Preparation method of glycopyrronium bromide impurity reference substance
Through the simplified synthesis route, the compound GLA221-03-01 was used to react with nitrification reagents, reducing agents and diazotizing reagents to prepare glycopyrrogen impurities, solving the problems of expensive starting materials and difficult synthesis, and achieving high purity and high yield of glycopyrrogen impurities.
Patent Information
- Application Number
- CN202311450677.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-02
- Publication Date
- 2025-05-06
AI Technical Summary
In the prior art, the starting material for synthesis of glycopyrrogen impurities is expensive, difficult to synthesize, low yield, and the chemical purity of the product cannot be guaranteed.
Compound GLA221-03-01 is used to react with nitrification reagent in a specific solvent, then react with reducing agent, then mix with diazotization reagent and catalyst, and finally react with methane bromine to prepare glycopyroxyl bromine impurities.
It provides an easy-to-get starting material, simplified synthesis route, simple operation, high product purity, yield reaches more than 68%, and purity reaches 98%.
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Figure CN119930490A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a method for preparing a glycopyrrolate impurity reference substance. Background Art
[0002] Glycopyrrolate ((S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1,1-dimethylpyrrolidine-1-ammonium bromide) was launched in the United States in 1982. It is a quaternary ammonium anticholinergic drug that inhibits gastric secretion and regulates gastrointestinal motility. It also has a stronger anti-salivation effect than atropine, but has no central anticholinergic activity. After oral administration, it can quickly reduce acid, relieve spasms and relieve pain. Its structure is shown below:
[0003]
[0004] The conventional method or process for synthesizing glycopyrrolate generally uses α-cyclopentylmandelic acid as a starting material, firstly performs an esterification reaction to generate α-cyclopentylmandelic acid methyl ester, then uses metallic sodium or sodium hydride as a base to perform an ester exchange reaction with 1-methyl-3-pyrrolidinol in an n-heptane solvent to obtain an intermediate product, and then performs a quaternization reaction with methyl bromide in an ethyl acetate solvent after purification to obtain a crude glycopyrrolate, and finally recrystallizes with a mixed solvent of butanone and ethyl acetate to obtain a refined glycopyrrolate.
[0005] Since most impurities in drugs have potential toxicity and biological activity, which will affect the safety and effectiveness of drugs, impurity synthesis and control are important aspects of chemical drug quality control.
[0006] Among them, (S)-3-((R)-2-(4-chlorophenyl)-2-cyclopentyl-2-hydroxyacetoxy)-1,1-dimethylpyrrolidine-1-ammonium bromide (hereinafter referred to as glycopyrrolate impurity) is an impurity in the production process of glycopyrrolate, and the impurity is a related substance I listed in the European Pharmacopoeia (i.e., EP10.0 impurity I), and its structure is as follows:
[0007]
[0008] Thomas Allmendinger et al. (Org. Process Res. Dev. 2012, 16, 1754-1769) reported a method for preparing a glycopyrrolate impurity, wherein cyclopentyloxyethyl acetate and 4-chlorophenylmagnesium bromide are subjected to nucleophilic addition followed by hydrolysis, followed by condensation reaction with 3-hydroxy-1-methyltetrahydropyrrole, and then quaternization reaction with methyl bromide to obtain a glycopyrrolate impurity. The preparation method is as follows:
[0009]
[0010] However, the above-mentioned synthetic route has expensive starting materials, great difficulty in synthesis, and cannot guarantee the photochemical purity of the product, has low yield, long reaction route and high cost. Summary of the invention
[0011] In order to solve the problems of expensive starting materials, great synthesis difficulty, low yield, etc., the present invention provides a method for preparing a glycopyrrolate impurity reference substance, which can be used for glycopyrrolate impurity research.
