JP6240507B2 - 結晶化による前駆体化合物の精製 - Google Patents
結晶化による前駆体化合物の精製 Download PDFInfo
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- JP6240507B2 JP6240507B2 JP2013545271A JP2013545271A JP6240507B2 JP 6240507 B2 JP6240507 B2 JP 6240507B2 JP 2013545271 A JP2013545271 A JP 2013545271A JP 2013545271 A JP2013545271 A JP 2013545271A JP 6240507 B2 JP6240507 B2 JP 6240507B2
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- 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)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
Description
R1はC1-5直鎖又は枝分れアルキル基を表し、
R2はアミノ保護基を表し、
vは0〜4の整数であり、
Xはハロゲン又は−O−SO2−R3基(式中、R3はハロゲン、直鎖又は枝分れC1-10アルキル、直鎖又は枝分れC1-10ハロアルキル又はC6-10アリールである。)から選択される脱離基を表す。)
(a)以下の式Iaの化合物を脱ベンジル化する段階と、
(b)段階(a)からの反応混合物を結晶化して次の式Ibの精製化合物を得る段階と、
(c)段階(b)で得られる式Ibの化合物と適当な形態のX(ただし、Xは式Iで定義した通りである。)との反応によって式Iの化合物に転化する段階と
を含む方法に関する。
(i)本明細書に定義する方法に従って式Iの化合物を用意する段階と、
(ii)式Iの化合物と好適な[18F]フッ化物源との反応によって式IIaの化合物を得る段階と、
(iii)段階(ii)で得られる式IIaの化合物を脱保護して、R31及びR32を除去する段階と
を含む方法も提供する。
(i)本明細書で定義される式Iの化合物を含有する槽と、
(ii)槽内を本明細書で定義される[18F]フッ化物の好適な供給源によって溶出する手段と、
(iii)過剰な[18F]フッ化物を除去するためのイオン交換カートリッジと、
(iv)式IIaの化合物の脱保護を行い、式IIの化合物を形成するためのカートリッジと
を含む。
例1は、従来技術による式Iの化合物を得るための方法について述べる比較例である。
例において使用する略語一覧
aq. 水性
TLC 薄層クロマトグラフィー
hr 時間
mmol ミリモル
ml ミリリットル
g グラム
w/w 重量/重量
Et2O ジエチルエーテル
min 分
sat. 飽和
1(a)化合物1aの合成及び精製
McConathy et al(Appl Radiat Isotop 2003; 58:657−666)に記載された方法によって3−ベンジルオキシシクロブタン−1−オンを調製した。3−ベンジルオキシシクロブタン−1−オンをシアン化カリウム、炭酸アンモニウム及び塩化アンモニウムと反応させた。反応混合物から結晶化によって5−(3−ベンジルオキシシクロブタン)ヒダントインを単離し、Ba(OH)2(sat.aq.)中、環流下で開環を行った。反応混合物をH2SO4で中和し、沈殿したBaSO4を濾別し、濾液から溶媒を留去することによりアミノ酸を単離した。1−アミノ−3−ベンジルオキシシクロブタンカルボン酸をエタノール中でSOCl2及びEt3Nにより1−アミノ−3−ベンジルオキシシクロブタンカルボン酸エチルエステルに転化した。反応混合物を減圧により濃縮することで、塩混合物として単離された1−アミノ−3−ベンジルオキシシクロブタンカルボン酸エチルエステルを得た。Et3N及びエタノール中、boc無水物を用いてアミノ基をBocにより保護した。抽出操作及びそれに引き続きフラッシュクロマトグラフィーを行うことにより、3−ベンジルオキシ−1−tert−ブトキシカルボニルアミノ−シクロブタンカルボン酸エチルエステル(化合物1a)を単離した。
