KR20140032828A - New synthetic method of glycopyrrolate and pharmaceutical formulations containing this active ingredient - Google Patents

Abstract

The present invention relates to a method for synthesizing RS and Sr racemic glycopyrrolate represented by structural formula I by making α-cyclopentylmandelic acid racemic body (R/S racemic) represented by structural formula 3 react with 1-methyl-3-pyrrolidinol methyl bromide represented by structural formula 5. In the novel method for synthesizing glycopyrrolate of the present invention, by-products produced during reaction can be easily removed through crystallization, purification process can be facilitated, synthesizing time can be reduced, and glycopyrrolate optimized for 35 regulations in US pharmacopoeial forum can be synthesized. In addition, collection of unreacted substance can be facilitated, yield of RS or SR glycopyrrolate can be increased by reusing RR or SS glycopyrrolate so that the yield can be more increased by the collection method. [Reference numerals] (AA) Standard Glycopyrrolate

Description

TECHNICAL FIELD The present invention relates to a novel method for synthesizing glycopyrrolate and a pharmaceutical composition containing the active ingredient,

The present invention relates to a novel process for the synthesis of pyrrolidinyl cyclopentyldermadelate derivatives (generic name: glycopyrrolate) of the following structural formula I:

Glycopyrrolate is a quaternary amine substance that has many pharmacological actions and has recently been developed as an anesthetic field, pre-operative body fluid, suppression of saliva secretion, bronchial secretion control, gastric ulcer treatment and its adjuvant, hyperhidrosis, and facial hyperhidrosis In particular, despite the fact that the material patent of the raw material itself has already been approved by the US FDA as an inhibitor of saliva secretion (salivation) from the US on July 28, 2010, have.

This material is a high cost material and new synthetic methods are being developed. However, although the foreign substance has a simple structure, synthesis process of total synthesis is not easy, and it is still expensive, and it is synthesized only in a few places in the world.

This material has four isomers of RR ', SS', RS ', and SR' as shown in Table 1 below (Table 1: Glycopyrrolate isomers RR, SS, RS, SR chemical structure)

[Table 1]

Conventionally, it has been known that the pharmacological actions of these four isomers are not significantly different from each isomer. Therefore, four stereoisomers as a pharmaceutical are unique substances that are registered in the US Pharmacopoeia as a mixture. Of course, the efficacy sequences are compared by measuring the isomeric pharmacological activity of each isomer, but there is little difference between the major differences and significant toxicity, so it was registered in the US Pharmacopoeia without any stereoisomers.

Therefore, the pharmacological effect of this substance is excellent, so that even when a very small amount of the substance is used, pharmacological action is exhibited and a large amount of the substance is used.

It is one of the raw materials for pharmaceuticals that can not solve the fact that raw materials are expensive even in a situation where demand is increasing. Although researchers have been working hard to supply this compound at low cost, it has not been able to escape the limited synthesis method and can not escape from the classical synthesis method.

However, according to recent 35th edition of the US Pharmacopoeia, only two isomers of RS 'and SR' have been found to have pharmacological effects, and only these two isomers are listed (see USP Pharmacopoeia 35 revision, page 3356).

The glycopyrrolate marketed under the trade name AHR-504, Nodapton, Robanul, etc. has a molecular weight of 398.34 g / mol and a molecular formula of C ₁₉ H ₂₈ BrNO ₃ , MP) 193.2 캜 to 194.5 캜, and its chemical structure is shown in the following structural formula (I).

(Formula I)

A conventional synthesis method for the racemates of four isomers is as in Scheme 1 below.

A recent synthetic manufacturing method patent for this material is well described in the historical background of the development of this material in detail in the United States Patent Nos. 2,956,062 and 7,576,210 B2 (2009, Aug. 18). Also, a patent developed using a foreign substance as a pharmacological drug type is registered in US Patent 2003/0211134 A1 up to the treatment of hyperhidrosis.

The above patent describes a method for synthesizing a derivative of glycopyrrolate and synthesizing a novel stereoisomer and a method for preparing a mediator synthetic intermediate as a pharmacological study of a wide range of effects on each isomer. Contents are included, so important synthetic data are described in a comprehensive and collective manner to facilitate understanding.

