JP5544423B2 - N置換ピリジニウム化合物の調製のための方法及び物質 - Google Patents
N置換ピリジニウム化合物の調製のための方法及び物質 Download PDFInfo
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- JP5544423B2 JP5544423B2 JP2012522014A JP2012522014A JP5544423B2 JP 5544423 B2 JP5544423 B2 JP 5544423B2 JP 2012522014 A JP2012522014 A JP 2012522014A JP 2012522014 A JP2012522014 A JP 2012522014A JP 5544423 B2 JP5544423 B2 JP 5544423B2
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- substituted
- pyridinium
- salt
- hydroxymethyl
- amino
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- -1 N-substituted pyridinium compounds Chemical class 0.000 title claims description 40
- 238000000034 method Methods 0.000 title claims description 34
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- 125000004122 cyclic group Chemical group 0.000 claims description 5
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- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ACYMGUSQXQEHGA-UHFFFAOYSA-N cyclohex-2-en-1-amine Chemical class NC1CCCC=C1 ACYMGUSQXQEHGA-UHFFFAOYSA-N 0.000 description 1
- 150000003946 cyclohexylamines Chemical class 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical class NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- QPMJENKZJUFOON-PLNGDYQASA-N ethyl (z)-3-chloro-2-cyano-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)C(\C#N)=C(/Cl)C(F)(F)F QPMJENKZJUFOON-PLNGDYQASA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 238000007144 microwave assisted synthesis reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- MIPHRQMEIYLZFZ-UHFFFAOYSA-N oxolan-3-amine Chemical class NC1CCOC1 MIPHRQMEIYLZFZ-UHFFFAOYSA-N 0.000 description 1
- AAFDSAVDFQTFBA-UHFFFAOYSA-N penta-2,4-dienimidamide Chemical group NC(=N)C=CC=C AAFDSAVDFQTFBA-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 150000005375 primary alkyl halides Chemical class 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000005376 secondary alkyl halides Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000005377 tertiary alkyl halides Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
我々は、驚いたことに、例えばペンタメチニウム塩5−ジメチルアミノ−4−メトキシカルボニル−ペンタ−2,4−ジメチル−ジエニリデンアンモニウムテトラフルオロボレートが一工程で異なった第一級アミン類(R−NH2)と環化して対応する1−R−置換ニコチン酸メチルエステルになることを見出した。この方法を使用して、例えばNADのカルバアナログの合成における前駆体であるニコチンアミド「カルバリボシド」の(3−カルバモイル−1−((1R,2S,3R,4R)−2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−ピリジニウム;クロリド)を得ることができる。
(a)式I
に係るペンタメチニウム塩を提供し、
ここで、X−は対イオンであり、
R1は、O−メチル、O−エチル、O−プロピル、及びO−イソブチルから選択されるアルコキシであり、
R2からR5は独立してメチル又はエチルであり、
b)工程(a)のペンタメチニウム塩を式II
の第一級アミンと反応させ、
ここで、R6は直鎖状、分枝状、又は環状の置換されていてもよいアルキルであり、
c)これによって、X−、R1、及びR6が上の定義の通りである式III
のN置換ピリジニウム化合物を得る、工程を具備する方法に関する。
更に好ましい実施態様では、本発明は、本発明に係る方法におけるペンタメチニウム塩の使用に関し、ここで、R2からR5はそれぞれメチルである。
好ましくは、アミノアルコールは、任意の天然に生じるか又は任意の市販の非天然のアミノ酸から誘導される。好ましくは、アミノアルコールは、セリノール、スレオニノール、フェニルアラニノール、2,5−ジアミノ−1−ペンタノール(オルニチン由来)及び2,6−ジアミノ−1−ヘキサノール(リジン由来)からなる群から選択される。
