CN113698369A - Method for removing specific single impurity in cabazitaxel - Google Patents
Method for removing specific single impurity in cabazitaxel Download PDFInfo
- Publication number
- CN113698369A CN113698369A CN202111011257.3A CN202111011257A CN113698369A CN 113698369 A CN113698369 A CN 113698369A CN 202111011257 A CN202111011257 A CN 202111011257A CN 113698369 A CN113698369 A CN 113698369A
- Authority
- CN
- China
- Prior art keywords
- cabazitaxel
- precursor
- reaction
- specific single
- impurity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a method for removing specific single impurity in cabazitaxel, which has the technical scheme key points that the method comprises the following steps: s1, dissolving and cleaning a cabazitaxel precursor with tetrahydrofuran, adding 4-dimethylaminopyridine, dropwise adding acetic anhydride while stirring, adding water to quench the reaction after the reaction is completed, adding dichloromethane to extract, concentrating an organic phase until no solvent is evaporated out, and obtaining a cabazitaxel precursor derivative; s2: dissolving a cabazitaxel precursor derivative in methanol, adding a hydrochloric acid methanol solution, stirring for reaction, after the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding purified water, separating out a solid, centrifuging, and drying to obtain a cabazitaxel crude product; s3: the invention has the advantages that 7-methoxy docetaxel which is most difficult to remove is converted into 7-methoxy-10-acetyl docetaxel without damaging the structure of a cabazitaxel precursor, the reaction of a cabazitaxel mainline is not influenced, and the yield is ensured.
Description
Technical Field
The invention relates to the technical field of preparation of antitumor drugs, and particularly relates to a method for removing specific single impurities in cabazitaxel.
Background
Cabazitaxel (Cabazitaxel, XRP-6258, trade name Jevtana) is a drug developed by Sanofi-aventis, Senoffel, France, which was approved by the U.S. Food and Drug Administration (FDA) for marketing on 17/6.2010. The medicine is an injection, and is mainly used for treating advanced, hormone refractory, and prostate cancer aggravated during or after docetaxel treatment.
Cabazitaxel has many impurities, wherein an impurity involved in almost all synthetic routes is 7-methoxy docetaxel, which is generated by the precursor impurities of cabazitaxel (an impurity generation mechanism is shown as follows) due to the fact that partial materials cannot simultaneously complete methylation at the 7-position and the 10-position in a synthetic process, and finally, 7-methoxy docetaxel is obtained by deprotection, wherein the impurity generation mechanism is shown as follows:
the impurities have special properties, the structure of the impurities is similar to that of cabazitaxel, the retention time of the impurities in liquid chromatography is very close to that of cabazitaxel, and TLC cannot realize separation of 7-methoxy docetaxel and cabazitaxel, so that effective purification cannot be performed through column chromatography (normal phase/reverse phase), and the impurities are the impurities which are most difficult to remove in a cabazitaxel process. The content of the impurities in the cabazitaxel crude product is high, and if efficient purification is not realized, a high-purity cabazitaxel product cannot be obtained. Practice has shown that it is difficult to reduce this impurity to the level of 0.1% by recrystallization alone, while ensuring a certain yield.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for removing specific single impurity in cabazitaxel, the method ensures that cabazitaxel does not react by derivatization treatment of impurities, and then performs column chromatography separation, so that the product has good purity (the single impurity is less than 0.1%), high yield and capability of large-scale preparation.
The technical purpose of the invention is realized by the following technical scheme:
a method for removing a specific single impurity from cabazitaxel, wherein the single impurity is 7-methoxy docetaxel, comprising the following steps:
s1, dissolving and cleaning a cabazitaxel precursor with tetrahydrofuran, adding 4-dimethylaminopyridine, dropwise adding acetic anhydride while stirring, adding water to quench the reaction after the reaction is completed, adding dichloromethane to extract, concentrating an organic phase until no solvent is evaporated out to obtain a cabazitaxel precursor derivative, wherein the cabazitaxel precursor does not react in S1, and cabazitaxel precursor impurities are converted into cabazitaxel precursor impurity derivatives through reaction;
s2: dissolving a cabazitaxel precursor derivative with methanol, adding a hydrochloric acid methanol solution, stirring for reaction, after the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding purified water, separating out a solid, centrifuging, and drying to obtain a cabazitaxel crude product, wherein the cabazitaxel precursor impurity derivative is converted into 7-methoxy-10-acetyl docetaxel;
s3: purifying and crystallizing the cabazitaxel crude product by column chromatography, and separating 7-methoxy-10-acetyl docetaxel from cabazitaxel to obtain a cabazitaxel finished product;
the reaction route of the preparation process is as follows:
further, in step S1, the ratio of the amount of 4-dimethylaminopyridine to the amount of cabazitaxel precursor as the raw material is 0.5 to 1.0 (W/W).