The above synthetic background shows that glycopyrrolate is an expensive substance (eg, 30,000 ~ 40,000,000 won / Kg), and it can be understood that the synthesis yield is low and it is not easy to produce.

An important synthetic pathway is a three- or four-step pathway through which four chemical compounds, Racemic (RS), which is recognized as the USP (USP), can be synthesized without isolating the isomers during synthesis Diastereoisomers) complex.

However, because of these characteristics, it is difficult to manage the intermediate stage process. Therefore, it is necessary to use a method in which the separation process in the middle, that is, the decompression distillation purification method based on the esterification, is applied or the separation and purification is carried out by the column chromatography method, purification causes a lot of losses. Conventional researchers have searched for a method of proceeding to the next reaction as much as possible without purification in a reaction solution, and many patents have been proposed.

For example, in US Pat. No. 7,576,210 B2 (Aug. 18, 2009), the synthesis ratios of the two isomers are somewhat high, but the yields of the individual isomers are low, If we look at the actual test results, we can see that the actual yield is 45% yield, as described in each of the individual examples.

This is the reason why the acidic part where the famous Mitsunobu reaction is used is reported to be poorly reacted when the acidity is low.

According to Izumi Sakamoto et al. (Chem.Pharm.bull. 51 (4) 474-476 (2003)), when the pKa value, which is an index representing the acidity, is 13 or more, the reaction does not occur at all.

However, since the alcohol side material used in the synthesis of glycopyrrolate contains a substance (3-hydroxy-1-methylpyrrolidine) which weakens the acidity due to the amine group, the reaction state is not easy and the synthesis yield varies greatly It is considered.

In addition, the conventional Mitsunobu reaction has a disadvantage in that the dihydrodiethyl azodicarboxylate and triphenylphosphine oxide (TPP = O) generated by the reagent interfere with the separation of the product, resulting in poor yield do.

In order to avoid this, there are many patents in which a metal sodium catalyst is used as a catalyst for trans esterification reaction without passing through the Mitsunov reaction. (See U.S. Patent No. 7,576,210 B2, the same patent, above).

In the case of synthesizing by the conventional method, the synthesis is firstly carried out by a Grignard reaction, a secondary methyl esterification reaction, a trans esterification step or a Mitsunobu reaction, a quaternization step by Methylbromide, And the final recrystallization step (the crystallization step, which is a crucial factor in the yield and also has a lot of patent applications), is the route through the conventional reaction route, in which the description process is dominant consist of.

This is illustrated in Scheme 2 below.

U.S. Pat. No. 7,576,219 B2 Korea Patent 10-0950524 US Patent 2,956,062 Korea 10-0487992 United States Patent 5,962,505 United States Patent 5,996,797

Pure Appl. Chem., Vol. 71, no. 6, pp. 1053-1057 Chem. Pharm. Bull. 51 (4) 474-476 (2003)

However, as described in the above method, since the final yield is low and basically, the problem caused by the high cost of the raw material to be supplied to the path can not be solved and the expert can not understand the conventional concept, the active pharmaceutical ingredients (API) The price of glycopyrrolate is formed at a high price.

The applicant of the present invention has solved this problem and completed the invention capable of producing racemates of four isomers of RR ', SS', RS 'and SR' at high purity and high yield, -0046357, which is currently pending in the Korean Intellectual Property Office.

However, according to these methods, it is possible to produce four isomeric racemates of these RR ', SS', RS 'and SR', and only two kinds of RS 'and SR' , The racemates of the four isomers of RR ', SS', RS 'and SR' were split to prepare the racemate of these two isomers only. To prepare racemates of the two isomers of RS 'and SR' or to prepare racemates of the two isomers of the new RS 'and SR'. However, a method for producing racemates of two isomers of RS 'and SR' has not yet been developed efficiently.

The present invention has completed the present invention by developing a method capable of shortening the reaction pathway and increasing the yield of the synthesis of glycopyrrolate and selectively producing a racemate composed only of isomers of RS 'and SR' If it is displayed, it is like the following scheme 3.

Scheme 3. Synthetic scheme by new method (NMR-MeBr Salt)

The reaction in the above reaction formula will be described step by step.

