CN104817550A - Preparation method of rivaroxaban - Google Patents
Preparation method of rivaroxaban Download PDFInfo
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- CN104817550A CN104817550A CN201510275587.1A CN201510275587A CN104817550A CN 104817550 A CN104817550 A CN 104817550A CN 201510275587 A CN201510275587 A CN 201510275587A CN 104817550 A CN104817550 A CN 104817550A
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- KUNJFYPSCBNJSE-LBPRGKRZSA-N Cc(cc1)ccc1NC[C@@H](CNC(c([s]1)ccc1Cl)=O)O Chemical compound Cc(cc1)ccc1NC[C@@H](CNC(c([s]1)ccc1Cl)=O)O KUNJFYPSCBNJSE-LBPRGKRZSA-N 0.000 description 1
- KBMNFWWFHGCRTO-RUQIKYNFSA-N O[C@@H](CNC(c([s]1)ccc1Cl)O)CI Chemical compound O[C@@H](CNC(c([s]1)ccc1Cl)O)CI KBMNFWWFHGCRTO-RUQIKYNFSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
The invention discloses a preparation method of rivaroxaban, belonging to the field of chemical synthesis of medicine. The preparation method of rivaroxaban comprises the following steps: reacting 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dyhydroxy propyl]-amide with iodine under the catalytic action of triphenylphosphine and imidazole to produce 5-chlorothiophene-2-carboxylic acid-[(s)-3-iodo-2-hydroxy propyl]-amide; then reacting 5-chlorothiophene-2-carboxylic acid-[(s)-3-iodo-2-hydroxy propyl]-amide with 4-(4-aminophenyl)-3-morpholinone to produce 5-chlorothiophene-2-carboxylic acid{(R)-2-hydroxy-3-[4-(3-oxomorpholine-4-yl) phenyl amino]-propyl} amide; and finally introducing CO2 to react to produce rivaroxaban. The preparation method provided by the invention has the advantages that expensive and poisonous raw materials are not used, the production cost is low, the production safety is high, the environment pollution is hardly caused. Therefore, the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, relate to a kind of preparation method of razaxaban.
Background technology
Razaxaban (Rivaroxaban), chemical name is for being the chloro-N-of 5-({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-base) phenyl]-1,3-oxazoline-5-base } methyl) thiophene-2-carboxamide derivatives, structural formula is as follows:
Razaxaban is that Bayer and Johson & Johnson develop jointly, and obtain listing approval in Canada and European Union respectively in September And October, 2008, commodity are called Xarelto.In China, in June, 2009, razaxaban official listing was sold, commodity are by name visit auspicious appropriate.Up to the present, razaxaban gets the Green Light in more than 100 country in the whole world, and is successfully being gone on the market more than 75 countries by Beyer Co., Ltd.Razaxaban is the inhibitor of the factor Xa of the highly selective with Orally active, and it is used to treat thrombus, comprises palsy.Compared with current widely used traditional anticoagulant clinically, razaxaban has following characteristics: it is high that it has bioavailability, disease therapy spectrum is wide, convenient oral, without liver toxicity, is that reversibility is combined with Xa factor, bleeding event is low, the advantage of monitoring without the need to conventional coagulation function becomes eager clinical demand, for clinician, also means and can simplify postoperative anticoagulant therapy.
WO00147919 discloses a kind of preparation method of razaxaban, and its synthetic route is as follows:
The method is obtained by reacting 2-[(2R)-2-hydroxyl-3-[[4-(3-oxo-4-morpholinyl) phenyl] is amino] propyl group]-1H-isoindole-1,3 (2H)-diketone (III) by (S)-N-Racemic glycidol phthalic imidine (I) and 4-(4-aminophenyl) morpholine-3-ketone (II).Subsequently, with phosgene equivalent, (III) is converted into 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-5-oxazolidinyl] methyl]-1H-isoindole-1,3 (2H)-diketone (IV).Remove phthalimide protecting group and obtain 4-[4-[(5S)-5-(aminomethyl)-2-carbonyl-3-oxazolidinyl] phenyl]-3-morpholine ketone (V), last and 5-chlorothiophene-2-carbonyl chlorine (VI) is obtained by reacting razaxaban.The not easily separated removal of impurity that the method produces, some raw materials not easily reclaim, and are unsuitable for suitability for industrialized production.