Further, in step S1, the ratio of the amount of acetic anhydride to the raw material cabazitaxel precursor is 0.4-0.8 (W/W). .
Further, in step S1, the ratio of the tetrahydrofuran to the cabazitaxel precursor is 8-10 (W/W).
Further, in step S1, the reaction temperature is 20-25 ℃ and the reaction time is 1-2 h.
Further, in step S1, the ratio of the amount of dichloromethane to the cabazitaxel precursor is 20 to 30 (W/W).
Further, in step S2, the concentration of the hydrochloric acid methanol solution is 1-2 mol/L.
Further, in step S2, the ratio of the methanol solution of hydrochloric acid to the cabazitaxel precursor derivative is 2-2.5 (W/W).
Further, in step S2, the reaction temperature is 15-20 ℃ and the reaction time is 2-4 h.
Further, in step S3, the column chromatography purification is normal phase silica gel column chromatography purification, and the mobile phase is ethyl acetate and n-heptane.
In conclusion, the invention has the following beneficial effects:
1. in step S1, the cabazitaxel precursor impurity reacts to be converted into a cabazitaxel precursor impurity derivative, while the cabazitaxel precursor does not react; in step S2, the cabazitaxel precursor is deprotected to convert to cabazitaxel, and the cabazitaxel precursor impurity derivative is deprotected to convert to 7-methoxy-10-acetyl docetaxel; the most difficult-to-remove cabazitaxel impurity (7-methoxy docetaxel) is converted into 7-methoxy-10-acetyl docetaxel, and the difference between the polarity of the 7-methoxy-10-acetyl docetaxel aversion and the polarity of cabazitaxel is larger, so that the cabazitaxel can be effectively removed through conventional normal-phase column chromatography, and a high-purity cabazitaxel product can be obtained.
2. The whole process does not damage the structure of the cabazitaxel precursor, ensures that the reaction of the cabazitaxel main line is not influenced, finally obtains cabazitaxel still and ensures the yield of the process.
Drawings
FIG. 1 is an HPLC chromatogram of the starting material cabazitaxel precursor used in example 1 of the present invention.
Fig. 2 is an HPLC profile of cabazitaxel precursor derivatives obtained in example 1 of the present invention.
Fig. 3 is an HPLC chromatogram of a cabazitaxel finished product obtained in example 1 of the present invention.
Fig. 4 is a cabazitaxel MS spectrum obtained in example 1 of the present invention.
FIG. 5 is a 1H NMR spectrum of cabazitaxel obtained in example 1 of the present invention.
FIG. 6 is a Cabazitaxel 13C NMR spectrum obtained in example 1 of the present invention.
Fig. 7 is an HPLC chromatogram of the cabazitaxel finished product obtained in comparative example 1 of the present invention.
Fig. 8 is an HPLC chromatogram of a cabazitaxel finished product obtained in comparative example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the present invention is provided with reference to the accompanying drawings and the detailed description. The advantages and features of the present invention will become more apparent from the following description. It is to be noted that the drawings are in a very simplified form and are all used in a non-precise scale for the purpose of facilitating and distinctly aiding in the description of the embodiments of the present invention. It should be understood that the structures, ratios, and the like shown in the drawings and described in the specification are only for the purpose of understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, so they do not have the essential meaning in the art, and any structural modifications, ratio changes, or adjustments may be made without affecting the function and the achievable purpose of the present disclosure.