H2供給源に接続した反応フラスコ中N2雰囲気下で、化合物1a(例1aに従って調製、31.83g、91mmol)をエタノール(600ml)及び酢酸(8ml、139mmol)に溶解させた。得られた混合物に湿らせた炭素担持Pd(6.28g、10%w/w)を添加した。N2の供給を停止し、反応フラスコ中を軽く脱気した後H2を充填する操作を2回繰り返した。必要に応じて、反応混合物にH2を追加で添加した。反応混合物を室温にて2日間撹拌して完全に転化させた(TLCにより反応の進行状況を監視)。反応混合物をガラス繊維フィルターにより濾過し、濾過ケークをエタノール(160ml)で洗浄し、減圧下、40℃未満の温度で濾液から溶媒を留去し、粗製化合物1b(24.64g)を得た。粗製化合物1bを二塩化メタン(500ml)に再溶解し、SiO2(65g)を添加し、減圧下、40℃未満の温度で溶媒を留去して、クロマトグラフィーによる精製に供するための被吸着物を得た。
化合物1b(20.1g、78mmol)を二塩化メタン(500ml)に溶解し、ピリジン(19ml、235mmol)を添加し、得られた溶液を5℃未満の温度に冷却し、トリフリン酸無水物(19.5ml、115mmol)を30分間かけて少しずつ添加した。添加する間、反応温度を5℃未満の温度に保ち、添加が完了したところで、反応混合物を氷浴上で1時間撹拌し(TLCにより反応の進行状況を監視)、水(500ml)を添加して反応を停止させた。混合物をEt2O(950ml)で抽出し、水相を廃棄し、有機相をHCl(500ml、1M)、飽和食塩水(500ml、sat.aq.)で洗浄し、Na2SO4(56g)上で乾燥した。粗製混合物をガラス焼結ロートにより濾過し、濾過ケークをEt2O(100ml)で洗浄し、減圧下、30℃未満の温度で合わせた濾液から溶媒を留去して、粗製化合物1(28.11g)を得た。粗製化合物1を二塩化メタン(400ml)に再溶解し、SiO2(80g)を添加し、減圧下、30℃未満の温度で溶媒を留去してクロマトグラフィーによる精製に供するための被吸着物を得た。
例1(b)に記載した方法(水素化、濾過及び溶媒留去を含み、フラッシュクロマトグラフィーを含まない)によって調製した粗製化合物1b 0.5300gを室温にて5mlの無水エタノールに溶解した。この溶液に窒素を吹き込むことにより、ゆっくりと濃縮した。この操作の間、結晶の核が形成されそして成長した。約1時間後、溶媒留去を停止した。残存したエタノールの量は0.3500g(0.43ml)であり、混合物はかなりの量の結晶を含んでいた。1mlのn−ヘプタンを添加し、窒素吹き込みによる溶媒留去を継続した。溶媒混合物が殆ど留去される時点(約0.2mlの溶媒が残存)で溶媒留去を停止し、1mlのn−ヘプタンを添加した。15分後、結晶を濾別し、約3mlのn−ヘプタンで洗浄した。結晶を減圧下で乾燥し、濾液から窒素吹き込みにより溶媒を留去してその後減圧下で乾燥した。結晶の単離収量は0.4873g(91.9%)であり、回収率は92.9%であった。
粗生成物:化合物1aから化合物1bへの水素化から得られる粗製反応混合物であり、触媒濾過及び洗浄後のエタノール溶液の形態。エタノール=2.5〜3.8リットル。
装置:減圧エバポレータ、エバポレーション用フラスコ、濾過装置。運転は、初期には大型のエバポレーション用フラスコ中で、容量が減少した後は小型のフラスコに移して実施することができる。代わりに、500又は1000ml容量の小型のフラスコ中で、連続的に内容物を入れ替えて又は少量ずつ実施することもできる。
1.透明な溶液を、減圧下のフラスコ中にて溶媒留去により100〜200mlの全容量まで濃縮する。溶液が核形成し、生成物が結晶化し、濃厚な懸濁液を形成する。
2.200mlのn−ヘプタンを添加し、10分間撹拌(回転)し、懸濁液を容量約150mlまで濃縮する。
3.新しく200mlのn−ヘプタンを添加し、段階2を繰り返す。
4.30分間の回転(室温以下)の後、懸濁液を濾過し、結晶をn−ヘプタンで洗浄する。
5.結晶を減圧下で乾燥する。
Claims (7)
- 次の式Iの化合物を得る方法であって、
R1はC1-5直鎖又は枝分れアルキル基を表し、
R2はアミノ保護基を表し、
vは0であり、
Xはハロゲン又は−O−SO2−R3基(式中、R3はハロゲン、直鎖又は枝分れC1-10アルキル、直鎖又は枝分れC1-10ハロアルキル又はC6-10アリールである。)から選択される脱離基を表す。)
(a)以下の式Iaの化合物であって、syn型異性体とanti型異性体の混合物である化合物を脱ベンジル化する段階と
(b)段階(a)からの反応混合物の濾液から溶媒を留去して得た粗製化合物Ibをエタノールに溶解し、濃縮し、次にn−ヘプタンを添加しては濃縮する操作を繰り返し、乾燥することにより結晶化を行って、syn型異性体が富化された次の式Ibの精製化合物を得る段階と、