WO2003000256 disclose a kind of with benzene methoxy acyl group p-Nitroaniline for the preparation method of razaxaban prepared by raw material, its synthetic route is as follows:
Wherein, a:(1) .n-BuLi (2). butyric acid-R-glycidyl esters (3) .NH
4cl/H
2o; B:(1). phthalic diamide, DEAD/PPh
3; (2) .NH
2nH
2h
2o, ethanol; (3) .5-chlor-2-thiophenecar-boxylic acid, EDC/HOBT; C:Zn/HCl; EDC:1-ethyl-(3-dimethylamino third class) carbodiimide; HOBT:1-hydroxyl-1H-benzotriazole xH
2o.
The method is reacted with butyric acid-R-glycidyl esters by benzene methoxy acyl group p-Nitroaniline (I) and is generated product (II) under n-Butyl Lithium catalysis; react with 5-chlor-2-thiophenecar-boxylic acid under diethyl azodiformate exists subsequently and generate product (III); generate product (IV) finally by zinc/hydrochloric acid generation reduction reaction, (IV) continues to react final and obtains target product razaxaban.Although the method step is few, need the middle n-Butyl Lithium used and diethyl azodiformate all more expensive, benzene feedstock methoxy acyl group p-Nitroaniline is uncommon yet, and n-Butyl Lithium, hydrazine hydrate danger are higher, uncomfortable suitability for industrialized production.
WO2004060887 discloses a kind of preparation method of razaxaban, and its synthetic route is as follows:
Wherein, a:1,2-2 hydroxypropylamine hydrochloric acid; B:HBr; C:4-(4-aminophenyl)-3 morpholone mais; D: carbonyl chloride (phosgene) or carbonyl chloride analogue.
The method is with 5-chlorothiophene-2-formyl chloride (I) and 1, 2-2 hydroxypropylamine hydrochloric acid generation nucleophilic addition generates 5-chlorothiophene-2-carboxylic acid-[(s)-2, 3-dihydroxypropyl]-acid amides (II), 5-chlorothiophene-2-carboxylic acid-[the bromo-2-hydroxypropyl of (s)-3-]-acid amides (III) is generated through bromination reaction, be that catalyzer and the reaction of 4-(4-aminophenyl)-3 morpholone mai generate 5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group again with trimethylpyridine } acid amides (IV), last and carbonyl chloride (phosgene) or carbonyl chloride analogue cyclization generation target product razaxaban.The method has used HBr, trimethylpyridine and carbonyl chloride, and trimethylpyridine is not too conventional, and price is higher, and Hydrogen bromide is strongly corrosion liquid, and carbonyl chloride (phosgene) strong toxicity, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is the deficiency for above-mentioned preparation method, provide a kind of preparation method of razaxaban, the method does not use expensive and poisonous starting material, production cost is low, production security is high, and the pollution produced environment is little, is suitable for suitability for industrialized production.
Technical scheme of the present invention is as follows: a kind of preparation method of razaxaban, is characterized in that, comprises the steps:
(1) 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides under the catalysis of triphenylphosphine, imidazoles and Iod R carry out obtaining 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides (intermediate I);
(2) 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides and 4-(4-aminophenyl)-3-morpholone mai are obtained by reacting 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides (intermediate II);
(3) 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides and CO
2be obtained by reacting razaxaban.Its synthetic route is as follows:
Concrete steps are as follows:
(1) by 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides is dissolved in organic solvent, adds iodine, triphenylphosphine and imidazoles, react 2 ~ 6 hours at 30 ~ 60 DEG C; Intermediate I is obtained through aftertreatment after having reacted;
(2) add intermediate I and 4-(4-aminophenyl)-3-morpholone mai at the mixed solvent of water and organic solvent, heating reflux reaction 5 ~ 20 hours, is down to room temperature, obtains the reaction solution containing intermediate II;
(3) temperature control 20 ~ 40 DEG C, continues to pass into CO in the reaction solution of (2)
2gas is separated out to product, obtains razaxaban through aftertreatment.