Example 1:
step S1: 1.72kg of cabazitaxel precursor (containing 6.482% of cabazitaxel precursor impurity, and having liquid phase detection pattern shown in figure 1) is stirred and dissolved with 15kg of tetrahydrofuran, 0.88kg of 4-dimethylaminopyridine is added, and 0.74kg of acetic anhydride is dropwise added under stirring. Reacting at room temperature (25 ℃) for 2h, adding water to quench the reaction, adding 35kg of dichloromethane to extract, concentrating an organic phase until no solvent is evaporated, and obtaining 1.4kg of cabazitaxel precursor derivatives. (HPLC is shown in figure 2, the Cabazitaxel precursor impurity is basically converted into Cabazitaxel precursor impurity derivatives)
S2: 1.4kg of cabazitaxel precursor derivative is dissolved in 31kg of methanol, 2.8kg of 1mol/L hydrochloric acid methanol solution is added, and the mixture is stirred and reacted for 4 hours at 15 ℃. After the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding 50kg of purified water, separating out a solid, centrifuging and drying to obtain 1.1kg of a cabazitaxel crude product I;
s3: purifying the 1.1kg of cabazitaxel crude product by normal phase silica gel column chromatography (the mobile phase is ethyl acetate and n-heptane) to obtain cabazitaxel crude product II, and recrystallizing to obtain 405.5g of cabazitaxel finished product with purity of 99.9%, wherein the HPLC chromatogram is shown in figure 3.
As shown in fig. 4, the MS spectrum of cabazitaxel in the present example, wherein the mass-to-charge ratio M/z is 858.3[ M + Na ═]+The molecular weight can be inferred to be 835, consistent with the target compound.
FIG. 5 shows the results of cabazitaxel of the present example1The H NMR spectrum of the mixture is shown,1H NMR(500MHz,CDCl3)δ：8.11(2H,d,J＝7.5Hz,ArH),7.62(1H,t,J＝7.0Hz,ArH),7.51(2H,t,J＝7.5Hz,ArH),7.41(4H,m,ArH),7.34(1H,m,ArH),6.24(1H,t,J＝8.3Hz,H13),5.66(1H,d,J＝6.5Hz,H2),5.55(1H,d,J＝9Hz,H32),5.29(1H,m,H31),4.99(1H,d,J＝9.5Hz,H5),4.83(1H,s,H10),4.65(1H,s,H37),4.31(1H,d,J＝8.5Hz,H20),4.20(1H,d,J＝8Hz,H20),3.89(1H,dd,J＝10Hz,6.5Hz,H7),3.84(1H,d,J＝6.5Hz,H3),3.47(3H,s,H29),3.32(3H,s,H28),2.71(1H,m,H6),2.38(3H,s,H27),2.30(2H,m,2H14),1.91(3H,s,H18),1.84(1H,m,H6),1.74(3H,s,H19),1.38(9H,s,H40),1.24(3H,s,3H16/3H17),1.22(3H,s,3H16/3H17).
as shown in FIG. 6, this example shows cabazitaxel13A C NMR spectrum in which,13C NMR(125MHz,CDCl3)δ：206.816,204.834,172.592,170.315,166.842,155.267,138.617,138.466,135.587,133.499,130.047,129.24,128.68,128.538,127.903,126.777,84.041,82.584,81.664,80.682,80.053,78.655,77.251,74.564,73.69,72.373,57.228,56.91,56.852,56.211,47.337,43.241,35.256,32.046,30.773,28.139,26.762,22.567,20.655,14.504.
example 2:
step S1: 170g of cabazitaxel precursor (containing 8.428% of cabazitaxel precursor impurity) was dissolved in 1.7L of tetrahydrofuran with stirring, 170g of 4-dimethylaminopyridine was added, and 136g of acetic anhydride was added dropwise with stirring. Reacting at room temperature (20 ℃) for 1h, adding water to quench the reaction, adding 5.1kg of dichloromethane to extract, concentrating an organic phase until no solvent is evaporated out, and obtaining 142g of cabazitaxel precursor derivative.
S2: 142g of cabazitaxel precursor derivative is dissolved in 4L of methanol, 355g of 2mol/L methanol hydrochloride solution is added, and the mixture is stirred and reacted for 2 hours at the temperature of 20 ℃. After the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding 5L of purified water, separating out a solid, centrifuging and drying to obtain 113g of a cabazitaxel crude product I;
s3: and (3) purifying the 113g of cabazitaxel crude product by normal-phase silica gel column chromatography (the mobile phase is ethyl acetate and n-heptane) to obtain a cabazitaxel crude product II, and recrystallizing to obtain 42.3g of cabazitaxel finished product with the purity of 99.9%.
Comparative example 1:
step S1: 170g of cabazitaxel precursor (containing 8.428% of cabazitaxel precursor impurity) is dissolved in 4L of methanol, 355g of 1mol/L methanol hydrochloride solution is added, and the mixture is stirred and reacted for 2 hours at the temperature of 20 ℃. After the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding 5L of purified water, separating out a solid, centrifuging and drying to obtain 125g of a cabazitaxel crude product I;
s2: purifying the 125g of cabazitaxel crude product by normal phase silica gel column chromatography (mobile phase is ethyl acetate and n-heptane) to obtain cabazitaxel crude product II, and recrystallizing to obtain 42.3g of cabazitaxel with purity of 97.435%, wherein HPLC (high performance liquid chromatography) is shown in figure 7, wherein the content of 7-methoxy docetaxel (impurity B in the figure) is up to 1.721%.
Comparative example 2:
step S1: 170g of cabazitaxel precursor (containing 8.428% of cabazitaxel precursor impurity) is dissolved in 4L of methanol, 355g of 2mol/L methanol hydrochloride solution is added, and the mixture is stirred and reacted for 4 hours at 15 ℃. After the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding 5L of purified water, separating out a solid, centrifuging and drying to obtain 132g of a cabazitaxel crude product I;
s2: dissolving 132g of crude cabazitaxel I in 1.3L of dichloromethane and 130ml of methanol, stirring at room temperature, dropwise adding 2.5L of n-heptane, separating out a solid, performing suction filtration, and repeating the recrystallization operation on a filter cake for 2 times to obtain 22.8g of cabazitaxel with the purity of 96.218%, wherein an HPLC (high performance liquid chromatography) spectrum is shown in the attached figure 8, wherein the content of 7-methoxy docetaxel (impurity B in the figure) is as high as 2.558%.
As can be seen from the comparative example, the impurity 7-methoxydocetaxel present in the conventional process cannot be effectively removed using a common purification means. Cabazitaxel can be obtained with higher yield by column chromatography, but the impurity B is still as high as 1.7 percent; the cabazitaxel obtained by recrystallization has low yield, and the impurity B can reach 2.5 percent. By the method, the original specific 7-methoxy docetaxel can be converted into the 7-methoxy-10-acetyl docetaxel, so that a very obvious impurity removal effect is achieved. The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A method for removing specific single impurity in cabazitaxel, wherein the single impurity is 7-methoxy docetaxel, comprising the following steps:
s1, dissolving and cleaning a cabazitaxel precursor with tetrahydrofuran, adding 4-dimethylaminopyridine, dropwise adding acetic anhydride while stirring, adding water to quench the reaction after the reaction is completed, adding dichloromethane to extract, concentrating an organic phase until no solvent is evaporated out to obtain a cabazitaxel precursor derivative, wherein the cabazitaxel precursor does not react in S1, and cabazitaxel precursor impurities are converted into cabazitaxel precursor impurity derivatives through reaction;
s2: dissolving a cabazitaxel precursor derivative with methanol, adding a hydrochloric acid methanol solution, stirring for reaction, after the reaction is completed, adding a sodium bicarbonate solution until the pH value is 6-7, dropwise adding purified water, separating out a solid, centrifuging, and drying to obtain a cabazitaxel crude product, wherein the cabazitaxel precursor impurity derivative is converted into 7-methoxy-10-acetyl docetaxel;
s3: purifying and crystallizing the cabazitaxel crude product by column chromatography, and separating 7-methoxy-10-acetyl docetaxel from cabazitaxel to obtain a cabazitaxel finished product;
the reaction route of the preparation process is as follows:
2. the method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S1, the ratio of the amount of 4-dimethylaminopyridine to the amount of the cabazitaxel precursor as the raw material is 0.5-1.0 (W/W).
3. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S1, the ratio of the amount of acetic anhydride to the cabazitaxel precursor is 0.4-0.8 (W/W).
4. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S1, the ratio of the amount of tetrahydrofuran to the amount of cabazitaxel precursor is 8-10 (W/W).
5. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S1, the reaction temperature is 20-25 ℃ and the reaction time is 1-2 h.
6. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S1, the ratio of the amount of dichloromethane to the cabazitaxel precursor is 20-30 (W/W).
7. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S2, the concentration of the hydrochloric acid methanol solution is 1-2 mol/L.
