HRP20140339T1 - Sinteza bortezomiba - Google Patents
Sinteza bortezomiba Download PDFInfo
- Publication number
- HRP20140339T1 HRP20140339T1 HRP20140339TT HRP20140339T HRP20140339T1 HR P20140339 T1 HRP20140339 T1 HR P20140339T1 HR P20140339T T HRP20140339T T HR P20140339TT HR P20140339 T HRP20140339 T HR P20140339T HR P20140339 T1 HRP20140339 T1 HR P20140339T1
- Authority
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- Croatia
- Prior art keywords
- formula
- compound
- organoboric
- image
- iii
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Links
- 230000015572 biosynthetic process Effects 0.000 title claims 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title 1
- 229960001467 bortezomib Drugs 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 18
- 150000001875 compounds Chemical class 0.000 claims 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 15
- 238000000034 method Methods 0.000 claims 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 6
- 239000002253 acid Substances 0.000 claims 6
- 150000008064 anhydrides Chemical class 0.000 claims 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 6
- 239000002904 solvent Substances 0.000 claims 6
- 230000008878 coupling Effects 0.000 claims 4
- 238000010168 coupling process Methods 0.000 claims 4
- 238000005859 coupling reaction Methods 0.000 claims 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 4
- 238000010511 deprotection reaction Methods 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 238000005406 washing Methods 0.000 claims 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims 2
- 239000012455 biphasic mixture Substances 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 2
- 230000008025 crystallization Effects 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- 150000003512 tertiary amines Chemical class 0.000 claims 2
- -1 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate Chemical compound 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
Classifications
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- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Transplantation (AREA)
- AIDS & HIV (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (8)
1. Postupak velikih razmjera za formiranje spoja formule (XIV):
[image]
ili njegovog anhidrida organoborne kiseline, koji sadrži korake:
(aa) spajanja spojaformule (XVIII):
[image]
ili njegove kisele adicijske soli, sa spojem formule (XIX):
[image]
u kojem:
P1je zaštitna grupa za amino grupu koja se može odvojiti; i
X je OH ili odlazeća grupa;
da se formira spojformule (XX):
[image]
gdje P1je kao što je definiran u prethodnom tekstu, pri čemu navedeni korak spajanja (aa) sadrži korake:
(i) spajanja spoja formule (XVIII) sa spojem formule (XIX) gde X je OH u prisutnosti2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluronij tetrafluoroborata (TBTU) i tercijarnog amina u diklorometanu;
(ii) izvođenja izmjene otapala da se diklorometan zamijeni etil acetatom; i
(iii) izvođenja ispiranja vodom etil acetatneotopine;
(bb) uklanjanja zaštitne grupe P1da se formira spoj formule (XXI):
[image]
ili njegova kisela adicijska sol, pri čemu navedeni korak uklanjanja (bb) zaštitne grupe sadrži korake:
(i) tretmana spoja formule (XX) sa HCl u etil acetatu;
(ii) dodavanja heptanau reakcijsku smjesu; i
(iii) izolacije putem kristalizacije spojaformule (XXI) kao njegove HCl adicijske soli;
(cc) spajanja spoja formule (XXI) sa reagensom formule (XXII)
[image]
gdje X je OH ili dolazeća grupa, da bi formira spoj formule (XXIII):
[image]
pri čemu navedeni korak spajanja (cc) sadrži korake:
(i) spajanja spoja formule (XXI) sa 2-pirazinkarboksilnom kiselinom u prisustvu TBTU i tercijarnog amina u diklorometanu;
(ii) izvođenja izmjene otapala da se dilklorometan zamijeni etil acetatom; i
(iii) izvođenja ispiranja vodom etil acetatneotopne; i
(dd) deprotekcije grupe organoborne kiseline da se formira spoj formule (XIV) ili njegov anhidrid organoborne kiseline, pri čemu navedeni korak deprotekcije (dd) sadrži korake:
(i) osiguravanje dvofazne smjese koja sadrži spoj formule (XXIII), organski akceptor organoborne kiseline, niži alkanol, C5-8ugljovodičnootapalo i vodenuotopinu mineralne kiseline;
(ii) mješanja dvofazne smjese da se dobijespoj formule (XIV);
(iii) odvajanja slojeva otapala; i
(iv) ekstrakcije spojaformule (XIV), ili njegovog anhidrida organoborne kiseline, u organskootapalo.
2. Postupak prema patentnom zahtjevu 1, naznačen time što P1je terc-butoksikarbonil.
3. Postupak prema patentnom zahtjevu 1 ili 2, naznačen time što je etil acetatni otopina iz koraka (aa)(iii) sušen azeotropno i zatim tretiran plinovitimHCl.
4. Postupak prema patentnom zahtjevu 1, naznačen time što korak (dd)(iii) sadrži korake:
(1) odvajanja slojeva otapala;
(2) podešavanja vodenog sloja do bazne pH vrijednosti;
(3) ispiranja vodenog sloja organskim otapalom; i
(4) podešavanja vodenog sloja do pH vrijednosti manje od 8.
5. Postupak prema patentnom zahtjevu 4, naznačen time što je u koraku (dd)(iii)(4), vodeni sloj podešen do pH vrijednosti manje od 6.
6. Postupak prema patentnom zahtjevu 4, naznačen time što je u koraku (dd)(iv), spoj formule (XIV), ili njegov anhidrid organoborne kiseline, ekstrahiran u diklorometanu, otapalo je izmijenjeno u etil acetat i spoj formule (XIV) ili njegov anhidrid organoborne kiseline, su kristalizirani dodavanjem heksana ili heptana.
7. Postupak prema patentnom zahtjevu 6, naznačen time što dodavanje heksana ili heptana rezultira u kristalizaciji cikličnog trimernog anhidrida organoborne kiseline formule (XXIV):
[image]
8. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što se u postupku koristi 5 molovanajmanje jednog početnog materijala.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55753504P | 2004-03-30 | 2004-03-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20140339T1 true HRP20140339T1 (hr) | 2014-05-09 |
Family
ID=34968044
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20212002TT HRP20212002T1 (hr) | 2004-03-30 | 2005-03-24 | Sinteza estera i spojeva borove kiseline |
| HRP20240307TT HRP20240307T3 (hr) | 2004-03-30 | 2005-03-24 | Sinteza spojeva estera borne kiseline i kiseline |
| HR20110846T HRP20110846T1 (hr) | 2004-03-30 | 2011-11-14 | Sinteza spojeva estera organoborne kiseline i organoborne kiseline |
| HRP20140339TT HRP20140339T1 (hr) | 2004-03-30 | 2014-04-08 | Sinteza bortezomiba |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20212002TT HRP20212002T1 (hr) | 2004-03-30 | 2005-03-24 | Sinteza estera i spojeva borove kiseline |
| HRP20240307TT HRP20240307T3 (hr) | 2004-03-30 | 2005-03-24 | Sinteza spojeva estera borne kiseline i kiseline |
| HR20110846T HRP20110846T1 (hr) | 2004-03-30 | 2011-11-14 | Sinteza spojeva estera organoborne kiseline i organoborne kiseline |
Country Status (41)
| Country | Link |
|---|---|
| US (14) | US7714159B2 (hr) |
| EP (5) | EP3385267B1 (hr) |
| JP (4) | JP4558039B2 (hr) |
| KR (1) | KR100939598B1 (hr) |
| CN (5) | CN103396427B (hr) |
| AR (3) | AR049374A1 (hr) |
| AT (1) | ATE521612T1 (hr) |
| AU (1) | AU2005230930B2 (hr) |
| BR (1) | BRPI0509587A (hr) |
| CA (4) | CA2738706C (hr) |
| CL (2) | CL2010000350A1 (hr) |
| CR (1) | CR8653A (hr) |
| CY (3) | CY1112053T1 (hr) |
| DK (4) | DK4008721T3 (hr) |
| DO (1) | DOP2011000293A (hr) |
| EA (1) | EA012927B1 (hr) |
| EC (1) | ECSP066960A (hr) |
| ES (3) | ES2457593T3 (hr) |
| FI (1) | FI4008721T3 (hr) |
| HK (4) | HK1100004A1 (hr) |
| HR (4) | HRP20212002T1 (hr) |
| HU (1) | HUE056859T2 (hr) |
| IL (3) | IL178250A (hr) |
| LT (2) | LT4008721T (hr) |
| ME (1) | ME01975B (hr) |
| MX (1) | MX367324B (hr) |
| MY (1) | MY145427A (hr) |
| NL (3) | NL1028639C2 (hr) |
| NO (4) | NO338905B1 (hr) |
| NZ (3) | NZ550522A (hr) |
| PE (3) | PE20142402A1 (hr) |
| PL (4) | PL3385267T3 (hr) |
| PT (4) | PT4008721T (hr) |
| RS (4) | RS65253B1 (hr) |
| SG (5) | SG151322A1 (hr) |
| SI (3) | SI1756121T1 (hr) |
| TW (1) | TWI386212B (hr) |
| UA (1) | UA90108C2 (hr) |
| UY (3) | UY28830A1 (hr) |
| WO (1) | WO2005097809A2 (hr) |
| ZA (1) | ZA200608689B (hr) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
| RS65253B1 (sr) | 2004-03-30 | 2024-03-29 | Millennium Pharm Inc | Sinteza jedinjenja estra organoborne kiseline i organoborne kiseline |
| WO2008075376A1 (en) * | 2006-12-18 | 2008-06-26 | Natco Pharma Limited | Polymorphic forms of bortezomib and process for their preparation |
| WO2009004350A1 (en) * | 2007-07-03 | 2009-01-08 | Pliva Hrvatska D.O.O. | Methods for preparing bortezomib and intermediates used in its manufacture |
| US7442830B1 (en) | 2007-08-06 | 2008-10-28 | Millenium Pharmaceuticals, Inc. | Proteasome inhibitors |
| KR20160040735A (ko) * | 2007-08-06 | 2016-04-14 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | 프로테아좀 억제제 |
| EA034601B1 (ru) * | 2007-08-06 | 2020-02-25 | Милленниум Фармасьютикалз, Инк. | Способ получения бороновых кислот |
| AU2016253697A1 (en) * | 2007-08-06 | 2016-11-24 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
| US20110118274A1 (en) * | 2007-08-23 | 2011-05-19 | Cornell Research Foundation, Inc. | Proteasome inhibitors and their use in treating pathogen infection and cancer |
| MX2010002836A (es) * | 2007-09-12 | 2010-03-31 | Reddys Lab Ltd Dr | Bortezomib y proceso para la produccion del mismo. |
| US7838673B2 (en) | 2007-10-16 | 2010-11-23 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
| EA027346B1 (ru) | 2008-06-17 | 2017-07-31 | Милленниум Фармасьютикалз, Инк. | Соединения боронатного эфира и его фармацевтические составы |
| AU2013204889A1 (en) * | 2008-09-29 | 2013-05-16 | Millennium Pharmaceuticals, Inc. | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
| AR075090A1 (es) | 2008-09-29 | 2011-03-09 | Millennium Pharm Inc | Derivados de acido 1-amino-2-ciclobutiletilboronico inhibidores de proteosoma,utiles como agentes anticancerigenos, y composiciones farmaceuticas que los comprenden. |
| EP2238973A1 (en) | 2009-04-07 | 2010-10-13 | Cephalon France | Lyophilized preparations of proteasome inhibitors |
| CN101899062B (zh) * | 2009-05-26 | 2015-04-15 | 上海威智医药科技有限公司 | α-手性硼酸及硼酸酯的合成工艺 |
| EP2270019A1 (en) | 2009-06-19 | 2011-01-05 | LEK Pharmaceuticals d.d. | New synthetic route for the preparation of alpha-amino boronic esters |
| EP2280016A1 (en) | 2009-07-27 | 2011-02-02 | LEK Pharmaceuticals d.d. | New synthetic route for the preparation of alpha-amino boronic esters via substituted alk-1-ynes |
| JP2012530116A (ja) | 2009-06-19 | 2012-11-29 | レツク・フアーマシユーテイカルズ・デー・デー | 脱ハロゲン化なしにハロゲノアルケンを水素化する方法 |
| EP2516449A1 (en) | 2009-12-22 | 2012-10-31 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
| WO2011090940A1 (en) | 2010-01-19 | 2011-07-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
| WO2011098963A1 (en) | 2010-02-09 | 2011-08-18 | Ranbaxy Laboratories Limited | Process for the preparation of bortezomib |
| CN101781326B (zh) * | 2010-02-11 | 2013-08-21 | 福建南方制药股份有限公司 | 一种制备手性氨基硼酸的中间体及其制备方法 |
| WO2011107912A1 (en) | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Polymorphic forms of bortezomib |
| US8263578B2 (en) | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
| US9061037B2 (en) * | 2010-03-18 | 2015-06-23 | Innopharma, Inc. | Stable bortezomib formulations |
| CN107266485A (zh) | 2010-03-31 | 2017-10-20 | 米伦纽姆医药公司 | 1‑氨基‑2‑环丙基乙硼酸衍生物 |
| CN101812026B (zh) * | 2010-04-12 | 2013-08-28 | 亚邦医药股份有限公司 | 一种硼替佐米的合成方法 |
| CA2927832C (en) | 2010-05-18 | 2021-03-23 | Cerulean Pharma Inc. | Cyclodextrin-containing polymer-therapeutic agent conjugates and their use |
| US8884009B2 (en) | 2010-10-14 | 2014-11-11 | Synthon Bv | Process for making bortezomib and intermediates for the process |
| TW201309303A (zh) | 2011-03-03 | 2013-03-01 | Cephalon Inc | 用於治療狼瘡的蛋白酶體抑制劑 |
| CN102206188B (zh) * | 2011-04-08 | 2013-02-27 | 苏州二叶制药有限公司 | N-(吡嗪-2-基羰基)-l-苯丙氨酸的制备方法 |
| US8497374B2 (en) | 2011-05-12 | 2013-07-30 | Scinopharm Taiwan, Ltd. | Process for preparing and purifying bortezomib |
| CN102268029B (zh) * | 2011-05-19 | 2013-10-09 | 苏州二叶制药有限公司 | 化合物（1s,2s,3r,5s）-蒎烷二醇-l-苯丙氨酸-l-亮氨酸硼酸酯的制备 |
| EP2723751A1 (en) | 2011-06-22 | 2014-04-30 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
| CN102351890B (zh) * | 2011-09-30 | 2014-07-02 | 重庆泰濠制药有限公司 | 一种硼替佐米的合成方法 |
| CN102492021B (zh) * | 2011-12-13 | 2013-10-23 | 重庆泰濠制药有限公司 | 硼替佐米的制备工艺 |
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