また好ましい第一級アミン類は、フラノシル糖部分又はそのようなフラノシル糖部分のアナログで置換されたアミン類であり、それは場合によってはOH基でリン酸化され、又は保護されたヒドロキシル基で妥協する一方、保護基はベンジル、アセチル、シリル及びトリチルであり、又はOH基の代わりにF又はメトキシ基で妥協する。好ましくは、NAD又はニコチンアミドモノヌクレオシド及びそのアナログの合成に適したフラノシル糖又はそのようなアナログが使用される。
好ましいフラノシルアミン類はD及びLリボース、キシロース及びアラビノースのβ及びαアノマーである。
5−ジメチルアミノ−4−メトキシカルボニル−ペンタ−2,4−ジエニリデン−ジメチル−アンモニウムテトラフルオロボレートの合成
実施例1.1:メチル−(2E)−3−(3−ジメチルアミノ)プロパ−2−エノエートの合成
700mlの無水THF中のメチルプロピオレート(68.0ml,0.764mol)の溶液に同じ溶媒(392ml,0.783mol)中のN,N−ジメチルアミンの2M溶液を室温で1時間以内に添加した。溶媒の除去後、エバポレーターで1時間(37℃、10−20mbar)乾燥させ、淡黄色の固形物を生じた。粉砕した固形物をn−ヘキサンで洗浄して、TLC及び1H NMRに従って純粋であった93.0g(94%)のメチル−(2E)−3−(3−ジメチルアミノ)プロパ−2−エノエートを得た。
テトラフルオロホウ酸(250ml,2.00mol)を加えてピリジン(157.7ml,1.95mol)を25分以内に冷却し(0℃)、無色沈殿物を得た。酸を完全に添加した後、混合物を同じ温度で更に30分攪拌した。ついで、反応混合物を濾過した。残留物を冷エタノールで洗浄し、高真空下で12時間乾燥させて、201.9g(60%)のピリジニウムテトラフルオロボレートを無色の結晶として得た。
ピリジニウムテトラフルオロボレート(283.7g,1.70mol)を442.5mlの無水酢酸/酢酸(2:1)中のメチル−(2E)−3−(3−ジメチルアミノ)プロパ−2−エノエートの溶液に加えた。得られた懸濁液を0℃に冷却し、激しく攪拌し、氷浴で冷却しながら3−ジメチルアミノアクロレイン(169.9ml,1.70mol)をゆっくり(3時間)加え、黄褐色の沈殿物を得た。室温で2時間更に攪拌した後、反応混合物を濾過した。残りの固形物をジエチルエーテルで数回洗浄し、減圧下で乾燥させた。i−プロパノール/エタノール(2:1)からの結晶化により、326.7g(65%)のペンタメチニウム塩が黄色結晶として得られた。
3−アミノ−5−ヒドロキシメチル−シクロペンタン−1,2−ジオールの合成
EtOH中のKOHの1M溶液(54.5ml,54.5mmol)を、540mlのEtOHに溶解した塩酸塩の冷却(0℃)溶液に加えた。室温で15分攪拌した後、形成された無色の沈殿物を濾過によって除去した。濾液を減圧下で濃縮した。残りの油をエバポレーター(1時間、40℃)で乾燥させて、9.01g(112%)のアミノカルバリボースを淡黄色の油として得た。得られた生成物は、更なる精製なしに次の工程で使用される。
1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−3−メトキシカルボニル−ピリジニウム−メタンスルホネートの合成
ビナミジニウム塩(298.1g,1.00mol)を1500mlのDMFに溶解させ、1当量のメタンスルホン酸(65.02ml,1.00mol)を加えた。この混合物を、1250mlのMeOH中の3−アミノ−5−ヒドロキシメチル−シクロペンタン−1,2−ジオール(165.3g,0.90mol)及び3−アミノ−5−ヒドロキシメチル−シクロペエンタン−1,2−ジオール(25.8g,0.15mol)の還流溶液(90℃)に連続的に非常にゆっくりと(5時間以内)滴下した。ビナミジニウム塩溶液を完全に添加した後、反応混合物を室温まで冷却し、再び0.15当量のメタンスルホン酸を加えた。混合物を同じ温度で12時間攪拌した。減圧下で溶媒を除去した後、赤褐色の油を得、これを更に3時間(45℃、4mbar)乾燥させた。収量:693.0g(191%,塩及び多量の溶媒を含む)。
3−カルバモイル−1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−ピリジニウム−メタンスルホネート
実施例3からの粗1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−3−メトキシカルボニル−ピリジニウム−メタンスルホネートを更なる精製なしに対応するアミドに迅速に転換した。
粗1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−3−メトキシカルボニル−ピリジニウム−メタンスルホネート118.3g,173.7mmol)を100.0mlのメタノールに溶解させた。メタノール性アンモニア(7M,350.0ml,2.45mol)の添加後、反応混合物を2.5時間攪拌した。減圧下で溶媒を除去した後、赤褐色の油を得、これを更に3時間(40℃、10mbar)乾燥させた。この粗生成物は活性炭で前もって精製し、cNADの合成に対して直接使用される(国際公開第2007/012494号)。
3−N,N−ジメチルカルバモイル−1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−ピリジニウム−メタンスルホネートの合成
3−N,N−ジメチルカルバモイル−1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−ピリジニウム−メタンスルホネートを、実施例3からのメチルエステルをTHF中のジメチルアミンの溶液と反応させることによって、3−カルバモイル−1−(2,3−ジヒドロキシ−4−ヒドロキシメチル−シクロペンチル)−ピリジニウム−メタンスルホネートと同様にして得た。
ビナミジニウム塩のTAMRA染料へのカップリング
ビナミジニウム塩を変性TAMRA染料と反応させることによって、N−TAMRA−置換ニコチン酸エステルが形成される。
環化反応はアミノ修飾TAMRA染料で実施する。
アミノ修飾TAMRA染料(上記を参照−5−及び6異性体の混合物)(19.8mg,35.93μmol)をメタノールHCl(0.125M,201μl,25.15μmol)に溶解させた。混合物を65℃に加熱し、MeSO3H(MeOH/DMF(1:1)中0.154M、233μl,35.93μmol)中のビナミジニウム塩(10.7mg,35.93μmol)の溶液を同じ温度で2.5時間以内にゆっくりと添加した。ビナミジニウム塩溶液の添加後、反応混合物を室温で16時間攪拌した。溶媒を減圧下で除去し、アセトニトリル/水勾配を用いたHPLC(Hypersil ODS)により精製した。精製した生成物をメタノール性HClに溶解させ、減圧下で蒸発させて、16.6mg(60%)のTAMRAピリジニウムコンジュゲートを得た。
MS:ESI:M+=636.98(24)
Claims (7)
- N置換カルボキシル化ピリジニウム化合物の合成方法において、
a)式I
のペンタメチニウム塩を提供し、
ここで、X−は対イオンであり、
R1は、O−メチル、O−エチル、O−プロピル、及びO−イソブチルから選択されるアルコキシであり、
R2からR5は独立してメチル又はエチルであり、
b)工程(a)のペンタメチニウム塩を式II
の第一級アミンと反応させ、
ここで、R6は直鎖状、分枝状、又は環状の置換されていてもよいアルキルであり、
第一級アミンと対応するプロトン化アミンの双方が存在し、
c)これによって、X−、R1、及びR6が上の定義の通りである式III
のN置換ピリジニウム化合物を得る、
工程を具備する方法。 - 第一級アミンのその対応するプロトン化アミンに対する比が2:1から1:50である請求項1に記載の方法。
- 第一級アミンのその対応するプロトン化アミンに対する比が1:1から1:20である請求項1に記載の方法。
- R1がOCH3である請求項1に記載の方法。
- R2からR5がメチルである請求項1に記載の方法。
- 式IIの第一級アミンが2,3ジヒドロキシ−4−ヒドロキシメチル−1−アミノシクロペンタンである請求項1から5の何れか一項に記載の方法。
- 式IIの第一級アミンが(1R,2S,3R,4R)−2,3ジヒドロキシ−4−ヒドロキシメチル−1−アミノシクロペンタンである請求項1から6の何れか一項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09166456 | 2009-07-27 | ||
EP09166456.5 | 2009-07-27 | ||
PCT/EP2010/004524 WO2011012271A2 (en) | 2009-07-27 | 2010-07-23 | Method and substances for preparation of n-substituted pyridinium compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013500289A JP2013500289A (ja) | 2013-01-07 |
JP5544423B2 true JP5544423B2 (ja) | 2014-07-09 |
Family
ID=41119996
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---|---|---|---|
JP2012522014A Active JP5544423B2 (ja) | 2009-07-27 | 2010-07-23 | N置換ピリジニウム化合物の調製のための方法及び物質 |
Country Status (7)
Country | Link |
---|---|
US (1) | US9085535B2 (ja) |
EP (1) | EP2459536B1 (ja) |
JP (1) | JP5544423B2 (ja) |
CN (1) | CN102471272B (ja) |
CA (1) | CA2769156C (ja) |
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ES2529023T3 (es) * | 2011-01-26 | 2015-02-16 | F. Hoffmann-La Roche Ag | Método y sustancias para la preparación de compuestos de piridinio N-sustituidos |
PL2936124T3 (pl) | 2012-12-20 | 2017-08-31 | F.Hoffmann-La Roche Ag | Sposoby oceniania medycznych krzywych pomiarowych |
CA2884919C (en) | 2012-12-20 | 2021-05-04 | F. Hoffmann-La Roche Ag | Method for analyzing a sample of a body fluid |
EP2781919A1 (en) | 2013-03-19 | 2014-09-24 | Roche Diagniostics GmbH | Method / device for generating a corrected value of an analyte concentration in a sample of a body fluid |
JP2019529935A (ja) | 2016-10-05 | 2019-10-17 | エフ ホフマン−ラ ロッシュ アクチェン ゲゼルシャフト | 多検体診断用試験エレメントのための検出試薬および電極配置、ならびにそれらを使用する方法 |
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CN112851730B (zh) * | 2021-01-08 | 2023-02-21 | 厦门瑞林药业有限公司 | 一种nmn中间体nr氯化物合成方法 |
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CA2769156C (en) | 2015-02-10 |
WO2011012271A2 (en) | 2011-02-03 |
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CA2769156A1 (en) | 2011-02-03 |
US9085535B2 (en) | 2015-07-21 |
CN102471272A (zh) | 2012-05-23 |
CN102471272B (zh) | 2014-09-10 |
US20120190855A1 (en) | 2012-07-26 |
ES2524972T3 (es) | 2014-12-16 |
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