CN106967087A - The preparation technology of mezlocillin sodium - Google Patents
The preparation technology of mezlocillin sodium Download PDFInfo
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- CN106967087A CN106967087A CN201710379220.3A CN201710379220A CN106967087A CN 106967087 A CN106967087 A CN 106967087A CN 201710379220 A CN201710379220 A CN 201710379220A CN 106967087 A CN106967087 A CN 106967087A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation technology of mezlocillin sodium, belong to technical field of medicine synthesis.Described preparation technology be by the water of ampicillin three acid with the imidazolidinone of 1 chloroformyl, 3 mesyl 2 acylation reaction is carried out under the conditions of low-temperature alkali, through decolourize, filtering, acidifying, washing and dehydration after, add sodium salt crystallization and be made；Before acylation reaction, ampicillin need to use triethylamine to carry out dissolved clarification, and the imidazolidinone of 1 chloroformyl, 3 mesyl 2 is added in reaction system in two times after being mixed with ethyl acetate solvent.Dissolution mechanism of the present invention due to changing the water acid of ampicillin three; change the feed postition of the imidazolidinone of 1 chloroformyl, 3 mesyl 2; so that the side reaction in course of reaction is reduced; and purifying water washing is used after being acidified; anhydrous sodium acetate is used during crystallization so that impurity is further reduced, compared with original grinds medicine; no matter the product prepared takes advantage in terms of amount of impurities, or impurity level.
Description
Technical field
The present invention relates to a kind of preparation technology of mezlocillin sodium, belong to technical field of medicine synthesis.
Background technology
Mezlocillin sodium is a kind of wide spectrum semi-synthetic penicillins antibiotic, and its molecular structural formula is as follows：
The medicinal forms of mezlocillin sodium are injection, are researched and developed by Bayer A.G, are listed first in Germany within 1977,
Listed by U.S. FDA official approval in the U.S. within 1981, since 1980s, successively the U.S., Japan, Italy,
The states such as Holland, Switzerland, China list.At present, domestic mezlocillin sodium production of raw medicine enterprise there are about 16, its synthesis technique master
The water of ampicillin three acid is used to prepare mezlocillin through condensation reaction with 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone,
Then it is made through decolourizing, filtering, be freeze-dried into salt with the step of sodium salt (sodium acid carbonate or sodium iso-octoate) solution one again, synthesizes work
Skill is as follows：
With the development that imitation medicine quality and curative effect Conformance Assessment work, chemicals new registration classification is ratified before implementing
The imitation medicine of listing, it is all not according to it is former grinding drug quality and the examination ＆ approval of the curative effect principle of correspondence, be both needed to carry out Conformance Assessment work
Make.It is compared by grinding medicine with original, the mezlocillin sodium under the conditions of existing process is equal in amount of impurities and impurity level
There is larger gap.Therefore, it is necessary to which its synthesis technique is further studied and optimized.
The content of the invention
It is an object of the invention to provide a kind of preparation technology of mezlocillin sodium, solve and be prepared under the conditions of existing process
To mezlocillin sodium amount of impurities it is many, grind the problem of medicine gap is big with original, obtained mezlocillin sodium grinds medicine with original
Compare, ground in terms of impurity better than original.
The preparation technology of mezlocillin sodium of the present invention, by the water of ampicillin three acid and 1- chloroformyl -3- first sulphurs
Acyl group -2- imidazolidinones carry out acylation reaction under the conditions of low-temperature alkali, after decolourizing, filtering, be acidified, wash and be dehydrated, plus
Enter sodium salt crystallization and be made；Before acylation reaction, ampicillin need to use triethylamine to carry out dissolved clarification, 1- chloroformyl -3- first sulphurs
Acyl group -2- imidazolidinones are added in reaction system in two times after being mixed with ethyl acetate solvent.Synthesis route is as follows：
Wherein it is preferred to which technical scheme is as follows：
The mol ratio of the water acid of ampicillin three and 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone is 1:1.05~
1.15。
The consumption of triethylamine is by dissolved clarification and adjusts material liquid pH and is defined to 8.5~9.5.
1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone is 1 in the ratio between front and rear addition twice:1~1.1.
First into reaction system 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone and ethyl acetate mixture
Afterwards, add sodium acid carbonate and be adjusted to salt.
The addition of sodium acid carbonate is 0.25~0.30 times of the water of ampicillin three acid.
The volumetric usage (L) of ethyl acetate is 10 times of the sour quality consumption (kg) of the water of ampicillin three, and ethyl acetate is preceding
The ratio between addition twice is 1 afterwards:1.
Crystallization uses anhydrous sodium acetate/methanol system, and the sour mol ratio with anhydrous sodium acetate of the water of ampicillin three is 1:
1.05~1.15.
Washing times are 2~3 times, and the purifying water consumption (L) during washing is the sour quality (kg) of the water of ampicillin three every time
10 times.
The preparation technology of mezlocillin sodium of the present invention, specifically includes following steps：
(1) purified water is added into there-necked flask, it is 1~5 DEG C to control temperature, adds the water of ampicillin three acid, three second are added dropwise
Amine dissolved clarification, then adds the mixture of part 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone and ethyl acetate, control temperature
Spend for 1~5 DEG C, time for adding is 30~40min, then add sodium acid carbonate, stir 15min, by remaining 1- chloroformyls-
The mixture of 3- mesyl -2- imidazolidinones and ethyl acetate is added drop-wise in above-mentioned solution, time for adding be 100~
30min is reacted after 120min, completion of dropping, activated carbon is added, decolourized, filtering；
(2) feed liquid is warming up to 15~20 DEG C, it is 0.8~1.3 to add hydrochloric acid and be acidified to pH, and stratification takes upper strata, point
Secondary addition purified water, is washed 2~3 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, nothing is then added into feed liquid
The methanol solution of water acetic acid sodium, stands growing the grain 1h, suction filtration, and forced air drying obtains product at 45 DEG C.
The present invention's is characterized in that：The water acid of ampicillin three uses triethylamine dissolved clarification, and 1- chloroformyl -3- first sulphurs
Acyl group -2- imidazolidinones are added in two times after being mixed with ethyl acetate, and centre is adjusted to salt using sodium acid carbonate, are acidified feed liquid
Impurity is removed using washing, crystallization uses sodium acetate and methanol system.
Beneficial effects of the present invention are as follows：
Dissolution mechanism of the present invention due to changing ampicillin three water acid, change 1- chloroformyl -3- mesyls -
The feed postition of 2- imidazolidinones so that the side reaction in course of reaction is reduced, and purifying water washing, crystallization are used after acidifying
When use anhydrous sodium acetate so that impurity is further reduced, compared with original grinds medicine, and no matter the product prepared is in impurity number
Taken advantage in terms of amount, or impurity level.
Embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 5 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 9.5, dissolved clarification adds and includes 6.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 5 DEG C of temperature, and time for adding 30min adds sodium acid carbonate 6.0g, stirs 15min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 6.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 120min, it is 7.2 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 5 DEG C of temperature, filtering；
(2) feed liquid is warming up to 19 DEG C, it is 1.2 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 15min
Layering, takes upper strata, purified water 200mL is added by several times, wash 3 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.3g and methanol 30mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 45 DEG C of air blast are done
It is dry to obtain product 19.8g.
Embodiment 2
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 2 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 9.0, dissolved clarification adds and includes 6.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 2 DEG C of temperature, and time for adding 30min adds sodium acid carbonate 5.5g, stirs 15min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 6.5g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 120min, it is 6.8 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 2 DEG C of temperature, filtering；
(2) feed liquid is warming up to 16 DEG C, it is 0.9 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 15min
Layering, takes upper strata, purified water 200mL is added by several times, wash 2 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.3g and methanol 25mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 45 DEG C of air blast are done
It is dry to obtain product 20.3g.