[0012] In order to achieve the above-mentioned purpose of the present invention, the specific technical solution adopted by the present invention is:
[0013] A method for preparing a glycopyrrolate impurity reference substance comprises the following steps:
[0014] (1) Compound GLA221-03-01 is mixed with a nitrating agent in solvent 1, and reacted to obtain compound GLA221-03-02;
[0015] (2) Compound GLA221-03-02 is mixed with a reducing agent in solvent 2, and reacted to obtain compound GLA221-03-03;
[0016] (3) Compound GLA221-03-03, a diazotizing agent and a catalyst are mixed in solvent 3 and reacted to obtain compound GLA221-03-04;
[0017] (4) mixing compound GLA221-03-04 and methyl bromide in solvent 4, and reacting to obtain glycopyrrolate impurity;
[0018] The synthetic route is:
[0019]
[0020] Preferably, the nitrating agent in step (1) is nitric acid, preferably concentrated nitric acid; and the solvent 1 is sulfuric acid.
[0021] Preferably, in step (1), the mass volume ratio of the compound GLA221-03-01 to the nitrating agent is 1 g:0.4-1 mL, preferably 1 g:0.5 mL; the mass volume ratio of the compound GLA221-03-01 to the solvent 1 is 1 g:1-20 mL, preferably 1 g:1-10 mL, and more preferably 1 g:3 mL.
[0022] Preferably, the reaction temperature in step (1) is -20 to 0°C, the reaction time is 3 to 5 hours, and the reaction condition is a nitrogen atmosphere.
[0023] Preferably, the reducing agent in step (2) is selected from at least one of iron powder, palladium on carbon, and platinum dioxide; and the solvent 2 is selected from at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, and acetic acid.
[0024] Preferably, in step (2), the mass ratio of the compound GLA221-03-02 to the reducing agent is 1:0.1-1, preferably 1:0.2; the mass volume ratio of the compound GLA221-03-02 to the solvent 2 is 1 g:5-20 mL, preferably 1 g:10 mL.
[0025] Preferably, the reaction temperature in step (2) is 20-30° C., the reaction time is 7-9 h, and the reaction conditions are hydrogen atmosphere or addition of ammonium chloride.
[0026] Preferably, the diazotizing agent in step (3) is tert-butyl nitrite; the catalyst is selected from at least one of cuprous chloride, cuprous cyanide, cuprous bromide and cuprous sulfate; and the solvent 3 is selected from one or both of hydrochloric acid and acetic acid.
[0027] Preferably, in step (3), the molar ratio of the compound GLA221-03-03, the diazotizing agent and the catalyst is 1:1-5:1-5, preferably 1:1.5-2.5:1.5-2.5; the mass volume ratio of the GLA221-03-03 to the solvent 3 is 1 g:10-25 mL.
[0028] Preferably, in step (3), the mixing temperature is 0-5°C, and the mixing time is 20-40 min; the reaction temperature is 20-30°C, and the reaction time is 2-4 h, and the reaction condition is a nitrogen atmosphere.
[0029] Preferably, the solvent 4 in step (4) is selected from at least one of tetrahydrofuran, butanone and acetonitrile; the mass volume ratio of the GLA221-03-04 to the solvent 4 is 1 g:10-25 mL; the molar ratio of the GLA221-03-04 to methyl bromide is 1:4-6.
[0030] Preferably, the mixing temperature in step (4) is -20 to 0°C, the reaction temperature is 20-30°C, and the reaction time is 2-5h.
[0031] Compared with the prior art, the present invention has the following beneficial effects:
[0032] (2) The present invention provides a new idea for the synthesis of glycopyrrolate impurity (GLA221-03) reference substance;
[0033] (3) The starting materials of the synthesis method provided by the present invention are easily available, chiral separation is avoided, the operation is simple, and the reaction is easy to monitor;
[0034] (4) The materials required by the present invention are easy to store and harmless, the product is easy to purify, and the yield is ≥68%, and the purity of the final product is ≥98%, which can meet the preparation requirements of the impurity and is of great significance to the research on the glycopyrrolate impurity reference substance. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 1H-NMR spectrum of pure GLA221-03 in Example 1, the solvent is deuterated DMSO;
[0036] Figure 2 is the LC-MS spectrum of the pure product of GLA221-03 in Example 1;
[0037] Figure 3 The HPLC liquid phase spectrum of the pure GLA221-03 in Example 1 is shown in FIG. DETAILED DESCRIPTION
[0038] The technical solutions in the embodiments of the present invention are further clearly described. The described embodiments are only a part of the present invention and are used to explain the present invention but not to limit the present invention. Therefore, other embodiments obtained by other technicians in the field without creative work all belong to the protection scope of the present invention.
[0039] Example 1
[0040] Step 1: Synthesis of compound GLA221-03-02.
[0041]
[0042] GLA221-03-01 (5.5 g, 18.13 mmol, 1 eq) was added into a 250 mL three-necked flask. Under N2 protection, the temperature was lowered to below 0°C. A mixed acid solution of H2SO4 (16.5 mL, 3 V) and HNO3 (2.25 mL, 0.5 V) was added dropwise (the temperature increased rapidly at the beginning of the addition). The temperature was controlled and stirred for 4 h to obtain compound GLA221-03-01.
[0043] TLC plate is as follows: (developing solvent: DCM / MeOH=10 / 1R f =0.6, DCM and water extraction spot plate, iodine display), a small amount of raw materials remain. The reaction solution was dropped into 1.1L ice saturated NaHCO3 (pH=7), extracted twice with DCM, the organic phases were combined, washed once with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated to obtain 6.1g of yellow oil, compound GLA221-03-02, liquid phase purity of 95%, yield of 98%.
[0044] Step 2: Synthesis of compound GLA221-03-03.
[0045]
[0046] Compound GLA221-03-02 (14.5 g, 41.62 mmol, 1 eq) obtained in step 1, MeOH (145 mL, 10 v), and pd / c (2.9 g, 20% w / t) were added to a 500 mL single-necked bottle, replaced with H2, and reacted at room temperature for 8 h to obtain compound GLA221-03-03.
[0047] TLC plate is as follows: (developing solvent: DCM / MeOH=10 / 1R f =0.5), a small amount of raw material remained. Post-treatment: The reaction solution was directly filtered and concentrated to obtain 13.45 g of yellow oil. Dry column chromatography: DCM:MeOH=40:1 washed out 11.2 g of product, compound GLA221-03-03, liquid phase purity was 97%, and the yield was 85%.
[0048] Step 3: Synthesis of compound GLA221-03-04.
[0049]
[0050] Add the compound GLA221-03-03 (6.1 g, 19.16 mmol, 1 eq) prepared in step 2 and AcOH (61 mL, 10 V) into a 250 mL single-necked bottle, control the temperature at 20 °C, add dropwise a solution of tert-butyl nitrite (3.85 g, 37.36 mmol, 1.95 eq) in AcOH (30.5 mL, 5 V), and stir for 1.5 h. This is recorded as reaction solution 1.
[0051] Add HCl (61 mL, 10 V) and CuCl (3.79 g, 38.31 mmol, 2 eq) into a 500 mL three-necked flask, protect with N2, and control the temperature at 0°C. This is referred to as reaction solution 2.
[0052] The reaction solution 1 was added dropwise to the reaction solution 2, and the mixture was stirred at the temperature for 0.5 h. The mixture was heated to room temperature and stirred for 2.5 h to obtain compound GLA221-03-04.
[0053] TLC monitoring (developing solvent: DCM:MeOH=10:1R f=0.6), the raw materials were basically reacted. Water was added to the reaction solution, extracted twice with DCM, the organic phases were combined, washed twice with saturated NaCl aqueous solution, dried with anhydrous Na2SO4, filtered and concentrated to obtain 6g of yellow solid. Dry column chromatography: DCM: MeOH = 20:1, respectively washed out 5g of the relatively pure product, light yellow solid, and then recrystallized with ACN (18V) to obtain 4g of off-white solid, compound GLA221-03-04, liquid phase purity was 99%, and the yield was 61%.
[0054] Step 4: Synthesis of glycopyrrolate impurity (GLA221-03).
[0055]
[0056] The compound GLA221-03-04 (4 g, 11.84 mmol, 1 eq) prepared in step 3 and THF (20 mL, 5 V) were added to a 100 mL three-necked flask, cooled to -10°C, and a tetrahydrofuran solution (1 mol / L) of methyl bromide (59.2 mL, 59.20 mmol, 5 eq) was added dropwise, and stirred at room temperature for 1 h to obtain the compound glycopyrrolate impurity.
[0057] TLC plate is as follows: (developing solvent: DCM: MeOH = 10:1R f =0.4). The raw materials reacted completely, and the reaction liquid was directly filtered to obtain 4.5 g of off-white solid, with a liquid phase purity of 98.95% and a yield of 87%.
[0058] The above glycopyrrolate impurity (GLA221-03) was tested by nuclear magnetic resonance, liquid chromatography-mass spectrometry and HPLC liquid chromatography, and the test results were as follows: Figure 1 , Figure 2 , Figure 3 As shown in Table 1.
[0059] MS(ES+):m / z[M] + :352.1.
[0060] 1 H NMR (400MHz, DMSO) δ8.49(d,J=7.5Hz,1H),7.67(d,J=14.3Hz,1H),6.66(d,J=7.4Hz,1H),4.18(m,1H),4.10(m,1H),3.88(m,2H),3.83- 3.73(m,1H),3.59(d,J=10.9Hz,4H),3.22(m,1H),3.04-2.86(m,1H),2.69(m,1H),1.78(m,4H),1.21(m,1H),1.07(m,2H),0.86(m,1H).
[0061] Table 1 HPLC liquid phase spectrum peak table (detector A 210nm)
[0062] Peak Retention time area high area% 1 12.900 63594 21741 1.050 2 13.693 5991316 1049884 98.950 total 6054910 1071625 100.000
[0063] Example 2
[0064] Step 1: The synthesis of compound GLA221-03-02 was consistent with Example 1.
[0065] Step 2: Synthesis of compound GLA221-03-03.
[0066]
[0067] Take the compound GLA221-03-02 (9.1 g, 26.12 mmol, 1 eq) obtained in step 1 and EtOH (455 mL, 50 V), Fe (14.59 g, 261.19 mmol, 10 eq), NH4Cl (6.99 g, 130.6 mmol, 5 eq) into a 1 L single-necked bottle and reflux for 1 h to obtain compound GLA221-03-03.
[0068] TLC plate is as follows: (developing solvent: DCM / MeOH=10 / 1R f =0.5), a small amount of raw materials remained. The reaction solution was directly filtered with diatomaceous earth and concentrated to obtain a yellow oil. Adding DCM + MeOH resulted in an insoluble white solid, which was filtered and the mother liquor was directly concentrated to obtain 15g of a yellow liquid. Dry column chromatography: DCM: MeOH = 20:1 produced 6.6g of a light yellow liquid, with a liquid purity of 97.3% and a yield of 80%.
[0069] Step 3: The synthesis of compound GLA221-03-04 was consistent with Example 1.
[0070] Step 4: Synthesis of glycopyrrolate impurity (GLA221-03).
[0071]
[0072] The compound GLA221-03-04 (4 g, 11.84 mmol, 1 eq) prepared in step 3 and acetonitrile (20 mL, 5V) were added to a 100 mL three-necked flask, cooled to -10 °C, a tetrahydrofuran solution (1 mol / L) of bromomethane (59.2 mL, 59.20 mmol, 5 eq) was added dropwise, and stirred at room temperature for 1 h to obtain the compound glycopyrrolate impurity.
[0073] TLC plate is as follows: (developing solvent: DCM: MeOH = 10:1R f=0.4). The raw materials reacted completely, and the reaction solution was directly filtered to obtain 4.0 g of off-white solid. The purity of glycopyrrolate impurity in liquid phase was 98.1%, and the yield was 78%.
[0074] Example 3
[0075] Step 1: The synthesis of compound GLA221-03-02 was consistent with Example 1.
[0076] Step 2: Synthesis of compound GLA221-03-03.
[0077]
[0078] Take the compound GLA221-03-02 (14.5 g, 41.62 mmol, 1 eq) obtained in step 1, MeOH (145 mL, 10 v), and platinum dioxide (2.9 g, 20% w / t) into a 500 mL single-necked bottle, replace with H2, and react at room temperature for 8 hours to obtain compound GLA221-03-03.
[0079] TLC plate is as follows: (developing solvent: DCM / MeOH=10 / 1R f =0.5), a small amount of raw materials remain. Post-treatment: The reaction solution is directly filtered and concentrated to obtain 13.1g of yellow oil. Dry column chromatography: DCM:MeOH=40:1 flushed out 13g of product, liquid phase purity is 98%, and the yield is 98%.
[0080] Step 3: The synthesis of compound GLA221-03-04 was consistent with Example 1.
[0081] Step 4: Synthesis of glycopyrrolate impurity (GLA221-03).
[0082]
[0083] The compound GLA221-03-04 (4 g, 11.84 mmol, 1 eq) prepared in step 3 and THF (32 mL, 8 V) were added to a 100 mL three-necked flask, cooled to -10 ° C, and a tetrahydrofuran solution (1 mol / L) of methyl bromide (59.2 mL, 59.20 mmol, 5 eq) was added dropwise, and stirred at room temperature for 3 h to obtain the compound glycopyrrolate impurity.
[0084] TLC plate is as follows: (developing solvent: DCM: MeOH = 10:1R f =0.4). The raw materials reacted completely, and the reaction solution was directly filtered to obtain 3.5 g of off-white solid. The purity of glycopyrrolate impurity in liquid phase was 98%, and the yield was 68%.
[0085] Comparative Example 1
[0086] The preparation process is consistent with that in Example 1, with the only difference being that in step 1: GLA221-03-01 (5 g, 1 eq) was added into a 250 mL three-necked flask, protected by N2, cooled to below 0°C, and a mixed acid solution of acetic acid (15 mL, 3 V) and HNO3 (2.5 mL, 0.5 V) was added dropwise (the temperature increased rapidly at the beginning of the addition), and the temperature was controlled and stirred for 4 h to obtain compound GLA221-03-01.
[0087] The rest was consistent with Example 1. In step 1, 3 g of white solid (GLA221-03-02) was obtained with a yield of 52% and a purity of 95%.
[0088] Comparative Example 2
[0089] The preparation process is the same as that of Example 1, except that in step 3: the compound GLA221-03-03 (3 g, 1 eq) prepared in step 2 and AcOH (30 mL, 10 V) are added to a 250 mL single-mouth bottle, the temperature is controlled at 20° C., a solution of sodium nitrite (1.26 g, 1.95 eq) in water (15 mL, 5 V) is added dropwise, and stirred for 1.5 h, which is recorded as reaction solution 1. The rest is the same as that of Example 1, and 1.1 g of a white solid (GLA221-03-04) is obtained in step 3, with a yield of 33% and a purity of 90%.
[0090] Comparative Example 3
[0091] The preparation process was the same as that of Example 1, except that in step 4: compound GLA221-03-04 (2 g, 1 eq) prepared in step 3 and DMF (10 mL, 5 V) were added to a 100 mL three-necked flask. After the TLC reaction was complete, the product did not precipitate and could not be extracted, resulting in no product being taken out.
[0092] Comparative Example 4
[0093] Referring to the existing reported literature (Org. Process Res. Dev. 2012, 16, 1754-1769), the experimental operation is as follows:
[0094] Step 1: Synthesis of (4-chloro-phenyl)-cyclopentylglycolic acid.
[0095]
[0096] Compound 1 (10.5 g) and THF (400 mL) were added to a 1L three-necked flask, cooled to -78 °C, 2M chlorophenylmagnesium bromide in ether solution (88 mL) was added dropwise, and stirred at low temperature for 1 h. The reaction solution was then poured into 180 mL of saturated ammonium chloride solution, 140 mL of ethyl acetate was added for extraction, and the organic phase was dried and concentrated to obtain concentrate 3. Concentrate 3 was then added with THF (200 mL), methanol (200 mL), and then 117 mL of 1M lithium hydroxide aqueous solution was added dropwise, and the temperature was raised to reflux for reaction for 18 h. After the reaction was complete, it was cooled to room temperature, ethyl acetate was added for extraction, and after drying and concentration, column chromatography was performed to obtain compound 4, 3.5 g, with a yield of 22.3%.
