CN111662329A - 一种福沙匹坦双葡甲胺的合成方法 - Google Patents
一种福沙匹坦双葡甲胺的合成方法 Download PDFInfo
- Publication number
- CN111662329A CN111662329A CN202010571808.0A CN202010571808A CN111662329A CN 111662329 A CN111662329 A CN 111662329A CN 202010571808 A CN202010571808 A CN 202010571808A CN 111662329 A CN111662329 A CN 111662329A
- Authority
- CN
- China
- Prior art keywords
- mesoporous carbon
- weight
- palladium
- meglumine
- stirring
- 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.)
- Granted
Links
- 229960002891 fosaprepitant Drugs 0.000 title claims abstract description 22
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 10
- 238000010189 synthetic method Methods 0.000 claims abstract description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 claims description 11
- 229960001372 aprepitant Drugs 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 239000011148 porous material Substances 0.000 claims description 5
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 229960003194 meglumine Drugs 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 238000011085 pressure filtration Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- 230000001502 supplementing effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- QFIRONPERRUJAN-UHFFFAOYSA-N [NH2-].[Na+].C[Si](N[Si](C)(C)C)(C)C Chemical compound [NH2-].[Na+].C[Si](N[Si](C)(C)C)(C)C QFIRONPERRUJAN-UHFFFAOYSA-N 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000010791 quenching Methods 0.000 abstract description 2
- 230000000171 quenching effect Effects 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 230000002779 inactivation Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 3
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000000039 congener Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzyl ester Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010571808.0A CN111662329B (zh) | 2020-06-22 | 2020-06-22 | 一种福沙匹坦双葡甲胺的合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010571808.0A CN111662329B (zh) | 2020-06-22 | 2020-06-22 | 一种福沙匹坦双葡甲胺的合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111662329A true CN111662329A (zh) | 2020-09-15 |
CN111662329B CN111662329B (zh) | 2021-03-30 |
Family
ID=72389254
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010571808.0A Active CN111662329B (zh) | 2020-06-22 | 2020-06-22 | 一种福沙匹坦双葡甲胺的合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111662329B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113583044A (zh) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | 一种用于预防化疗相关性恶心呕吐的药物的制备方法 |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011045817A2 (en) * | 2009-10-15 | 2011-04-21 | Sandoz Private Limited | Process for the preparation of fosaprepitant, intermediate and pharmaceutical acceptable salt thereof |
CN102407108A (zh) * | 2011-10-13 | 2012-04-11 | 南京大学连云港高新技术研究院 | 一种介孔碳担载的钯催化剂及其制法与用途 |
CN102631916A (zh) * | 2011-11-03 | 2012-08-15 | 常州大学 | 一种负载钯的介孔碳催化剂及其应用 |
CN102850398A (zh) * | 2011-06-27 | 2013-01-02 | 上海医药工业研究院 | 制备福沙匹坦的方法 |
CN102977142A (zh) * | 2011-09-02 | 2013-03-20 | 江苏豪森药业股份有限公司 | 福沙匹坦二甲葡胺的制备方法 |
CN103030668A (zh) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | 一种制备福沙匹坦二甲葡胺的方法 |
CN103204878A (zh) * | 2013-03-29 | 2013-07-17 | 山东罗欣药业股份有限公司 | 一种福沙吡坦二甲葡胺的合成方法 |
CN103769087A (zh) * | 2012-10-17 | 2014-05-07 | 南京大学连云港高新技术研究院 | 一种蒽醌加氢制双氧水的担载型钯催化剂及制备方法 |
CN104098604A (zh) * | 2013-04-10 | 2014-10-15 | 山东省生物药物研究院 | 一种制备福沙匹坦二甲葡胺的方法 |
CN104650142A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 一种福沙匹坦二甲葡胺的制备方法 |
CN105254668A (zh) * | 2013-05-14 | 2016-01-20 | 北京百川汇德医药技术开发有限公司 | 一种福沙匹坦及其可药用盐的制备新方法 |
CN106179334A (zh) * | 2016-07-08 | 2016-12-07 | 浙江工业大学 | 一种介孔炭载钯催化剂及其应用 |
WO2018211410A1 (en) * | 2017-05-17 | 2018-11-22 | Glenmark Pharmaceuticals Limited | Improved process for preparation of fosaprepitant or salt thereof |
