greater than 250:1 (for example between 250~3000:1), greater than 300:1 (for example between 300~3000:1), greater than 350:1 (for example Between 350~3000:1), or greater than 400:1 (for example, between 400~3000:1).

Invention Scheme 25. The pharmaceutical composition according to Invention Scheme 23-24, wherein the pharmaceutically acceptable salt of the compound of formula I is its hydrochloride.

Invention scheme 26. The pharmaceutical composition according to invention scheme 23-24, wherein the pharmaceutically acceptable salt of the compound of formula I is its dihydrochloride.

Invention scheme 27. The pharmaceutical composition according to invention scheme 23-24, wherein the solvate of the compound of formula I or its salt is a hydrate.

Invention Aspect 28. The pharmaceutical composition according to Invention Aspect 23-24, wherein the hydrate is a monohydrate.

Invention scheme 29. The pharmaceutical composition according to invention scheme 23-24, wherein said compound of formula I dihydrochloride monohydrate is (S)-(-)-2-amino-6-(propylamino)-4 ,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate.

In the compound of the present invention, the main component is the compound of formula I or its pharmaceutically acceptable salt or their solvate, and the compound of formula II or its pharmaceutically acceptable salt or their solvate is considered as a trace impurity . Therefore, in this sense, although the compound of the present invention can be simply understood as comprising a mixture of various substances, it is essentially a compound of formula I or its pharmaceutically acceptable salt or their solvate, which contains a trace amount (for example, relatively In terms of the molar percentage of the compound of formula I, less than 0.5%, such as less than 0.4% or less) as an impurity amount of the compound of formula II or its pharmaceutically acceptable salt or their solvate.

For the compounds of the present invention, many known methods can be used to measure the amount of the compound of formula I and the compound of formula II contained in them, and the relative amount of the two can be calculated. For example, reference can be made to the HPLC method described in CN101769902A, which is incorporated herein by reference in its entirety.

Particularly, in the present invention, if not otherwise stated, the following HPLC method (which is a normal phase HPLC method) is used to determine the amount of the compound of formula I and the compound of formula II in the compound of the present invention and the relative amount of the two:

(1) Instruments and conditions:

High performance liquid chromatography: Shimadzu: LC-10ATvp, SPD-M10Avp, SCL-10Avp, DGU-12A;

Chromatographic column: AD-H (Daicel, 4.6mm×250mm, 5μm);

Mobile phase: n-hexane-absolute ethanol-diethylamine=80:20:0.1;

Flow rate: 1.0ml/min;

Injection volume: 20μl;

Detection wavelength: 262nm;

(2) Operation steps: Weigh 5 mg of (S)-(-) pramipexole dihydrochloride monohydrate and its optical isomer (R)-(+) pramipexole respectively, and place them in a 25ml volumetric flask Add absolute ethanol to dissolve and dilute to the mark, shake well, filter, and use as a mixed sample solution. Separately weigh 5 mg of (S)-(-)pramipexole dihydrochloride monohydrate, put it in a 25ml volumetric flask, add absolute ethanol to dissolve and dilute to the scale, shake well, filter, and use as (S)-( -) Pramipexole qualitative control solution. Another weigh (R)-(+) pramipexole 5mg, put in a 25ml volumetric flask, add absolute ethanol to dissolve and dilute to the scale, shake well, filter, as (R)-(+) pramipexole qualitative control solution.

Draw respectively 20 μ l of each qualitative contrast solution and mixed sample solution and inject liquid chromatograph, carry out high performance liquid chromatography analysis according to the above-mentioned conditions, record chromatogram; Use the retention time of each qualitative contrast solution to compare each chromatographic peak in the mixed sample solution The assignment (i.e. determination of the retention times of the two isomers in the chromatogram of the mixed sample solution) is performed and the resolution between the two isomer peaks is calculated. In the typical chromatogram (not provided) of the mixed sample solution obtained under the above chromatographic conditions, (R)-(+) pramipexole elutes first, and (S)-(-) pramipexole elutes later (retention time is about 14min ), and the separation degree of the two is >4, which can meet the determination requirements (those skilled in the field of pharmaceutical analysis understand that generally speaking, the separation degree is greater than 2, which means that it has a good resolution and can meet the separation requirements).