Embodiment 3
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 4 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 8.7, dissolved clarification adds and includes 6.3g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 4 DEG C of temperature, and time for adding 40min adds sodium acid carbonate 5.0g, stirs 15min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 6.7g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 100min, it is 7.0 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 4 DEG C of temperature, filtering；
(2) feed liquid is warming up to 18 DEG C, it is 1.0 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 10min
Layering, takes upper strata, purified water 200mL is added by several times, wash 2 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.5g and methanol 35mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 45 DEG C of air blast are done
It is dry to obtain product 20.5g.
Embodiment 4
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 2 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 9.1, dissolved clarification adds and includes 6.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 3 DEG C of temperature, and time for adding 30min adds sodium acid carbonate 5.5g, stirs 15min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 6.5g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 120min, it is 6.7 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 3 DEG C of temperature, filtering；
(2) feed liquid is warming up to 20 DEG C, it is 1.3 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 30min
Layering, takes upper strata, purified water 200mL is added by several times, wash 3 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.6g and methanol 40mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 50 DEG C of air blast are done
It is dry to obtain product 18g.
Embodiment 5
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 3 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 9.0, dissolved clarification adds and includes 6.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 3 DEG C of temperature, and time for adding 20min adds sodium acid carbonate 5.0g, stirs 20min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 6.5g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 120min, it is 6.8 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 3 DEG C of temperature, filtering；
(2) feed liquid is warming up to 17 DEG C, it is 0.8 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 30min
Layering, takes upper strata, purified water 200mL is added by several times, wash 3 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.5g and methanol 30mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 45 DEG C of air blast are done
It is dry to obtain product 21g.
Embodiment 6
The preparation technology of mezlocillin sodium comprises the following steps：
(1) 180mL purified waters are added into 1000mL there-necked flasks, 2 DEG C of temperature is controlled, the water of ampicillin three acid 20g is added,
Add triethylamine and adjust pH to 8.5, dissolved clarification adds and includes 6.2g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL
The mixture of ethyl acetate, controls 3 DEG C of temperature, and time for adding 35min adds sodium acid carbonate 5.5g, stirs 15min, Ran Hou
It is secondary to be added drop-wise to the mixture comprising 7.0g 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidones and 100mL ethyl acetate
In above-mentioned solution, time for adding 110min, it is 6.5 to control pH, completion of dropping reaction 30min, adds activated carbon 1g in feed liquid, takes off
Color 30min, 4 DEG C of temperature, filtering；
(2) feed liquid is warming up to 15 DEG C, it is 1.0 to add the hydrochloric acid that volumetric concentration is 4mol/L and be acidified to pH, stands 15min
Layering, takes upper strata, purified water 200mL is added by several times, wash 2 times, washing terminates, and takes upper strata to add saturated aqueous common salt dehydration, material
Anhydrous sodium acetate 4.5g and methanol 30mL mixture is added in liquid, is stirred, growing the grain 1h is stood, suction filtration, 45 DEG C of air blast are done
It is dry to obtain product 22g.
Claims (10)
1. a kind of preparation technology of mezlocillin sodium, by the water of ampicillin three acid and 1- chloroformyl -3- mesyl -2- imidazoles
Alkanone carries out acylation reaction under the conditions of low-temperature alkali, through decolourize, filtering, acidifying, washing and dehydration after, add sodium salt crystallization and
It is made, it is characterised in that：Before acylation reaction, ampicillin uses triethylamine dissolved clarification, 1- chloroformyl -3- mesyl -2- miaows
Oxazolidone is added in reaction system in two times after being mixed with ethyl acetate solvent.
2. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：The water acid of ampicillin three and 1- chlorine
The mol ratio of formoxyl -3- mesyl -2- imidazolidinones is 1:1.05~1.15.
3. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：The consumption of triethylamine with dissolved clarification simultaneously
Adjustment material liquid pH is defined to 8.5~9.5.
4. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：1- chloroformyl -3- methylsulfonyls
Base -2- imidazolidinones are 1 in the ratio between front and rear addition twice:1~1.1.
5. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：In the 1- into reaction system first
After the mixture of chloroformyl -3- mesyl -2- imidazolidinones and ethyl acetate, add sodium acid carbonate and be adjusted to salt.
6. the preparation technology of mezlocillin sodium according to claim 5, it is characterised in that：The addition of sodium acid carbonate is ammonia
0.25~0.30 times of benzyl XiLin San Shui acid.
7. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：The volumetric usage of ethyl acetate
(L) it is 10 times of the sour quality consumption (kg) of the water of ampicillin three, ethyl acetate is 1 in the ratio between front and rear addition twice:1.
8. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：Crystallization use anhydrous sodium acetate/
The mol ratio of methanol system, the water of ampicillin three acid and anhydrous sodium acetate is 1:1.05~1.15.
9. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：Washing times are 2~3 times, often
Purifying water consumption (L) during secondary washing is 10 times of the sour quality (kg) of the water of ampicillin three.
10. the preparation technology of mezlocillin sodium according to claim 1, it is characterised in that：Comprise the following steps：
(1) purified water is added into there-necked flask, it is 1~5 DEG C to control temperature, adds the water of ampicillin three acid, triethylamine is added dropwise molten
Clearly, the mixture of part 1-chlorocarbonyl-3-methylsulphonyl-2-imidazolidone and ethyl acetate is then added, it is 1 to control temperature
~5 DEG C, time for adding is 30~40min, then adds sodium acid carbonate, 15min is stirred, by remaining 1- chloroformyls -3- first sulphurs
The mixture of acyl group -2- imidazolidinones and ethyl acetate is added drop-wise in above-mentioned solution, and time for adding is 100~120min, is added dropwise
30min is reacted after finishing, activated carbon is added, decolourized, filtering；
(2) feed liquid is warming up to 15~20 DEG C, it is 0.8~1.3 to add hydrochloric acid and be acidified to pH, and stratification takes upper strata, added by several times
Enter purified water, wash 2~3 times, washing terminates, take upper strata to add saturated aqueous common salt dehydration, anhydrous vinegar is then added into feed liquid
The methanol solution of sour sodium, stands growing the grain 1h, suction filtration, and forced air drying obtains product at 45 DEG C.
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| CN201710379220.3A CN106967087A (en) | 2017-05-25 | 2017-05-25 | The preparation technology of mezlocillin sodium |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111471057A (en) * | 2020-04-28 | 2020-07-31 | 江苏海宏制药有限公司 | Process for preparing mezlocillin sodium by solvent crystallization |
| CN112903856A (en) * | 2021-01-22 | 2021-06-04 | 青岛农业大学 | Pretreatment method for detecting trace chloroformyl compound in water sample and application thereof |
Citations (2)
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|---|---|---|---|---|
| CN1634929A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Preparation process of mezlocillin sodium |
| CN1683375A (en) * | 2005-03-03 | 2005-10-19 | 黄春荣 | Process for preparing sodium azlocillin |
-
2017
- 2017-05-25 CN CN201710379220.3A patent/CN106967087A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634929A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Preparation process of mezlocillin sodium |
| CN1683375A (en) * | 2005-03-03 | 2005-10-19 | 黄春荣 | Process for preparing sodium azlocillin |
Non-Patent Citations (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111471057A (en) * | 2020-04-28 | 2020-07-31 | 江苏海宏制药有限公司 | Process for preparing mezlocillin sodium by solvent crystallization |
| CN112903856A (en) * | 2021-01-22 | 2021-06-04 | 青岛农业大学 | Pretreatment method for detecting trace chloroformyl compound in water sample and application thereof |
| CN112903856B (en) * | 2021-01-22 | 2023-02-17 | 青岛农业大学 | Pretreatment method for detecting trace chloroformyl compound in water sample and application thereof |
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Application publication date: 20170721 |