The organic solvent of described step (1) is any one in methylene dichloride, chloroform, toluene.
5-chlorothiophene-2-carboxylic acid in described step (1)-[(s)-2,3-dihydroxypropyl]-acid amides, I
2, triphenylphosphine and imidazoles mol ratio be 1:1.05 ~ 1.5:1.0 ~ 1.4:1.8 ~ 2.2.
The aftertreatment of described step (1) is: adopt saturated sodium bicarbonate solution washing 1-2 time, then use saturated sodium thiosulfate solution washing 1 time, collect organic phase, underpressure distillation, centrifugal, obtains intermediate I.
The mixed solvent of described step (2), can be tetrahydrofuran (THF)/purified water, ethanol/purified water, methyl alcohol/purified water any one, purified water in described mixed solvent: the proportioning (v/v) of organic solvent is=1:7 ~ 10.
The mol ratio of 5-chlorothiophene-2-carboxylic acid in described step (2)-[(s)-2,3-dihydroxypropyl]-acid amides and 4-(4-aminophenyl)-3-morpholone mai is 1:1.0 ~ 1.1.
CO in described step (3)
2the time that passes into be 4 ~ 12 hours.
The aftertreatment of described step (3) is: filter, filter cake washing, dries, then through recrystallizing and refining, obtains high purity razaxaban.
Compare the method in WO2004060887, innovative point of the present invention is as follows:
A. Hydrogen bromide is strongly corrosion liquid, volatile and have very large toxicity, is unfavorable for suitability for industrialized production.The present invention adopts I
2, and by triphenylphosphine and imidazoles carry out catalysis replace HBr, the substitution reaction of hydroxyl is more easily carried out, improve the yield of reaction, simultaneously because iodine is that solid material easilier than HBr stores and transports, the security that improve in production process, be conducive to suitability for industrialized production;
B. the iodine substituent after step (1) process, the activity comparing bromine substituent is stronger, easier and 4-(4-aminophenyl)-3-morpholone mai carries out substitution reaction, therefore under mixed solvent, reflux can be relatively easy to carry out being obtained by reacting intermediate II, does not need to use trimethylpyridine;
C. carbonyl chloride (phosgene) strong toxicity, is unfavorable for suitability for industrialized production.The present invention is by CO
2pass in the mixed solvent of water and organic solvent and carry out ring and be obtained by reacting razaxaban slowly, safer, cost is lower.
D. step (2)-(3) adopt the method for the treatment of different things alike, and simplify post-processing step, provide cost savings, be more conducive to suitability for industrialized production.
The invention has the beneficial effects as follows: razaxaban preparation method of the present invention compares with the method for above-mentioned bibliographical information, avoid and use expensive and hypertoxic starting material, reduce production cost, improve the security of production, decrease environment and produce pollution, there is good industrial prospect.
Embodiment
The present invention is further illustrated below by example.Example of the present invention is only used for the present invention being described and providing, and is not limitation of the present invention.So, under method prerequisite of the present invention, all protection scope of the present invention is belonged to simple modifications of the present invention.
Embodiment 1:
(1) by 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides 8.6kg adds in reactor, add toluene 52L, open and stir, add iodine 10kg, triphenylphosphine 11.6kg, imidazoles 5kg, heats up and is heated to 45 DEG C, insulation reaction 4 hours, wash twice with 25L saturated sodium bicarbonate solution respectively after being down to room temperature, use 25L saturated sodium thiosulfate solution washing more once, collect organic phase, underpressure distillation, centrifugal, obtain 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides (intermediate I);
(2) 64L ethanol, 7L purified water are added in reactor, open and stir, add intermediate I and 4-(4-the aminophenyl)-3-morpholone mai 7.27kg of step reaction gained, heating reflux reaction 12 hours, be down to room temperature, obtain 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides (intermediate II);
(3) temperature control 30 DEG C, passes into CO in the reaction product of (2)
2gas, separates out a large amount of solid gradually, after continuing to pass into 8 hours, filters to obtain white solid, filter cake absolute ethanol washing, obtains 11.6kg razaxaban crude product after oven dry.With Recrystallisation from acetic acid, use purified water and washing with alcohol respectively, vacuum drying, obtain razaxaban fine work and be about 9.9Kg, total recovery 62.2%.
Chemical purity: 99.9% (HPLC condition: chromatographic column is Dicel Chiralpak IC (250 × 4.6mm, 5 μm); Moving phase is 0.1% trifluoroacetic acid solution-acetonitrile (50:50); Determined wavelength is 250nm; Column temperature is 40 DEG C; Flow velocity is 1.0ml/min).
IR(KBr，cm
－1):3354，3074，29362868，1737，16691647，15461518，14281411，12201121，829。
1H NMR(400MHz，DMSO-d
6)δ(ppm)：3.60(2H，t),3.69(2H，t),3.844.17(2H，dd),3.96(2H，t),4.18(2H，s),4.83(1H，m),7.147.64(2H，d),7.36-7.55(4H，AA’BB’),8.89(1H，t)。
ESI-MSm/z：436[M+H]
+,458[M+Na]
+。
Embodiment 2:
(1) by 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides 5.0kg adds in reactor, add methylene dichloride 30L, open and stir, add iodine 6kg, triphenylphosphine 6kg, imidazoles 3kg, heats up and is heated to 40 DEG C, insulation reaction 4 hours, wash twice with 20L saturated sodium bicarbonate solution respectively after being down to room temperature, use 20L saturated sodium thiosulfate solution washing more once, collect organic phase, underpressure distillation, centrifugal, obtain 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides (intermediate I);
(2) 50L tetrahydrofuran (THF), 6L purified water are added in reactor, open and stir, add intermediate I and 4-(4-the aminophenyl)-3-morpholone mai 4.2kg of step reaction gained, heating reflux reaction 10 hours, be down to room temperature, obtain 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides (intermediate II);
(3) temperature control 30 DEG C, passes into CO in the reaction product of (2)
2gas, separates out a large amount of solid gradually, after continuing to pass into 8 hours, filters to obtain white solid, filter cake absolute ethanol washing, obtains 6.8kg razaxaban crude product after oven dry.With Recrystallisation from acetic acid, use purified water and washing with alcohol respectively, vacuum drying, obtain razaxaban fine work and be about 5.8Kg, total recovery 62.6%, chemical purity: 99.8%.
Claims (10)
1. a preparation method for razaxaban, is characterized in that,
(1) 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides under the catalysis of triphenylphosphine, imidazoles and Iod R carry out obtaining 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides;
(2) 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides and 4-(4-aminophenyl)-3-morpholone mai are obtained by reacting 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides;
(3) 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides and CO
2be obtained by reacting razaxaban.
2. the preparation method of a kind of razaxaban as claimed in claim 1, is characterized in that, specifically comprise the following steps:
(1) by 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dihydroxypropyl]-acid amides is dissolved in organic solvent, adds iodine, triphenylphosphine and imidazoles, react 2 ~ 6 hours at 30 ~ 60 DEG C; 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides is obtained through aftertreatment after having reacted;
(2) 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides and 4-(4-aminophenyl)-3-morpholone mai is added at the mixed solvent of water and organic solvent, heating reflux reaction 5 ~ 20 hours, be down to room temperature, obtain the reaction solution containing 5-chlorothiophene-2-carboxylic acid { (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino]-propyl group } acid amides;
(3) temperature control 20 ~ 40 DEG C, continues to pass into CO in the reaction solution of (2)
2gas is separated out to product, obtains razaxaban through aftertreatment.
3. the preparation method of a kind of razaxaban as claimed in claim 2, is characterized in that, the organic solvent of described step (1) is any one in methylene dichloride, chloroform, toluene.
4. the preparation method of a kind of razaxaban as claimed in claim 2, is characterized in that, 5-chlorothiophene-2-carboxylic acid in described step (1)-[(s)-2,3-dihydroxypropyl]-acid amides, I
2, triphenylphosphine and imidazoles mol ratio be 1:1.05 ~ 1.5:1.0 ~ 1.4:1.8 ~ 2.2.
5. the preparation method of a kind of razaxaban as claimed in claim 2, it is characterized in that, the aftertreatment of described step (1) is: adopt saturated sodium bicarbonate solution washing 1-2 time, use saturated sodium thiosulfate solution washing again 1 time, collect organic phase, underpressure distillation, centrifugal, obtain 5-chlorothiophene-2-carboxylic acid-[the iodo-2-hydroxypropyl of (s)-3-]-acid amides.
6. the preparation method of a kind of razaxaban as claimed in claim 2, it is characterized in that, the mixed solvent of described step (2), for tetrahydrofuran (THF)/purified water, ethanol/purified water, methyl alcohol/purified water any one, purified water in described mixed solvent: volume ratio=1:7 ~ 10 of organic solvent.
7. the preparation method of a kind of razaxaban as claimed in claim 2, it is characterized in that, the mol ratio of 5-chlorothiophene-2-carboxylic acid in described step (2)-[(s)-2,3-dihydroxypropyl]-acid amides and 4-(4-aminophenyl)-3-morpholone mai is 1:1.0 ~ 1.1.
8. as the preparation method of a kind of razaxaban in claim 2-7 as described in any one, it is characterized in that, CO in described step (3)
2the time that passes into be 4 ~ 12 hours.
9. as the preparation method of a kind of razaxaban in claim 2-7 as described in any one, it is characterized in that, the aftertreatment of described step (3) is: filter, filter cake washing, dries, then through recrystallizing and refining, obtains high purity razaxaban.
10. the preparation method of a kind of razaxaban as claimed in claim 9, is characterized in that, described filter cake washing adopts dehydrated alcohol.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
| CN108061767A (en) * | 2017-12-06 | 2018-05-22 | 重庆华邦制药有限公司 | The method of HPLC method separation determination Rivaroxaban intermediates and its related impurities |
| CN109553611A (en) * | 2017-09-23 | 2019-04-02 | 齐鲁制药有限公司 | The preparation method and purposes of Rivaroxaban intermediate |
| CN112110910A (en) * | 2019-06-19 | 2020-12-22 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban by using same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013156936A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban and intermediates thereof |
| WO2015011617A1 (en) * | 2013-07-23 | 2015-01-29 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban |
-
2015
- 2015-05-26 CN CN201510275587.1A patent/CN104817550B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013156936A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban and intermediates thereof |
| WO2015011617A1 (en) * | 2013-07-23 | 2015-01-29 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
| CN106008490B (en) * | 2016-01-11 | 2019-01-04 | 南京生命能科技开发有限公司 | A kind of new crystal of razaxaban and preparation method thereof |
| CN109553611A (en) * | 2017-09-23 | 2019-04-02 | 齐鲁制药有限公司 | The preparation method and purposes of Rivaroxaban intermediate |
| CN108061767A (en) * | 2017-12-06 | 2018-05-22 | 重庆华邦制药有限公司 | The method of HPLC method separation determination Rivaroxaban intermediates and its related impurities |
| CN108061767B (en) * | 2017-12-06 | 2020-07-21 | 重庆华邦制药有限公司 | Method for separating and measuring rivaroxaban intermediate and related impurities thereof by HP L C method |
| CN112110910A (en) * | 2019-06-19 | 2020-12-22 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban by using same |
| CN112110910B (en) * | 2019-06-19 | 2024-03-19 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban from rivaroxaban intermediate |
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Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Patentee after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Patentee before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |
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| CP03 | Change of name, title or address |