(c)段階(b)で得られる式Ibの化合物と、ヒドロキシル基との置換反応で脱離基X(ただし、Xは式Iで定義した通りである。)を形成するハロゲン化物又はスルホン酸化合物との反応によって式Iの化合物に転化する段階と
を含む方法。 - R1、R11及びR21がエチルである、請求項1記載の方法。
- R2、R12及びR22が、t−ブトキシカルボニル基、アリルオキシカルボニル基、フタルイミド基及びN−ベンジリデンアミン置換基から構成される群より選択される、請求項1又は請求項2記載の方法。
- Xが−O−SO2−R3基で表される基である、請求項1記載の方法。
- Xがトルエンスルホニルオキシ、ニトロベンゼンスルホニルオキシ、ベンゼンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、フルオロスルホニルオキシ及びパーフルオロアルキルスルホニルオキシからなる群から選択される、請求項4記載の方法。
- Xがトリフルオロメタンスルホニルオキシである、請求項5記載の方法。
- 式Iの化合物が次式のものであり、
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BRPI0619213B8 (pt) * | 2005-11-29 | 2021-07-27 | Nihon Mediphysics Co Ltd | composto precursor de composto orgânico marcado com haloênio radioativo |
DK2017258T3 (da) * | 2006-05-11 | 2012-07-09 | Nihon Mediphysics Co Ltd | Fremgangsmåde til fremstilling af en radioaktiv fluormærket organisk forbindelse |
NO345488B1 (no) * | 2006-12-27 | 2021-03-01 | Nihon Mediphysics Co Ltd | Fremgangsmåte for fremstilling av forløperforbindelse for radioaktiv fluormerket organisk forbindelse |
CN101939290B (zh) * | 2007-12-19 | 2013-11-06 | 日本医事物理股份有限公司 | 放射性氟标记的有机化合物的制备方法 |
WO2010013666A1 (ja) * | 2008-07-28 | 2010-02-04 | 宇部興産株式会社 | カルバメート化合物の製造方法 |
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GB201021530D0 (en) | 2011-02-02 |
WO2012084831A1 (en) | 2012-06-28 |
EP2655321B1 (en) | 2017-02-15 |
BR112013015003A2 (pt) | 2016-08-09 |
ES2621940T3 (es) | 2017-07-05 |
AU2011347530A1 (en) | 2013-07-25 |
JP2014509303A (ja) | 2014-04-17 |
DK2655321T3 (en) | 2017-04-18 |
KR101925650B1 (ko) | 2018-12-05 |
CA2821951C (en) | 2019-11-26 |
BR112013015003B1 (pt) | 2019-07-02 |
CA2821951A1 (en) | 2012-06-28 |
RU2586881C2 (ru) | 2016-06-10 |
RU2013127011A (ru) | 2015-01-27 |
KR20140003490A (ko) | 2014-01-09 |
CN107266339A (zh) | 2017-10-20 |
CN103261153A (zh) | 2013-08-21 |
EP2655321A1 (en) | 2013-10-30 |
AU2011347530B2 (en) | 2016-09-15 |
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