8. The method of claim 7, wherein the specific single impurity in cabazitaxel is removed: in step S2, the ratio of the methanol solution of hydrochloric acid to the cabazitaxel precursor derivative is 2-2.5 (W/W).
9. The method of claim 8, wherein the specific single impurity in cabazitaxel is removed: in step S2, the reaction temperature is 15-20 ℃ and the reaction time is 2-4 h.
10. The method for removing specific single impurities in cabazitaxel according to claim 1, wherein: in step S3, the column chromatography purification is normal phase silica gel column chromatography purification, and the mobile phase is ethyl acetate and n-heptane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111011257.3A CN113698369A (en) | 2021-08-31 | 2021-08-31 | Method for removing specific single impurity in cabazitaxel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111011257.3A CN113698369A (en) | 2021-08-31 | 2021-08-31 | Method for removing specific single impurity in cabazitaxel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113698369A true CN113698369A (en) | 2021-11-26 |
Family
ID=78657898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111011257.3A Pending CN113698369A (en) | 2021-08-31 | 2021-08-31 | Method for removing specific single impurity in cabazitaxel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113698369A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1151740A (en) * | 1994-06-28 | 1997-06-11 | 法玛西雅厄普约翰美国公司 | 7-ether-taxol analogs, antineoplastic use and pharmaceutical compsns. containing them |
| US6201140B1 (en) * | 1994-07-28 | 2001-03-13 | Bristol-Myers Squibb Company | 7-0-ethers of taxane derivatives |
| CN1826110A (en) * | 2003-07-18 | 2006-08-30 | 安万特医药股份有限公司 | Semi-solid formulations for the oral administration of taxoids |
| CN104086514A (en) * | 2014-06-19 | 2014-10-08 | 上海应用技术学院 | Paclitaxel derivatives and preparation method thereof |
-
2021
- 2021-08-31 CN CN202111011257.3A patent/CN113698369A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1151740A (en) * | 1994-06-28 | 1997-06-11 | 法玛西雅厄普约翰美国公司 | 7-ether-taxol analogs, antineoplastic use and pharmaceutical compsns. containing them |
| US6201140B1 (en) * | 1994-07-28 | 2001-03-13 | Bristol-Myers Squibb Company | 7-0-ethers of taxane derivatives |
| CN1826110A (en) * | 2003-07-18 | 2006-08-30 | 安万特医药股份有限公司 | Semi-solid formulations for the oral administration of taxoids |
| CN104086514A (en) * | 2014-06-19 | 2014-10-08 | 上海应用技术学院 | Paclitaxel derivatives and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20090275762A1 (en) | Crystalline Forms of Docetaxel and process for Preparation Thereof | |
| CN111470983B (en) | Preparation method of bromhexine hydrochloride | |
| JP2001122890A (en) | Method for producing clarithromycin crystal form ii | |
| CN109836401B (en) | Method for purifying docetaxel | |
| CN106749445B (en) | epirubicin hydrochloride intermediate compound III | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CN110551144B (en) | Preparation method of amoxicillin | |
| CN113666889B (en) | Preparation method of 10-methoxy docetaxel | |
| CN109988127B (en) | Method for synthesizing taxol from 7-differential-10-deacetyltaxol | |
| CN113698369A (en) | Method for removing specific single impurity in cabazitaxel | |
| CN115215820A (en) | Preparation method of cabazitaxel impurity F | |
| CN111072660B (en) | Simple preparation method of rilibatan | |
| CN106279207A (en) | A kind of synthetic method of cefdinir | |
| CN113754614B (en) | Preparation method of 7-methoxy docetaxel | |
| JPH0250908B2 (en) | ||
| CN115073328A (en) | Preparation method of cabazitaxel impurity | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| CN114249789B (en) | Preparation method of 7 alpha-methyl-3, 3-dimethoxy-5 (10) -androstene-17-one | |
| EP2414378B1 (en) | Separation of 4-aza-androst-1-ene-17-oic acid from 4-aza-androstan-17-oic acid | |
| CN113620911A (en) | Paclitaxel derivative and preparation method thereof | |
| CN111138386A (en) | Docetaxel semi-synthesis method | |
| CN108503586B (en) | Process for the preparation of tolvaptan intermediates | |
| CN108409561B (en) | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate | |
| CN114671891A (en) | Preparation method of everolimus ethylation impurities | |
| CN111004255A (en) | Preparation method of cefcapene lactone compound or hydrochloride thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |