CN115521317A - Method for preparing nafrafine intermediate - Google Patents
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- CN115521317A CN115521317A CN202210069174.8A CN202210069174A CN115521317A CN 115521317 A CN115521317 A CN 115521317A CN 202210069174 A CN202210069174 A CN 202210069174A CN 115521317 A CN115521317 A CN 115521317A
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- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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Abstract
The invention belongs to the technical field of drug synthesis, and provides a method for preparing a naftifine intermediate 6 beta-N-methyl-naltrexone, wherein naltrexone and methylamine are used as raw materials, and the reaction is carried out under the action of a chiral phosphoric acid catalyst to obtain 6 beta-N-methyl-naltrexone with higher yield and chiral purity; the method has the characteristics of easily obtained raw materials, mild reaction conditions and the like, and is simple and convenient in post-treatment and more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a naftifine intermediate 6 beta-N-methyl-naltrexone.
Background
Nalfuraphine (Nalfurafine) is a kappa opioid receptor agonist and is administered orally or intravenously to treat skin itch in CKD patients. Nalfuraphine can obviously reduce the pruritus symptom of patients, has small dependence on medicines psychologically or physically, and has the most common adverse reactions of insomnia and constipation. The chemical structural formula of nalfuraphine is as follows:
the synthesis routes of nalfuraphorphine-like compounds reported at present are many, for example, in chinese patents CN1111900A, CN102325775A, CN104119348A, JP2015166331A, US2014031543A1 and chem. Pharm. Bull, 1998,46 (2): 366-369, 3-furan acrylic acid is first converted into 3-furyl acryloyl chloride, which is then reacted with 6 β -N-methyl-naltrexone to prepare nalfuraphine. The relevant route is as follows:
from the above, the 6 β -N-methyl- (+) -naltrexone as a key intermediate for synthesizing naftifine hydrochloride directly affects the production, market supply and quality problems of the drug, and the structural formula is as follows:
and the current literature J.Med.chem.,1986,29,8,1551-1553; WO2020205735A1, US6277859B1, US5972953A, CN94190473 all have the preparation method of 6 beta-N-methyl-naltrexone; the preparation method of 6 beta-N-methyl-naltrexone mostly adopts naltrexone as an initial material, and the naltrexone and N-methylbenzylamine are subjected to reductive amination reaction, and then the benzyl is removed through catalytic hydrogenolysis to prepare the naltrexone. On one hand, the process needs benzyl protection for inducing generation for constructing a 6 beta-N-methyl structure, so that hydrogenation reaction with high risk is needed for subsequent protecting group removal, and meanwhile, N-methylbenzylamine is introduced by reductive amination reaction, wherein borohydride with high risk is used, and industrial amplification production is difficult to realize. The relevant route is as follows:
WO2010006119A1 and document J.Med.chem.,1986,29,8,1551-1553, wherein naltrexone is used as a raw material and methylamine or methylamine hydrochloride is used in NaBH 3 Reacting under the action of CN, and purifying by column chromatography to obtain about 6 alpha-N-methyl-naltrexone and 6 beta-N-methyl-naltrexone (yield is 32%). The relevant route is as follows:
in conclusion, in view of the above disadvantages of the current preparation method of 6 β -N-methyl-naltrexone, research and search for a reaction route suitable for industrial production of 6 β -N-methyl-naltrexone, which has simple operation process, high product yield and high purity, is still a problem to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing 6 beta-N-methyl-naltrexone preparation technology, the invention provides a novel 6 beta-N-methyl-naltrexone preparation method. The target product prepared by the method has higher purity and yield, and is suitable for industrial scale-up production.
The technical scheme of the invention is as follows:
a preparation method of 6 beta-N-methyl-naltrexone specifically comprises the following steps:
adding SM-1 and methylamine reagent into a reaction solvent at room temperature, and controlling the temperature to react; then adding SM-2 and hydrogen donor into the reaction solution, controlling the temperature until the reaction is finished, and obtaining the product I after post-treatment.
The synthetic route is as follows:
in a preferred embodiment, the methylamine reagent: one or more of methylamine gas, methylamine methanol solution, methylamine ethanol solution, methylamine tetrahydrofuran solution and methylamine hydrochloride.
In a preferred embodiment, the reaction substrate is selected from a group consisting of: acetonitrile, chloroform, dichloromethane, N-dimethylacetamide, N-dimethylformamide, N-methyl-2-pyrrolidone, ethyl acetate, ethanol, and methanol.