[0097] Step 2: Synthesis of compound 5.
[0098]
[0099] Compound 4 (3.5 g), DMF (20 mL), and CDI (3.35 g) were added to a 100 mL three-necked flask, stirred at room temperature for 30 min, and 3-hydroxy-1-methyltetrahydropyrrole (13220-33-2) was added, the temperature was raised to 60°C, and the reaction was continued for 18 h. After the reaction was complete, the mixture was cooled to room temperature, and a mixture of toluene and water was added for extraction. The organic phase was dried and concentrated, and then column chromatography was performed to obtain compound 4, 2.7 g, with a yield of 65.8%.
[0100] The last step of forming the quaternary ammonium salt is consistent with step 4 of Example 1, but the chirality of the product is not distinguished.
[0101] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.
Claims
1. A method for preparing a glycopyrrolate impurity reference substance, characterized in that, The following steps are involved: (1) Compound GLA221-03-01 is mixed with a nitrating agent in solvent 1, and reacted to obtain compound GLA221-03-02; (2) Compound GLA221-03-02 is mixed with a reducing agent in solvent 2, and reacted to obtain compound GLA221-03-03; (3) Compound GLA221-03-03, a diazotizing agent and a catalyst are mixed in solvent 3 and reacted to obtain compound GLA221-03-04; (4) mixing compound GLA221-03-04 and methyl bromide in solvent 4, and reacting to obtain glycopyrrolate impurity; The structural formulas of the compounds GLA221-03-01, GLA221-03-02, GLA221-03-03 and GLA221-03-04 are shown below:
2. The preparation method according to claim 1, characterized in that: In step (1), the nitrating agent is nitric acid, and the solvent 1 is sulfuric acid.
3. The preparation method according to claim 1, characterized in that: In step (1), the mass volume ratio of the compound GLA221-03-01 to the nitrating agent is 1 g: 0.4-1 mL, and the mass volume ratio of the compound GLA221-03-01 to the solvent I is 1 g: 1-20 mL.
4. The preparation method according to claim 3, characterized in that: The reaction temperature in step (1) is -20 to 0°C, the reaction time is 3 to 5 hours, and the reaction condition is a nitrogen atmosphere.
5. The preparation method according to claim 1, characterized in that: In step (2), the reducing agent is selected from at least one of iron powder, palladium on carbon, and platinum dioxide, and the solvent 2 is selected from at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, and acetic acid.
6. The preparation method according to claim 1, characterized in that: In step (2), the mass ratio of the compound GLA221-03-02 to the reducing agent is 1:0.1-1, the mass volume ratio of the compound GLA221-03-02 to the solvent 2 is 1 g:5-20 mL, the reaction temperature is 20-30 ° C, the reaction time is 7-9 h, and the reaction conditions are hydrogen atmosphere or adding NH4Cl.
7. The preparation method according to claim 1, characterized in that: In step (3), the diazotizing agent is tert-butyl nitrite, the catalyst is selected from at least one of cuprous chloride, cuprous cyanide, cuprous bromide and cuprous sulfate, and the solvent 3 is selected from one or both of hydrochloric acid and acetic acid.
8. The preparation method according to claim 7, characterized in that: In step (3), the molar ratio of the compound GLA221-03-03, the diazotizing agent and the catalyst is 1:1-5:1-5, and the mass volume ratio of the GLA221-03-03 to the solvent 3 is 1 g:10-25 mL.
9. The preparation method according to any one of claims 1 to 8, characterized in that: In step (4), the solvent 4 is selected from at least one of tetrahydrofuran, butanone and acetonitrile, the mass volume ratio of the GLA221-03-04 to the solvent 4 is 1 g:10-25 mL, and the molar ratio of the GLA221-03-04 to methyl bromide is 1:4-6.
10. The preparation method according to claim 1, characterized in that: The mixing temperature in step (4) is -20 to 0°C, the reaction temperature is 20-30°C, and the reaction time is 2-5h.