1) Benzoylformic acid (compound of formula 1) is first subjected to a Grignard reaction in cyclopentyl magnesium bromide (compound of formula 2) and ether to give racemate of α-cyclopentylmandelic acid (R / S racemic ) (Compound of formula 3) is synthesized (step 1 reaction).

2) 1-Methyl-3-pyrrolididonol methyl bromide (compound of formula 5) is prepared by separately reacting 1-methyl-3-pyrrolididol (compound of formula 4) with methyl bromide (step 2 reaction) .

3) R / S racemic (compound of formula 3) of? -Cyclopentylmandelic acid obtained in the first step reaction was reacted with 1-methyl-3-pyrrolididonolmethyl bromide (compound of formula 5 (3R, 2S) - (2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide as a main component, (2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide) and (3S, 2R ') - [ ] -1,1-dimethylpyrrolidinium bromide ((3S, 2'R) - [(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide Quot; glycopyrrolate ").

In this way, racemates of isomers of R, S'- and S, R 'are obtained which do not require splitting of the isomers in a simple manner.

When the RR and SS forms are reacted in the reaction after the salt (salt) reaction, no more RR or SS isomer is produced, and RS and SR only racemates are obtained.

The isomer separation solvent was extracted with primary ethyl acetate to remove the unreacted product. Secondly, isopropyl alcohol was used to separate RR 'and SS' (enantiomer and enantiomer), and the residue was subjected to heating and cooling with isopropyl alcohol Obtain RS ', SR' (mirror isomer, enantiomer) conforming to the US Pharmacopoeia USP35 (2012) specification.

The present invention relates to a process for the preparation of racemic (R / S) racemates of the? -Cyclopentylmandelic acid of formula 3 with 1-methyl-3-pyrrolididonolmethyl bromide of formula The method of the present invention for the synthesis of glycopyrrolate is capable of easily removing the by-products produced during the reaction by crystallization, facilitating purification and shortening the time of the synthesis process It was possible to synthesize glycopyrrolate conforming to the US Pharmacopoeia 35 standard. In addition, recovery of the unreacted material is easy and the glycopyrrolate of the RR form or the SS form is reused to increase the yield of the glyceropyrrolate of the RS form or the SR form, and the yield is further increased by the recovery method It is an excellent manufacturing method that is expected to be.

1 is an HPLC graph of a standard product.
FIG. 2 is an HPLC chart of a reaction solution in which NMP is synthesized with MeBr and salt to synthesize glycopyrrolate.
3 is an HPLC chart of the reaction solution of glycopyrrolate prepared in the present invention.

The invention of the present invention will be described in more detail by way of examples, which should not be construed as limiting the scope of the present invention.

Synthesis of? -cyclopentylmandelic acid (compound of formula 3)

15 g of benzoylformic acid (compound of formula 1) was dissolved in 330 mL of anhydrous ethyl ether and then cooled to 0 占 폚. Cyclopentylmagnesium bromide (compound of formula 2) 100 ml of 2M cyclopentylmagnesium bromide ether solution was slowly added dropwise at 0 占 폚 for 30 minutes. And the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid was added to terminate the reaction, followed by extraction with ether. The extracted ethereal solution was treated with residual hydrochloric acid with K2CO3 aqueous solution and extracted twice with ether. Anhydrous magnesium sulfate was added to the ether solution, dehydrated, and concentrated under reduced pressure to remove the ether solution. The obtained material was washed with purified water to obtain 8.8 g of? -Cyclopentylmandelic acid (compound of formula 3).

Yield: 40%

m.p .: 153 - 154 캜

¹ H-NMR (CDCl ₃ ): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.63-1.72 (8H, m), 2.93 (1H, m), 7.26-7.30, 7.33-7.36, 7.65-7.67 , m)

Synthesis of 1-methyl-3-pyrrolididonol methyl bromide salt (compound of formula 5)

2.6 mL of 1-Methyl-3-pyrrolidonol (compound of formula 4) was dissolved in 40 mL of acetone and then cooled to 0 占 폚. To this, 200 mL of methanol (MeOH) is slowly added dropwise to 298 mL of a 33% solution of hydrobromic acid / solution in glacial acetic acid at room temperature under a stream of nitrogen gas to pressurize the methyl bromide gas. And the mixture was stirred at room temperature for 24 hours. Remove the solvent. To obtain 4.38 g of 1-methyl-3-pyrrolididonol methyl bromide salt (compound of formula 5).

Yield: 94%

m.p: 357-359 DEG C

^{1 H-NMR (D2O):} 2.12 ~ 2.21 (1 H, m, C H H'CH 2 N), 2.52 ~ 2.62 (1 H, m, CH H 'CH 2 N), 3.14 (3 H, s, _{NCH 3), 3.25 (3 H} , s, NCH 3), 3.51 ~ 3.61 (2 H, m, CH 2 C H 2 N), 3.64 ~ 3.70 (1 H, m, CHC H HN), 3.72 ~ 3.80 ( 1 H, m, CHCH H N). _{13C-NMR (D 2 O)} : 30.21 (CH C H 2 CH 2), 51.59 (NCH 3), 51.98 (NCH 3), 63.16 (CH 2 C H 2 N), 67.25 (OH C H), 70.63 ( CH C H ₂ N)

Synthesis of glycopyrrolate (I)

7.55 g of? -Cyclopentyl mandelic acid (compound of formula 3) and 23.5 g of 1-methyl-3-pyrrolidonol methyl (N, N-dimethylformamide) were dissolved in 23 mL of anhydrous N, N- 4.38 g of 1-methyl-3-pyrorrlidonol * MeBr salt (compound of formula 5) and 9.0 g of triphenylphosphine are dissolved in a nitrogen stream at 0 ° C. Then add 6.74 mL of diisopropyl azodicarboxylate to 23 mL of anhydrous N, N-dimethylformamide and add slowly. And the mixture was stirred at room temperature for 2 hours. The N, N-dimethylformamide solvent is removed by distillation under reduced pressure. The crystals are washed with an excess amount of ethyl acetate (about 200 mL) to obtain pure product, and a small amount (about 40 mL) of iso-propyl alcohol is dissolved in the water at about 100 ° C. . Leave at 0 ~ -5 ℃ until crystals are formed. When crystals are formed, they are washed again with iso-propyl alcohol and ethyl acetate to obtain 6.0 g of glycopyrrolate (I).

Yield: 44%

m.p .: 193.5-194.8 DEG C

_{^{1 H-NMR (D 2 O}} ): 1.13-1.71 (8H, m, C (5) H 2, C (5 ') H 2, C (6) H 2, C (6') H 2), 2.03 -2.13 (1H, m, C ( 9) H H '), 2.59 ~ 2.71 (1H, m, C (9) H H'), 2.98 (3H, s, C (12) H 3), 3.03 ~ 3.12 (1H, m, C (4 ) H), 3.14 (3H, s, C (11) H 3), 3.43-3.58 (2H, m, C (8) H H ', C (10) H H') , 3.68 (1H, d, J = 14 Hz, C (10) H H '), 3.79 (1H, dd, J = 15, 6, C (8) H H'), 5.45 (1H, s, C ( M, C (3) H), 7.55-7.60 (2H, m, 3H), 7.30-7.35 C (2) H, C ( 2 ') H) 13C-NMR (D 2 O): 25.82 (C (8)), 26.13 (C (8')), 26.28 (C (7)), 26.77 (C (7)), 30.02 (C (12)), 53.19 (C (15)), 53.76 (C (14) C (9)), 80.76 (C (5), 126.09 (C (3)), 128.43 (C .

The conventional method (MeBr addition method after methylation first) The reaction formula is as follows.

Comparative Example 1

Synthesis of cyclopentylmandelic acid (compound of formula 3)

10 g of benzoylformic acid (compound of formula 1) was dissolved in 250 mL of anhydrous ethyl ether and then cooled to 0 占 폚. Cyclopentylmagnesium bromide (compound of formula 2) 67 ml of 2M ethylhexyl solution was gradually added dropwise at 0 占 폚 for 30 minutes. And the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid was added to terminate the reaction, followed by extraction with ether. The extracted ethereal solution was treated with residual hydrochloric acid with K2CO3 aqueous solution and extracted twice with ether. Anhydrous magnesium sulfate was added to the ether solution, dehydrated, and concentrated under reduced pressure to remove the ether solution. The obtained material was washed with purified water to obtain 5.8 g of cyclopentylmandelic acid (compound of formula 3).

Yield: 39.5%

Comparative Example 2

Synthesis of methylcyclopentylmandelate (compound of formula 6)

5.8 g of cyclopentylmandelic acid (compound of formula 3), 9.1 g of K ₂ CO ₃ and 11.2 g of methyl iodide are dissolved in 65 ml of dimethylformamide (DMF) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was terminated by adding purified water and extracted with n-hexane. The n-hexane solvent was distilled under reduced pressure to remove the solvent. The solvent-removed product was chromatographed with n-hexane: methylene chloride = 1.5: 1 to obtain 3.9 g of methylcyclopentylmandelate (compound of formula 6).

Yield: 63.2%

¹ H-NMR (CDCl 3): 1.32-1.37, 1.43-1.69 (8H, m), 2.90 (1H, m), 3.74 (3H, s), 7.25-7.37, 7.63-7.65

Comparative Example 3

Synthesis of N-methyl-3-pyrrolidinyl-cyclopentylmandelate (compound of formula 7)

3.9 g of methylcyclopentylmandilate (compound of formula 6) and 2.5 ml of N-methyl-3-pyrrolidoneol (compound of formula 4) are dissolved in 70 ml of n-Heptane and 35 ml of heptane is then distilled. 8 mg of a piece of sodium is added and distillation is continued for 2 hours while stirring with heating. New heptane is added at the same rate as the amount of distilled heptane. In addition, sodium is added at the end of the distillation and replenishment for one hour. The solution is cooled and extracted with 3N hydrochloric acid. The acidic extract is alkalized with concentrated sodium hydroxide solution and extracted three times with ether. The product obtained after distilling the ether solution was subjected to chromatography with Ethyl Acetate: Ethanol = 8: 1 to obtain 3.6 g of N-methyl-3-pyrrolidinyl-cyclopentylmandelate (compound of formula 7).

Yield: 71.3%

¹ H-NMR (CDCl 3): 1.27-1.35, 1.40-1.47, 1.54-1.60, 1.75-1.90 (8H, m), 2.12-2.30, 2.52-2.57, 2.64-2.81, (6H, m) M), 5.23 (1H, m), 7.23-7.36, 7.64-7.67 (5H, m)

Comparative Example 4

The glycopyrrolate (I)

400 mL of methanol is cooled to 0 ° C and stirred, and then 580 mL of a saturated acetic acid solution of bromic acid is slowly added dropwise. After stirring for 4 hours, methyl bromide is produced at room temperature. The resulting methyl bromide is passed through a solution of 3.6 g of N-methyl-3-pyrrolidinyl-cyclopentylmandelate (compound of formula 7) in 40 ml of anhydrous acetone at -5 to 5 ° C for 30 minutes. The reaction temperature is adjusted to 15 to 25 ° C and the mixture is stirred for 4 hours. The acetone solution is distilled off under reduced pressure, the solvent is removed, and then 38 mL of methanol is added to dissolve. Then, 25 mL of methyl ethyl ketone (MEK) is added. 30 ml of MEK is further added, and the mixture is heated to reflux for 30 minutes. The reaction temperature is cooled by 30 ° C per hour to -10 to 0 ° C. After washing with 8 mL of cold MEK, 4.0 g of recrystallized glycopyrrolate (I) was obtained.

Yield: 85.3%

m.p .: 193-194.5 DEG C

^{1 H-NMR (D2O):} 1.19-1.25 (1H, m), 1.46-1.69 (8H, m), 2.30-2.33 (1H, m), 2.68-2.75 (1H, m), 2.84 (3H, s) , 3.09 (3H, s), 3.46-3.59, 3.64-3.82 (4H, m), 5.46-5.50 (1H, m), 7.34-7.37, 7.41-7.44, 7.59-7.62

Comparison of the present invention and the conventional method

1. Glycopyrrolate as a recent stereoisomer has been revised in the US Pharmacopoeia 35 (2012) and it is newly registered, making it difficult to synthesize raw materials. In the past, four isomers (RR, RS, SS and SR) did not have any problems in terms of specifications. However, a new synthesis method was required because only RS and SR were recognized in the 35 revisions of the newly revised US Pharmacopoeia.

The present invention has found a remarkable improvement method that can be obtained by synthesizing the new standard material glycopyrrolate, and completed the present invention.

2. Three-step synthesis of glycopyrrolate (invention) and four-step synthesis

Starting from mandelic acid (alpha-cyclopentylmandelic acid), the process that is crucial to the primary yield improvement through the entire synthesis process is the ester reaction, which is commonly applied to this reaction, and the reaction proceeds in the conventional Mitsunobu reaction If the purity can not be secured in the purification process, the yield is likely to be mistaken and the actual yield is low when the final product is brought to the glycopyrrolate stage. This results in a yield error if the substance just before the final intermediate is an ester, not a solid, and its purity is not confirmed.

The total yield of the glycopyrrolate synthesized in four steps via the methylation reaction was 15.2% and the isomers were mixed. However, a new synthetic method, 1-methyl-3-pyrrolididolone and hydrobromic acid / Methyl-3-pyrrolididonol methyl bromide salt was synthesized and reacted with alpha-cyclopentylmandelic acid to obtain glycopyrrolate. As a result, it was found that the actual yield was increased from 15.2% to 16.5% there was. It is also possible to isolate isomers.

The new method of synthesizing glycopyrrolate of the present invention can easily remove the byproducts produced during the reaction by crystallization, facilitate purification and shorten the synthesis process time, and synthesize glycopyrrolate suitable for the US Pharmacopoeia 35 standard I could. In addition, recovery of the unreacted material is easy and the glycopyrrolate of the RR form or the SS form is reused to increase the yield of the glyceropyrrolate of the RS form or the SR form, and the yield is further increased by the recovery method It is an excellent manufacturing method that is expected to be.

3. HPLC Identification of Glycopyrrolate Standard and Composition

1) The HPLC graph of the standard product is shown in FIG. 1 attached.

2) The HPLC graph of the reaction solution in which NMP was synthesized with MeBr and salt by Glycopyrrolate synthesis is shown in FIG. 2 attached hereto.

Here, the front peak is a coexisting mixture of RR and SS, and the rear peak is a coexisting mixture of RS and SR.

3) The HPLC graph of the reaction solution of the glycopyrrolate prepared in the present invention is shown in FIG. 3 attached hereto.

Here, it is a glycopyrrolate obtained by refining NMP with salt of MeBr and synthesizing glycopyrrolate with ethyl acetate and IPA. This glycopyrrolate is suitable for USP 35 revised edition (2012), and the content of impurities RR and SS is 0.4% or less.

Based on the amendment of USP 35 (2012), the Glycopyrrolate compound is compared with the standard and HPLC test results

FIG. 1 shows Reten, Time as a standard product of glycopyrrolate of 4.88 min.

FIG. 2 is a graph showing the synthesis of a conventional glycopyrrolate as a glycopyrrolate compound. The synthesis of α-cyclopentylmandelic acid and N-methyl-3-pyrrolidinol (NMP) After the reaction, methyl bromide (MeBr) is reacted later. However, the present invention is a Glycopyrrolate compound synthesized by first reacting NMP with MeBr to form a salt and reacting with a-cyclopentylmandelic acid (Mitsunobu reaction). (RR, SS, RS, SR isomer mixtures). Reten, Time was 4.63 and 4.81 min.

FIG. 3 is a Glycopyrrolate composite of the present invention synthesized through a Mitsunobu reaction with? -Cyclopentylmandelic acid after synthesis of NMP * MeBr salt as a Glycopyrrolate compound of the present invention. This compound was purified using ethyl acetate and isopropyl alcohol. (RS, SR). Reten, Time was 4.94 min.

In conclusion, the products of both methods were identical.

Method of Manufacturing Aerosol Formulation Example

A spray gun is attached to a cylinder 6.5 cm in diameter and 20 cm in length in a cylindrical aerosol container (container allowable pressure 12 kg / cm 2 to 13 kg / cm 2 squared), a laminate film cylinder 300 cm The inside of the aerosol bottle was pushed in with nitrogen at a fill pressure of 5 kg / cm squared (possible pressure range of 3 kg / cm squared to 7 kg / cm squared, pressure vessel specification less than 8 kg / cm squared) The pressure for pushing the glycopyrrolate ethanol solution into the tube (bag) was set at a pressure (6 kg / cm squared) exceeding 1 kg / cm square more than the nitrogen use pressure preliminarily put in the container, and the glycopyrrolate ethanol solution % Aqueous ethanol solution, pH 4.0 standard, adjusted with dilute hydrochloric acid) is pushed under pressure and sealed.

When this formulation is used, when the upper nozzle of the aerosol can is pushed, nitrogen is present in the aerosol container and only the glycopyrrolate ethanol solution is finely sprayed out of the container by the filling pressure of nitrogen. ) To about 23 cm squared (4.8 cm X 4.8 cm). Apply about 1.0 to 1.2 mL per minute of usage per centimeter. (The local topical application capacity of a general glycopyrrolate alcohol solution is disclosed in Korean Patent No. 10-0950524.)

In the present invention, the Glycopyrrolate compound synthesized through the Mitsunobu reaction with α-cyclopentylmandelic acid after synthesis of a new NMP * MeBr salt is a mixture of RR, SS, RS and SR isomers as shown in Table 2 However, it is difficult to separate intermediates into RR and SS groups easily by conventional reactions. However, when this compound is purified by using ethyl acetate and isopropyl alcohol, the RR and SS bodies treated as impurities in the new USP 35 revision Can be separated. In addition, in the improved reaction method, when the reacted RR and SS are added in the same amount in advance, the reaction proceeds at a ratio of 1: 1 in the RR, SS group, RS, and SR groups, Can be maximized. However, since the intermediate is an oil in the conventional method, separation into RR, SS group, RS and SR groups is impossible and position-selective reaction is practically difficult. The present invention has accomplished the present invention by developing a high yield synthesis method of Glycopyrrolate suitable for USP 35 (2012) by improving the conventional reaction yield by performing NMP * MeBr salt Fumitonobu reaction.

Table 2 below is a summary table of comparison of synthesis yields, summarization table and evaluation explanation in the present invention.

[Table 2]

The method of synthesizing a new NMP-MeBr salt (salt) first and then synthesizing Glycopyrrolate by the subsequent Mitsunobu reaction has been reported in the new USP 35 revision in which the amounts of RR and SS forms treated as impurities are small, . Conventional Esther conversion method (Methylation, Trans methylation) was not easy to remove impurities due to the standard of 35 new US Pharmacopoeia (USP 35, 2012).

4. Glycopyrrolate isomers RR, SS, RS, and SR are shown in Table 1 below.

[Table 1]

5. Glycopyrrolate Ethanol Solution Aerosol-type Injection Formulation

It is a simple and good form of aerosol formulation in which a liquid filled in an inner tube is sprayed only under inert nitrogen pressure rather than in a mixed gas state without using a pollutant substance or an environmental influential substance (Freon gas) rather than a conventional aerosol preparation method. Especially in the case of this formulation, a solution of glycopyrrolate ethanol was suitable.

Claims (5)

The R / S racemic of? -Cyclopentylmandelic acid of formula 3 is reacted with 1-methyl-3-pyrrolididonol methyl bromide of formula 5 to give the RS of formula I, racemic glycopyrrol of SR ≪ / RTI >

The method according to claim 1, wherein the reaction is carried out by adding 1 equivalent of RR 'and SS' units of glycopyrrolate before the reaction. The method according to claim 1, wherein, after completion of the reaction, the reaction mixture is extracted first with ethyl acetate to remove unreacted materials, and then RR 'and SS' (enantiomers and enantiomers) are separated and removed using isopropyl alcohol (IPA) And the residue is heated and cooled with isopropyl alcohol to recrystallize to give RS ', SR' (enantiomer). The method of claim 1, wherein the compound of formula 5 is prepared by reacting N-methyl-3-pyrrolidinol of formula 4 with methyl bromide.

A pharmaceutical composition prepared in the form of an aerosol of the ethanol solution of glycopyrrolate obtained in claim 1.

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