CN108948080A (zh) * | 2017-05-22 | 2018-12-07 | 齐鲁制药有限公司 | 一种福沙匹坦药用盐的制备方法 |
CN110560085A (zh) * | 2019-08-30 | 2019-12-13 | 浙江工业大学 | 一种原位硫掺杂介孔碳负载钯金属催化剂及其制备方法与应用 |
-
2020
- 2020-06-22 CN CN202010571808.0A patent/CN111662329B/zh active Active
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011045817A2 (en) * | 2009-10-15 | 2011-04-21 | Sandoz Private Limited | Process for the preparation of fosaprepitant, intermediate and pharmaceutical acceptable salt thereof |
CN102850398A (zh) * | 2011-06-27 | 2013-01-02 | 上海医药工业研究院 | 制备福沙匹坦的方法 |
CN102977142A (zh) * | 2011-09-02 | 2013-03-20 | 江苏豪森药业股份有限公司 | 福沙匹坦二甲葡胺的制备方法 |
CN103030668A (zh) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | 一种制备福沙匹坦二甲葡胺的方法 |
CN102407108A (zh) * | 2011-10-13 | 2012-04-11 | 南京大学连云港高新技术研究院 | 一种介孔碳担载的钯催化剂及其制法与用途 |
CN102631916A (zh) * | 2011-11-03 | 2012-08-15 | 常州大学 | 一种负载钯的介孔碳催化剂及其应用 |
CN103769087A (zh) * | 2012-10-17 | 2014-05-07 | 南京大学连云港高新技术研究院 | 一种蒽醌加氢制双氧水的担载型钯催化剂及制备方法 |
CN103204878A (zh) * | 2013-03-29 | 2013-07-17 | 山东罗欣药业股份有限公司 | 一种福沙吡坦二甲葡胺的合成方法 |
CN104098604A (zh) * | 2013-04-10 | 2014-10-15 | 山东省生物药物研究院 | 一种制备福沙匹坦二甲葡胺的方法 |
CN105254668A (zh) * | 2013-05-14 | 2016-01-20 | 北京百川汇德医药技术开发有限公司 | 一种福沙匹坦及其可药用盐的制备新方法 |
CN104650142A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 一种福沙匹坦二甲葡胺的制备方法 |
CN106179334A (zh) * | 2016-07-08 | 2016-12-07 | 浙江工业大学 | 一种介孔炭载钯催化剂及其应用 |
WO2018211410A1 (en) * | 2017-05-17 | 2018-11-22 | Glenmark Pharmaceuticals Limited | Improved process for preparation of fosaprepitant or salt thereof |
CN108948080A (zh) * | 2017-05-22 | 2018-12-07 | 齐鲁制药有限公司 | 一种福沙匹坦药用盐的制备方法 |
CN110560085A (zh) * | 2019-08-30 | 2019-12-13 | 浙江工业大学 | 一种原位硫掺杂介孔碳负载钯金属催化剂及其制备方法与应用 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113583044A (zh) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | 一种用于预防化疗相关性恶心呕吐的药物的制备方法 |
CN113583044B (zh) * | 2021-06-15 | 2023-11-14 | 山东罗欣药业集团股份有限公司 | 一种用于预防化疗相关性恶心呕吐的药物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN111662329B (zh) | 2021-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111662329B (zh) | 一种福沙匹坦双葡甲胺的合成方法 | |
US20210002281A1 (en) | Compositions comprising folic acid derivatives, their preparations and methods of use | |
CN108863822B (zh) | 一种精制盐酸异丙肾上腺素的方法 | |
CN102850418B (zh) | 一种制备高纯度阿扎胞苷的结晶及干燥方法 | |
CN102617509B (zh) | 一种盐酸氯丙嗪的合成工艺 | |
CN109400600A (zh) | 10α-甲氧基-9,10-二氢麦角醇的制备新方法 | |
CN111269138B (zh) | 一种高效制备注射用盐酸丙帕他莫的方法 | |
CN112679508A (zh) | 一种托法替布中间体的制备方法 | |
KR101673979B1 (ko) | 화합물 jk12a 및 그 제조 | |
CN114539160A (zh) | 一种酸性光催化法合成多菌灵的生产工艺 | |
CN114516827A (zh) | 一种降低吲哚布芬基因毒性杂质含量的方法 | |
CN108976224B (zh) | 一种从发酵液中提取并纯化麦角新碱的方法 | |
CN108033962B (zh) | 一种合成(6s)-5-甲基四氢叶酸盐的方法 | |
CN113549040A (zh) | 一种吗替麦考酚酯杂质d的制备方法 | |
CN105294577B (zh) | 一种磺胺‑6‑甲氧基嘧啶的制备方法 | |
CN102344378B (zh) | 一种水性氨基酸制备氨基醇的方法 | |
CN109761829A (zh) | 一种高手性纯度依非韦伦中间体的制备方法 | |
CN114907226B (zh) | 一种盐酸丙帕他莫的工业化制备方法 | |
CN109422679B (zh) | 一种贝达喹啉的纯化及稳定晶型的制备方法 | |
CN109265413A (zh) | 一种盐酸地芬尼多的制备方法及精制方法 | |
CN115043835B (zh) | 一种维立西呱的精制纯化方法 | |
CN112300049B (zh) | 一种5-羟基色胺盐酸盐的制备方法 | |
CN113861164B (zh) | 一种烟碱的结晶制备方法 | |
CN117003746A (zh) | 一种硫酸阿托品晶型及其制备方法和应用 | |
CN115490744A (zh) | 一种3α-羟基-6α-乙基-7-酮-5β-胆-24-酸的制备方法 |
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 | ||
CB03 | Change of inventor or designer information |
Inventor after: Liu Zhi Inventor after: Zhuo Changcheng Inventor after: Li Xiang Inventor after: Xue Wangqian Inventor after: Liu Zichang Inventor after: Shen Jinyang Inventor before: Liu Zhi Inventor before: Zhuo Changcheng Inventor before: Li Xiang Inventor before: Xue Wangqian Inventor before: Liu Zichang |
|
CB03 | Change of inventor or designer information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |