JP2009520753A - 純粋な形態のα−キラルクロロメチル化合物の製造方法 - Google Patents
純粋な形態のα−キラルクロロメチル化合物の製造方法 Download PDFInfo
- Publication number
- JP2009520753A JP2009520753A JP2008546386A JP2008546386A JP2009520753A JP 2009520753 A JP2009520753 A JP 2009520753A JP 2008546386 A JP2008546386 A JP 2008546386A JP 2008546386 A JP2008546386 A JP 2008546386A JP 2009520753 A JP2009520753 A JP 2009520753A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- process according
- optically active
- thionyl chloride
- 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
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 238000009835 boiling Methods 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 22
- 239000012535 impurity Substances 0.000 claims abstract description 18
- 238000004821 distillation Methods 0.000 claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000006227 byproduct Substances 0.000 claims description 4
- 239000010409 thin film Substances 0.000 claims description 4
- 238000001944 continuous distillation Methods 0.000 claims description 3
- 238000000199 molecular distillation Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- -1 chloromethyl compound Chemical class 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
- C07C41/42—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
【選択図】なし
Description
a) 式(II)の光学活性アルコール:
b) ステップ a)で得られる、式(I)の光学活性化合物およびより高沸点の不純物を含む物質混合物から式(I)の化合物を蒸留除去するステップ
を含む、上記方法に関する。
カラム: Waters Symmetry C18 5 μm、150 x 3 mm
溶離液: A) 0.2体積%のH3PO4水溶液; B) CH3CN
勾配(溶離液 Bに基づいて): 0分(45%) 12分(95%) 13分(95%) 13.1分(45%)
流速: 1.2 ml/分、温度: 60℃、注入量: 5 μl
検出: 230 nmにおけるUV検出器
HPLC分析によると、この物質は98.1面積%の化合物(Ia)および0.67面積%のより高沸点の第2成分を含んでいた。この方法において、化合物(Ia)は6.61分で溶出され、第2成分は11.89分で溶出された。
Claims (15)
- 蒸留除去を0.0001 mbar〜10 mbarの範囲の圧力で行う、請求項1または2に記載の方法。
- 蒸留除去を50℃〜250℃の範囲の温度で行う、請求項1〜3のいずれかに記載の方法。
- 蒸留除去を連続蒸留の形態で行う、請求項1〜4のいずれかに記載の方法。
- 連続蒸留を、分子蒸留の形態で、または、短行程蒸発器、薄膜型蒸発器もしくは流下型蒸発器を用いて、または中程度の真空範囲での精留の形態で行う、請求項5に記載の方法。
- 物質混合物がより低沸点の不純物をさらに含む、請求項1〜6のいずれかに記載の方法。
- 25〜99重量%程度の式(I)の化合物からなる物質混合物を使用する、請求項1〜7のいずれかに記載の方法。
- 95〜99.9重量%の純度を有する式(I)の化合物を製造する、請求項1〜8のいずれかに記載の方法。
- 98〜99.9重量%の純度を有する式(I)の化合物を製造する、請求項1〜9のいずれかに記載の方法。
- より高沸点の不純物が式(I)の化合物の合成の副生成物である、請求項1〜10のいずれかに記載の方法。
- 式(II)の化合物を塩化チオニルおよびN,N-ジメチルホルムアミドと反応させることにより、式(I)の化合物を製造する方法。
- 式(I)の化合物と塩化チオニルを1:1〜1:5の範囲のモル比で使用する、請求項13に記載の方法。
- 塩化チオニルとN,N-ジメチルホルムアミドを1:0.01〜1:1の範囲のモル比で使用する、請求項13または14に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05112933 | 2005-12-23 | ||
PCT/EP2006/069632 WO2007074062A1 (de) | 2005-12-23 | 2006-12-13 | Verfahren zur herstellung einer alpha-chiralen chlormethylverbindung in reiner form |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2009520753A true JP2009520753A (ja) | 2009-05-28 |
Family
ID=37951840
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008546386A Pending JP2009520753A (ja) | 2005-12-23 | 2006-12-13 | 純粋な形態のα−キラルクロロメチル化合物の製造方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20080306311A1 (ja) |
EP (1) | EP1966113A1 (ja) |
JP (1) | JP2009520753A (ja) |
CN (1) | CN101346333A (ja) |
WO (1) | WO2007074062A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1400961B1 (it) * | 2010-06-04 | 2013-07-05 | Chemo Iberica Sa | Processo per la produzione di aliskiren |
TW201202178A (en) * | 2010-06-04 | 2012-01-16 | Chemo Iberica Sa | Process for producing Aliskiren |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03109344A (ja) * | 1989-09-22 | 1991-05-09 | Sumitomo Chem Co Ltd | 光学活性なベンジル誘導体およびその製法 |
JPH09188650A (ja) * | 1995-11-24 | 1997-07-22 | Ind Chim Caffaro Spa | 浸透性殺菌剤s−3−(4’−ターシャリーブチル)−フェニル−2−メチル・プロピルアミンのキラルな誘導体をエナンチオ選択的に合成する方法 |
JP2000001445A (ja) * | 1998-06-12 | 2000-01-07 | Mitsubishi Chemicals Corp | ω−ハロゲノアルキルスチレン誘導体の製造方法 |
JP2004504373A (ja) * | 2000-07-25 | 2004-02-12 | シュペーデル・ファルマ・アーゲー | 置換オクタノイルアミドの調製方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US700978A (en) * | 1902-02-20 | 1902-05-27 | Isaac E Palmer | Hammock. |
US5606078A (en) * | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
-
2006
- 2006-12-13 JP JP2008546386A patent/JP2009520753A/ja active Pending
- 2006-12-13 WO PCT/EP2006/069632 patent/WO2007074062A1/de active Application Filing
- 2006-12-13 US US12/158,543 patent/US20080306311A1/en not_active Abandoned
- 2006-12-13 EP EP06841346A patent/EP1966113A1/de not_active Withdrawn
- 2006-12-13 CN CNA2006800489454A patent/CN101346333A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03109344A (ja) * | 1989-09-22 | 1991-05-09 | Sumitomo Chem Co Ltd | 光学活性なベンジル誘導体およびその製法 |
JPH09188650A (ja) * | 1995-11-24 | 1997-07-22 | Ind Chim Caffaro Spa | 浸透性殺菌剤s−3−(4’−ターシャリーブチル)−フェニル−2−メチル・プロピルアミンのキラルな誘導体をエナンチオ選択的に合成する方法 |
JP2000001445A (ja) * | 1998-06-12 | 2000-01-07 | Mitsubishi Chemicals Corp | ω−ハロゲノアルキルスチレン誘導体の製造方法 |
JP2004504373A (ja) * | 2000-07-25 | 2004-02-12 | シュペーデル・ファルマ・アーゲー | 置換オクタノイルアミドの調製方法 |
Non-Patent Citations (1)
Title |
---|
JPN6012036001; Tetrahedron Letters 41巻, 2000, 第10085-10089頁 * |
Also Published As
Publication number | Publication date |
---|---|
EP1966113A1 (de) | 2008-09-10 |
US20080306311A1 (en) | 2008-12-11 |
CN101346333A (zh) | 2009-01-14 |
WO2007074062A1 (de) | 2007-07-05 |
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