In a preferred embodiment, the hydrogen donor SM-3 is specifically one or a combination of SM-3-1, SM-3-2, SM-3-3, SM-3-4 and SM-3-5, wherein SM-3-5 is particularly preferred. The structural formula of the related compound is as follows:
preferably, the feeding molar ratio of SM-1 to methylamine, SM-2 and SM-3 is 1: 2.5-6.0: 0.05-0.2: 1.05 to 1.4, wherein a ratio of 1:3.5:0.1:1.25.
in a preferable scheme, the reaction temperature after the methylamine is added is 15-40 ℃, wherein the reaction temperature is particularly preferably 20-25 ℃; the reaction temperature after addition of SM-2 and a hydrogen donor is 30 to 60 ℃, particularly preferably 40 to 45 ℃.
Preferably, the post-treatment comprises the following steps: and after the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, adding the reaction solution into purified water, adjusting the pH to 9-10 by using concentrated ammonia water to form a precipitate, filtering the obtained precipitate, and drying in vacuum to obtain the target product I.
The invention has the technical effects that:
the invention provides a new method for preparing 6 beta-N-methyl-naltrexone, the method is simple and easy to implement, the yield and purity of the obtained product are higher, and the method is suitable for industrial production.
Drawings
FIG. 1 is a 6 β -N-methyl-naltrexone hydrogen spectrum;
FIG. 2 is a partial magnified 6 β -N-methyl-naltrexone hydrogen spectrum;
FIG. 3 is a partial magnified 6 β -N-methyl-naltrexone hydrogen spectrum;
FIG. 4 is a partial magnified 6 β -N-methyl-naltrexone hydrogen spectrum;
FIG. 5 is a carbon spectrum of 6 β -N-methyl-naltrexone;
FIG. 6 is a partial magnified 6 β -N-methyl-naltrexone carbon spectrum;
FIG. 7 is an HPLC purity profile of 6 β -N-methyl-naltrexone obtained in example 6;
FIG. 8 is the HPLC purity profile of 6 β -N-methyl-naltrexone obtained in example 7.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
Data for structure confirmation of 6 β -N-methyl-naltrexone: see figures 1-6 for details.
Wherein 1 H NMR(600MHz,CDCl 3 ) δ ppm 6.64 (1h, d, j = 8.1hz), 6.54 (1h, d, j =8.0 hz), 4.56 (1h, d, j = 7.56hz) could be confirmed as β configuration; (see FIG. 3 for details of a partial enlarged hydrogen spectrum).
HPLC purity analysis of 6 β -N-methyl-naltrexone: the relative retention time of the 6 beta-N-methyl-naltrexone is about 19 min; the relative retention time of 6 alpha-N-methyl-naltrexone is at about 26min or 27 min. (see FIGS. 7 and 8 for details)
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 12.27g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 93.5%, the HPLC purity is 98.248%, and the isomer 6 alpha-N-methyl-naltrexone is 1.104%.
Example 2
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (2 mol/L,125 ml), the temperature is controlled to be 25-30 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and SM-3-1 (32.29g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, purified water (150 ml) is added, the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, the obtained precipitate is filtered and dried in vacuum to obtain the target product I, the yield is 88.5%, the HPLC purity is 98.214%, and the isomer 6 alpha-N-methyl-naltrexone is 1.135%.
Example 3
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine tetrahydrofuran solution (2 mol/L,120 ml), the temperature is controlled to be 35-40 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 12.27g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH value is adjusted to be 9 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 87.6%, the HPLC purity is 97.864%, and the isomer 6 alpha-N-methyl-naltrexone is 1.154%.
Example 4
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine methanol solution (4 mol/L,150 ml), the temperature is controlled to be 15-20 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and SM-3-2 (31.66g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, purified water (150 ml) is added, the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, the obtained precipitate is filtered and dried in vacuum to obtain the target product I, the yield is 92.6%, the HPLC purity is 98.046%, and the isomer 6 alpha-N-methyl-naltrexone is 1.115%.
Example 5
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,152.5 ml), the temperature is controlled to be 15-20 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 12.27g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH value is adjusted to 10 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 92.8%, the purity is 98.041% by HPLC, and the isomer 6 alpha-N-methyl-naltrexone is 1.108%.
Example 6
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (3.86g, 0.005mol) and SM-3-3 (12.51g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 45-50 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, purified water (150 ml) is added, the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 89.3%, the purity is HPLC 97.049%, and the isomer 6 alpha-N-methyl-naltrexone is 1.859%.
Example 7
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (3.09g, 0.004mol) and cyclohexanone (SM-3-5, 12.27g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 50-55 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH value is adjusted to be 9.5 by concentrated ammonia water, a precipitate is formed, the obtained precipitate is filtered and dried in vacuum, and the target product I is obtained, the yield is 87.5%, the HPLC purity is 96.347%, and the isomer 6 alpha-N-methyl-naltrexone is 1.994%.
Example 8
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (15.45g, 0.02mol) and SM-3-4 (10.26g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 35-40 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, purified water (150 ml) is added, the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 90.3%, the purity is 98.105%, and the isomer 6 alpha-N-methyl-naltrexone is 1.106%.
Example 9
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (16.22g, 0.021mol) and cyclohexanone (SM-3-5, 12.27g, 0.125mol) are added into reaction liquid, the temperature is controlled to be 35-40 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 92.8%, the HPLC purity is 98.110%, and the isomer 6 alpha-N-methyl-naltrexone is 1.126%.
Example 10
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 10.31g, 0.105mol) are added into reaction liquid, the temperature is controlled to be 50-55 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 88.7%, the HPLC purity is 97.058%, and the isomer 6 alpha-N-methyl-naltrexone is 1.659%.
Example 11
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 9.81g, 0.1mol) are added into reaction liquid, the temperature is controlled to be 55-60 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH is adjusted to be 9.5 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 87.9%, the HPLC purity is 97.026%, and the isomer 6 alpha-N-methyl-naltrexone is 1.698%.
Example 12
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 13.74g, 0.14mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH value is adjusted to be 10 by concentrated ammonia water, a precipitate is formed, the obtained precipitate is filtered and dried in vacuum, and the target product I is obtained, the yield is 92.6%, the purity is 97.846%, and the isomer 6 alpha-N-methyl-naltrexone is 1.241%.
Example 13
At room temperature, naltrexone (SM-1, 34.14g, 0.1mol) is added into methylamine ethanol solution (4 mol/L,87.5 ml), the temperature is controlled to be 20-25 ℃ for reaction, after the detection reaction is finished, SM-2 (7.72g, 0.01mol) and cyclohexanone (SM-3-5, 14.72g, 0.15mol) are added into reaction liquid, the temperature is controlled to be 40-45 ℃ for reaction, after the detection reaction is finished, the reaction liquid is decompressed and concentrated to be dry, the reaction liquid is added into purified water (150 ml), the pH is adjusted to be 9 by concentrated ammonia water to form precipitate, and the obtained precipitate is filtered and dried in vacuum to obtain the target product I, wherein the yield is 91.2%, the HPLC purity is 98.011%, and the isomer 6 alpha-N-methyl-naltrexone is 1.243%.
Claims (8)
1. A method for preparing a naftifine intermediate is characterized in that SM-1 and a methylamine reagent are added into a reaction solvent at room temperature, and temperature control reaction is carried out; then adding SM-2 and a hydrogen donor into the reaction solution, controlling the temperature until the reaction is finished, and obtaining I after post-treatment; the synthetic route is as follows:
2. the method of claim 1, wherein the methylamine reagent is: one or more of methylamine gas, methylamine methanol solution, methylamine ethanol solution, methylamine tetrahydrofuran solution and methylamine hydrochloride.
3. The method of claim 1, wherein the reaction solvent: one of acetonitrile, chloroform, dichloromethane, N-dimethylacetamide, N-dimethylformamide, N-methyl-2-pyrrolidone, ethyl acetate, ethanol and methanol.
4. The method according to claim 1, wherein the hydrogen donor SM-3 is specifically one or a combination of SM-3-1, SM-3-2, SM-3-3, SM-3-4, SM-3-5, with SM-3-5 being particularly preferred; the related compound has the following structural formula:
5. the method of claim 1, wherein the molar ratio of SM-1 to methylamine, SM-2, SM-3 fed is 1: 2.5-6.0: 0.05-0.2: 1.05 to 1.4.
6. The process of claim 1, wherein the reaction temperature after the addition of methylamine is 15 to 40 ℃.
7. The method of claim 1, wherein the reaction temperature after the addition of SM-2 and the hydrogen donor is 30 to 60 ℃.
8. The method of claim 1, wherein the post-processing: and after the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, adding the reaction solution into purified water, adjusting the pH to 9-10 by using concentrated ammonia water to form a precipitate, filtering the obtained precipitate, and drying in vacuum to obtain the target product I.
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