(3) Sample measurement: Dissolve the compound of the present invention with absolute ethanol to make a solution of about 200 μg/ml, filter it, and use it as the test solution. Draw 20 μ l of the test solution, inject it into the liquid chromatograph, carry out high-performance liquid chromatography analysis according to the above conditions, and record the chromatogram; record (S)-(-) pramipexole and (R)-(+) pramipexole two retention time and peak area.

The detection limit of the above-mentioned HPLC method for the two isomers can reach 0.01 μg/ml, which shows that this method can effectively detect trace amounts of isomers.

For the (R)-(+)pramipexole used in the test, its chromatographic purity can also be determined, especially the relative amount of (S)-(-)pramipexole that may be contained therein as an impurity.

It is clear to those skilled in the art that for both (S)-(-)pramipexole and (R)-(+)pramipexole, when equal molar amounts of the two substances are injected into the liquid chromatograph, When they are isomers, they have basically the same UV absorption coefficient (the two isomers are prepared with a mobile phase to prepare a solution of equimolar concentration, and they have the same absorbance at UV 262nm), and the two are basically the same in the liquid chromatogram. of the peak area. In addition, when (S)-(-)pramipexole exists in different forms, for example, it exists as a free base, or as a pharmaceutically acceptable salt such as dihydrochloride, or as a solvate such as ( S)-(-)pramipexole dihydrochloride monohydrate exists in the form of monohydrate, and when it is prepared into a solution of a certain absolute concentration (such as 200μg/ml absolute ethanol), their peaks in the chromatogram are different. , especially the smaller the molar molecular weight, the larger the peak area, such as the maximum peak area of free base (because its molar concentration is relatively maximum under the equal mass concentration in solution), and (S)-(-) pramipexole dihydrochloride The salt monohydrate has the smallest peak area (because its molarity is relatively smallest at equal mass concentrations in solution). Therefore, it is understood that when the compounds of the present invention (mainly (S)-(-)pramipexole of formula I, possibly containing minor/impurity amounts of (R)-(+)pramipexole of formula II) A form (such as its pharmaceutically acceptable salt such as its dihydrochloride, such as its solvate such as its dihydrochloride monohydrate) is injected into the liquid chromatograph, and the (S)-(-) general The molar ratio of Lamipexole and (R)-(+) Pramipexole can basically be easily and intuitively reflected by the peak area ratio of the two, that is, (S)-(-) Pramipexole and (R) -(+) pramipexole The molar ratio of the two is basically equal to the peak area ratio of the two. The inventor found that when the molar ratio of (S)-(-)pramipexole and (R)-(+)pramipexole was corrected to 1:1 in many batches (more than 20 times) of experiments The two are detected at a wavelength of 262nm under a variety of HPLC chromatographic conditions that can make the resolution between the compound of formula I and the compound of formula II greater than 3, and (S)-(-) pramipexole and (R)-(+ ) The peak area ratios of both pramipexole are between 1:(1.0007~1.0009), that is, there is only a deviation of about 8/10000 between the two algorithm results of the molar ratio and the peak area ratio. Therefore, under the HPLC chromatographic conditions that can make the resolution between the compound of formula I and the compound of formula II greater than 3, detect at 262nm wavelength, (S)-(-) pramipexole and (R)-(+) pramipexole The peak area ratio of the two laxoles is basically equal to the molar ratio.

In addition, for the pharmaceutical composition of the present invention, since the compound of various embodiments of the present invention is added as an active ingredient, there may also be (R)-(+) pramipexole, which can be understood as an impurity, in these pharmaceutical compositions. or a pharmaceutically acceptable salt or solvate thereof. It is clear to those skilled in the art that these pharmaceutical compositions can also accurately reflect (S)-(-)pramipexole and (R)-(+) The molar ratio of pramipexole, and generally speaking, this molar ratio measured when added to the pharmaceutical composition is the same as or close to the molar ratio measured by the raw material drug of the composition, that is, for example, the compound of the present invention .

The present inventors have found that when a magnesium-containing substance is brought into contact with (S)-(-)pramipexole, the amount of (R)-(+)pramipexole contained therein as an impurity changes. And by controlling the amount of (R)-(+) pramipexole in the compound of the present invention to a certain extent, this change is controllable. In one embodiment, the weight ratio of (S)-(-) pramipexole to magnesium-containing substances in the composition of the present invention can be determined empirically; in one embodiment, in the composition of the present invention (S)- (-)pramipexole (calculated as (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, excluding salts and solvates) with The weight ratio of magnesium substances is 1:0.1~10, for example 1:0.2~5.

Although the assay methods for the compounds of formula I and II among the compounds of the present invention have been described, it is clear to those skilled in the art that in fact such assay methods can be easily modified. For example, even in the normal phase HPLC method described above, the mobile phase used therein can be changed in a wide range according to different situations, such as making changes according to the specific filler, length, filler particle size, column temperature, mobile phase flow rate, etc. of the chromatographic column, Make the peak elution time of the compound of formula I within the range of 5-100min and achieve an effective degree of separation between the compound of formula I and the compound of formula II (for example, the degree of separation is greater than 3).

The compound of the present invention, pramipexole, is a non-ergot dopamine agonist. In vitro studies have shown that pramipexole has high specificity for D2 receptors and complete intrinsic activity, and its affinity for D3 receptors is higher than that of D2 and D4 receptors. The relevance of this binding of pramipexole to the D3 receptor for Parkinson's disease is unclear. The exact mechanism of pramipexole's treatment of Parkinson's disease is not clear, but it is currently believed to be related to the activation of dopamine receptors in the striatum. Electrophysiological experiments in animals have shown that pramipexole can affect the firing frequency of striatal neurons by activating dopamine receptors in striatum and substantia nigra. Pramipexole is rapidly and completely absorbed after oral administration. The absolute bioavailability is higher than 90%, and the maximum plasma concentration occurs between 1-3 hours after taking the drug. Taking it with food does not decrease the extent to which pramipexole is absorbed, but it does decrease its rate. Pramipexole exhibits linear kinetics with little variation in plasma levels between patients. The pramipexole tablet of the present invention can be used to treat the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa. For example, in the later stages of the disease, the efficacy of levodopa gradually decreases or changes and fluctuations occur (end-of-dose phenomena or "on-off" fluctuations), and this product is required.

Detailed ways

The present invention will be described in more detail through the following examples, and the following description is only for explaining the present invention, not limiting its content. The reaction raw materials of the present invention can be bought in the market, for example (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole used in some examples of compound preparation can be Prepare by purchasing commercially available products or according to the method provided by J.Med.Chem.1987, 30, 494-498.

Example 1

(1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

Add (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (227.33 g, 1 mol) into tetrahydrofuran (1362 ml), stir to dissolve, then add boron rapidly Sodium hydride (94.68g, 2.5mol) was stirred, then cooled to -5°C, and then slowly added dropwise _I2 (253.8g, 1mol) and 725ml of tetrahydrofuran (the mass concentration of _I2 was 35%) at -5～0°C After dropping the solution, slowly heat up to 35°C, keep it warm for 8 hours, then cool down to below 10°C, first add 45ml of tap water dropwise to avoid excessive reaction, then add dropwise 946.8ml of hydrochloric acid with a mass fraction of 37%, and then slowly heat up to Keep at 40°C for 30min, then recover tetrahydrofuran by vacuum distillation. After the recovery, the remaining solution is adjusted to pH = 12 with 30% sodium hydroxide solution, and a large amount of solids are precipitated. Cool down to below 10°C, stir for 30min, and use Brookfield Funnel suction filtration, water 600ml washing 2 times, 40 ℃ blast drying to obtain white solid (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (198.6 g, molar yield 94%).

(2) Preparation of pramipexole dihydrochloride monohydrate

(S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (198.6g, 0.94mol) obtained in (1) was dissolved in 1390ml of absolute ethanol , add 42g of activated carbon for needles, raise the temperature to 50°C, stir for 30min, filter, cool the filtrate to below 10°C, and keep it below 10°C, dropwise add 198ml of concentrated hydrochloric acid with a mass fraction of 37%, stir for 10h, and filter with suction. 200ml of 95% ethanol was washed twice, and vacuum-dried at 40°C to obtain the product (S)-(-)pramipexole dihydrochloride monohydrate (256.5g, molar yield 90.3%), which was white to off-white powder, Melts at 296°C to 301°C with decomposition. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6- The peak area ratio of propylamino-4,5,6,7-tetrahydrobenzothiazole is 142:1 (because the peak area ratio and the molar ratio only differ by 8/10000, so it can also be understood as the molar ratio in the present invention , the same below).

Example 1c: (R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole disalt for test Preparation of acid monohydrate

(R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole used in the present invention can refer to J.Med.Chem.1987,30,494- (+) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole was prepared by the method provided in 498, and then prepared by referring to the above method. In another experiment, the present inventors prepared (R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, and obtained (R)-(+) The chromatographic purity of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate is 99.62% (that is, (R)-(+)2-amino-6-propylamino- The molar ratio of 4,5,6,7-tetrahydrobenzothiazole to (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (peak area ratio ) is 262:1). It is clear to those skilled in the art that no matter how high the chromatographic purity of the (R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole is, as long as it accounts for the majority (for example Purity more than 70%, more than 80%, more than 90%, or more than 95%), it is used as the present invention to qualitatively determine its retention time in the chromatogram and be used for calculating its and (S)-(-) pramipexole The degree of separation in the chromatogram is sufficient to meet the requirements in the experimental operation of the present invention.

Example 2: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride

Refer to the method of Example 1 of CN1834092A to obtain (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6- The peak area ratio (also known as molar ratio) of propylamino-4,5,6,7-tetrahydrobenzothiazole is 117:1.

Example 3: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride

With reference to the literature (Wang Wenting, et al., the synthesis of pramipexole hydrochloride, China Journal of Pharmaceutical Industry, 2012, 43 (7): 524) records method (detailed in "experimental part" in the text), in the preparation process L-(+)-tartaric acid was used for chiral resolution to obtain (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6- The peak area ratio (also known as molar ratio) of propylamino-4,5,6,7-tetrahydrobenzothiazole is 98.5:1.

Example 4: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate

The product of Example 3 was spread on a petri dish with a thickness of less than 1 mm, and was gently blown with an air atmosphere of RH75% for 12 hours to balance, and it was determined to be (S)-(-)2-amino-6-propylamino-4,5 ,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6 The peak area ratio of -propylamino-4,5,6,7-tetrahydrobenzothiazole (also understood as molar ratio) is 98.5:1.

Example 5: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride

With reference to the method (described in detail in "experimental part" in the text) of the documents such as Jinhua (Jinhua, etc., the synthetic research of pramipexole hydrochloride, Chinese Journal of Medicinal Chemistry, 2011, 21 (6): 430), the preparation process Using L-(+)-tartaric acid for chiral resolution to obtain (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6- The peak area ratio (also known as molar ratio) of propylamino-4,5,6,7-tetrahydrobenzothiazole is 98.9:1.

Example 6: Preparation of (S)-(-)2-amino-6-propylamino-4 , 5 , 6 , 7-tetrahydrobenzothiazole dihydrochloride monohydrate

The pramipexole dihydrochloride monohydrate (the molar ratio of S-isomer and R isomer is 142) that embodiment 1 obtains is mixed with methanol-lactic acid (methanol and L-lactic acid volume ratio 20:1 ) was recrystallized once. A white crystalline powder is obtained, which melts and decomposes at 296°C to 301°C. As determined by HPLC, (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole and (R)-(+)2-amino-6- The peak area ratio (also known as molar ratio) of propylamino-4,5,6,7-tetrahydrobenzothiazole is 292:1.

Example 7: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate

With reference to the method of Example 6, recrystallization was performed twice, and the molar ratio of the S-isomer to the R-isomer in the product was 389:1.

Example 8: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate

With reference to the method of Example 6, the methanol-lactic acid mixture (methanol to L-lactic acid volume ratio 20:2) was used for recrystallization twice, and the molar ratio of the S-isomer to the R-isomer in the product was 875: 1.

Example 9: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate

With reference to the method of Example 6, the methanol-lactic acid mixture (methanol to L-lactic acid volume ratio 20:2) was used for recrystallization treatment 3 times, and the molar ratio of the S-isomer to the R-isomer in the product was 1535: 1.

Example 10: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride salt monohydrate

With reference to the method of Example 6, use 95% ethanol-lactic acid mixture (volume ratio of ethanol to L-lactic acid 20:1) to recrystallize twice, and the molar ratio of the S-isomer to the R-isomer in the product is 2175:1.

Example 11: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride salt monohydrate

With reference to the method of Example 6, use 95% ethanol-lactic acid mixture (volume ratio of ethanol to L-lactic acid 20:2) for recrystallization treatment 4 times, the molar ratio of S-isomer and R-isomer in the product is 2986:1, the total yield of the recrystallization treatment was 94%; when the recrystallization was repeated again, the molar ratio of the S-isomer to the R-isomer in the product was 3100:1, and the total yield of the recrystallization treatment was The rate was 92%; when the recrystallization was repeated again, the molar ratio of the S-isomer to the R-isomer in the product was 3800:1, and the total yield of the recrystallization treatment was 81%. The total yield will obviously continue to decrease, and its practicability as a pharmaceutical raw material in industrial production is low. Therefore, in one embodiment of the present invention, the molar ratio of the compound of formula I to the compound of formula II is between 350 and 3000:1.

Example 12: Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride Salt monohydrate and (R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate a mixture of two substances with different molar ratios

Take a certain amount of (R)-(+)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate obtained in Example 1c and a certain amount of obtained in Example 11 (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride monohydrate, mixed well, can easily get S-isomer and R - The isomer ratio is a mixture of different molar ratios, for example, a mixture in which the molar ratio of S-isomer to R-isomer is in the range of 50-3000:1. For example, take the mixture obtained by mixing 50 grams of S-isomer and 1 gram of R-isomer, the molar ratio of S-isomer to R-isomer is about 50:1, that is, the molar ratio is 50; for example Take the mixture obtained by mixing 500 grams of S-isomer with 1 gram of R-isomer, and the molar ratio of S-isomer to R-isomer is about 500:1. The specific ratio can be found in Table 1 below.

Embodiment 13: Compound test of the present invention and magnesium salt

Get each S-isomer compound (all in (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole meter of gained in embodiment 1～12 respectively, not Considering salt formation and solvate), mixed with magnesium stearate at a weight ratio of 1:0.2, 1:1 or 1:5, and ground into a homogeneous mixture. This mixture is carried out high temperature acceleration test, promptly places 6 months under the condition of 40 ℃ of relative humidity 70%. Determine the molar ratio of the S-isomer to the R-isomer of the sample after 6 months of high-temperature accelerated test treatment, and calculate the percentage change in molar ratio caused by high-temperature treatment, that is, without high-temperature accelerated treatment (understandable as 0 month) The difference obtained by subtracting the molar ratio of the sample in June from the molar ratio of the sample in June is divided by the percentage of the molar ratio of the sample in month 0, for example, for a certain sample, the S-isomer and R-isomer of month 0 The molar ratio of the body is 500:1 (ie 500), and the molar ratio in June is 450:1 (ie 450), then the percentage change in the molar ratio is (500-490)/500*100%=2%.

The difference in molar ratio after mixing materials with different compositions and magnesium stearate shows different trends, as shown in Table 1 below.

Table 1:

The above tests found that when the amount of R-isomer in pramipexole increases to a certain extent, the result of R-isomer obviously increases after it is mixed with magnesium salt, which is not expected for clinical use. In addition, the inventor used the conventional HPLC method that cannot separate isomers for the above mixture with magnesium salt (see, Qu Lili, HPLC Determination of Pramipexole Hydrochloride Content, Journal of Baotou Medical College, Volume 28, Article 4, No. 16- 17 page) measurement, all the samples in the above table have very low changes in pramipexole content, and the percentage difference between each sample and its corresponding sample without the accelerated test in June is not more than 2% (0-month sample percentage content minus the percentage content of the sample in June). The above results show that after mixing different ratios of pramipexole isomers and magnesium salts, the total amount of isomers has not changed significantly, but the relative amounts of S-isomers and R-isomers have changed to varying degrees. And the results show that when the isomer molar ratio is greater than 350 (that is, the relative S-isomer purity is greater than 99.72%), it shows good stability. Another reference is to use the method shown in the above Table 1, but replace the magnesium salt therein with magnesium silicate, and the result is the same as using magnesium stearate.

Example 14: Preparation of tablets containing pramipexole hydrochloride

Recipe for making 1000 tablets:

The obtained pramipexole hydrochloride of embodiment 8: 1g,

Mannitol-D: 121.5g,

Corn starch: 79.85g,

Colloidal silicon dioxide: 2.3g,

Povidone (K25): 2.35g,

Magnesium stearate: 3g.

Preparation:

(a) Each material is crushed in advance to pass 60-80 mesh. Mannitol-D, cornstarch (61.85g) were loaded into the fluidized bed granulator,

(b) dissolving pramipexole dihydrochloride and povidone in water to form a solution, and spraying the solution onto the granules in the fluidized bed granulator, granulating these mixtures to form a granulated mixture ,

(c) drying the granulated mixture to an endpoint moisture content of from about 1.0% to about 2.5%,

(d) mixing the granular mixture of step (c) with colloidal silicon dioxide, cornstarch (18 g) and magnesium stearate and blending to form the final blend,

(e) Use a tablet machine to compress the final blend into tablets (take about 20% of the final blend before tableting and pack it into a hard gelatin capsule shell to make capsules, each containing 1 mg of the active ingredient) .

The prepared tablet also refers to the method of Example 13 to measure the percentage change of the molar ratio after the accelerated test for 6 months. The percentage change is 1.3%.

Referring to the above method, different raw materials were used to prepare tablets, and the percentage change of the molar ratio after the accelerated test was determined for 6 months. The results are shown in Table 2. After showing that the formulation excipients containing magnesium salts were mixed, the molar ratio change percentage (%) of the tablet after 6 months showed a trend similar to that of the bulk drug; and when no magnesium salt was added, the R-isomer content was higher Raw materials, the percentage change of the molar ratio of the resulting preparation is small.

Table 2

* in the table indicates that magnesium stearate was not added during tablet preparation.

Example 15: Preparation of Sustained Release Tablet Containing Pramipexole Hydrochloride

Prescription (amount per tablet, mg):

Preparation:

(1) Pre-crushing each component into a fine powder of 60-80 mesh. In a mixer, the active ingredient is premixed with a small portion (about 15%) of hypromellose.

(2) Then in the mixer, the mixture in step (1) is mixed evenly with the remaining hypromellose, corn starch, and carbomer, and then colloidal silicon dioxide and magnesium stearate are added to make the material fully well mixed.

(3) Prepare sustained-release matrix tablets by compressing the final mixture in a suitable tablet machine.

Different sustained-release tablets were obtained by using different pramipexole hydrochloride raw materials prepared in the above examples of the present invention during the preparation of the sustained-release tablets. The percent change in molar ratio of these sustained-release tablets after the accelerated test was determined for 6 months, and the results are shown in Table 3. It shows that the molar ratio change percentage (%) of the tablets after 6 months after mixing with the preparation excipients containing magnesium salts has a similar trend to that of the raw materials; and when no magnesium salts are added, the raw materials with higher R-isomer content , the percentage change of the molar ratio of the resulting preparation is small.

table 3

* in the table indicates that magnesium stearate was not added when preparing sustained-release tablets.

Claims (18)

1. A pharmaceutical raw material whose active ingredient is compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzo Thiazoles: I or a pharmaceutically acceptable salt thereof, or their monohydrate; The pharmaceutical raw material also contains the compound (R)-(+)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole shown in the following formula II as an impurity: II or a pharmaceutically acceptable salt thereof, or their monohydrate; Under the HPLC chromatographic conditions that can make the separation degree between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical bulk drug, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is between 350~ Between 3000:1. 2. The pharmaceutical raw material according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is its hydrochloride. 3. The pharmaceutical raw material according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is its dihydrochloride. 4. The pharmaceutical raw material according to claim 1, wherein the active ingredient is (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole Dihydrochloride monohydrate. 5. The pharmaceutical raw material according to any one of claims 1-4, wherein the chromatographic peak area ratio of the compound of formula I to the compound of formula II is between 400-3000:1. 6. A pharmaceutical composition, which comprises the pharmaceutical raw material according to any one of claims 1-5, and pharmaceutically acceptable auxiliary materials. 7. The pharmaceutical composition according to claim 6, which is in the form of a tablet or capsule. 8. The pharmaceutical composition according to claim 6, which is in the form of an immediate release or sustained release tablet or capsule. 9. The pharmaceutical composition according to claim 8, wherein each tablet or capsule contains 0.1 to 5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or their monohydrate. 10. The pharmaceutical composition according to any one of claims 6-9, wherein the pharmaceutically acceptable excipient comprises a magnesium salt. 11. The pharmaceutical composition according to claim 10, wherein said magnesium salt is selected from the group consisting of: magnesium carbonate, magnesium bicarbonate, magnesium silicate, magnesium stearate. 12. The pharmaceutical composition according to claim 10, wherein the weight ratio of the compound of formula I to the magnesium salt is 1:0.1˜10. 13. The pharmaceutical composition according to claim 10, wherein the weight ratio of the compound of formula I to the magnesium salt is 1:0.2~5. 14. The pharmaceutical composition according to any one of claims 6-9, wherein the compound (S)-(-)-2-amino-6-(propylamino)-4,5 shown in the following formula I is included as an active ingredient ,6,7-Tetrahydrobenzothiazole: I or their pharmaceutically acceptable salts, or their monohydrates, and compounds (R)-(+)-2-amino-6-(propylamino)-4,5,6, 7-Tetrahydrobenzothiazole: II or a pharmaceutically acceptable salt thereof, or their monohydrate; Under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical composition, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is 350~3000 : between 1. 15. The pharmaceutical composition according to claim 14, wherein the chromatographic peak area ratio of the compound of formula I to the compound of formula II is between 400-3000:1. 16. The pharmaceutical composition according to claim 10, wherein the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7- Tetrahydrobenzothiazole: I or their pharmaceutically acceptable salts, or their monohydrates, and compounds (R)-(+)-2-amino-6-(propylamino)-4,5,6, 7-Tetrahydrobenzothiazole: II or a pharmaceutically acceptable salt thereof, or their monohydrate; Under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical composition, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is 350~3000 : between 1. 17. The pharmaceutical composition according to claim 11, wherein the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7- Tetrahydrobenzothiazole: I or their pharmaceutically acceptable salts, or their monohydrates, and compounds (R)-(+)-2-amino-6-(propylamino)-4,5,6, 7-Tetrahydrobenzothiazole: II or a pharmaceutically acceptable salt thereof, or their monohydrate; Under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical composition, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is 350~3000 : between 1. 18. The pharmaceutical composition according to claim 12, wherein the compound (S)-(-)-2-amino-6-(propylamino)-4,5,6,7- Tetrahydrobenzothiazole: I or their pharmaceutically acceptable salts, or their monohydrates, and compounds (R)-(+)-2-amino-6-(propylamino)-4,5,6, 7-Tetrahydrobenzothiazole: II or a pharmaceutically acceptable salt thereof, or their monohydrate; Under the HPLC chromatographic conditions that can make the separation between the compound of formula I and the compound of formula II greater than 3, in the HPLC spectrum obtained from the pharmaceutical composition, the chromatographic peak area ratio of the compound of formula I and the compound of formula II is 350~3000 : Between 1.