JP5775178B2 - N−置換ピリジニウム化合物の調製のための方法および物質 - Google Patents
N−置換ピリジニウム化合物の調製のための方法および物質 Download PDFInfo
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- JP5775178B2 JP5775178B2 JP2013550851A JP2013550851A JP5775178B2 JP 5775178 B2 JP5775178 B2 JP 5775178B2 JP 2013550851 A JP2013550851 A JP 2013550851A JP 2013550851 A JP2013550851 A JP 2013550851A JP 5775178 B2 JP5775178 B2 JP 5775178B2
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- methyl
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- alkyl
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- 238000000034 method Methods 0.000 title claims description 41
- -1 N-substituted pyridinium compounds Chemical class 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title description 3
- 239000000463 material Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 39
- 150000003141 primary amines Chemical class 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- YYMXSSYUIIBFOI-UHFFFAOYSA-N (4-amino-2,3-dihydroxycyclopentyl)methyl dihydrogen phosphate Chemical compound NC1CC(COP(O)(O)=O)C(O)C1O YYMXSSYUIIBFOI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- YYMXSSYUIIBFOI-KAZBKCHUSA-N [(1r,2r,3s,4r)-4-amino-2,3-dihydroxycyclopentyl]methyl dihydrogen phosphate Chemical compound N[C@@H]1C[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O YYMXSSYUIIBFOI-KAZBKCHUSA-N 0.000 claims description 2
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- 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
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001555 benzenes Chemical class 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
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 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
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000013078 crystal Substances 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000007144 microwave assisted synthesis reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 229910052760 oxygen Inorganic materials 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
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000005375 primary alkyl halides Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 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
- 239000000376 reactant Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 150000005376 secondary alkyl halides Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000005377 tertiary alkyl halides Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 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
- 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
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
Images
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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
- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
- C07C251/12—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton being acyclic
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- Life Sciences & Earth Sciences (AREA)
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- Molecular Biology (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
新規のアシルペンタメチニウム化合物も開示する。
a)式Iに示すペンタメチニウム塩を提供する工程、
適切かつ好ましい対イオン(X−)は、ドデシル硫酸、塩化物、PF6−、BF4−、およびClO4−である。好ましくは、その対イオンはドデシル硫酸、テトラフルオロホスフェート、またはテトラフルオロボレートである。
1態様において、本発明に従う方法は式Iに示すペンタメチニウム化合物を用いて実施され、ここでR1はメチル、エチル、プロピル、ブチルまたはイソプロピルである。1態様において、本発明はR1がCH3である本発明に従う方法におけるペンタメチニウム塩の使用に、すなわちN−置換3−アセチルピリジニウム化合物の生成に関する。
好ましい態様において、本発明は、以下の工程を含む、N−置換3−アルキルカルボニルピリジニウム化合物の合成のための方法に関する:
a)式Iに示すペンタメチニウム塩を提供する工程、
上記で定義されたように、R6は好ましくは線状または分枝状、または環状の、場合により置換されたアルキルである。好ましい態様において、アルキルは線状C1〜C6アルキル、もしくは分枝状C3〜C6アルキル、もしくは環状C5〜C6アルキルであり、または置換されたアルキルは置換された線状C1〜C6、もしくは置換された分枝状C3〜C6、もしくは置換された環状C5〜C6アルキルである。好ましくは、式IIに示す化合物は線状もしくは分枝状アルキルアミンであり、またはフラノシルアミンもしくはシクロペンチルアミンである。1態様において、R6はフラノシルまたはシクロペンチル残基である。
1態様において、本発明は、R1がメチル、エチル、プロピル、ブチルおよびイソプロピルからなる群から選択される、式Iに示すペンタメチニウム化合物に関する。
実施例の節において示される実験の焦点は、ペンタメチニウム塩である5−ジメチルアミノ−4−アセチル−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3−アミノ−5−[(ホスホノオキシ)メチル]−1,2−シクロ−ペンタンジオール ジアンモニウム塩を用いた変換にあった。リン酸化アミノ糖は、例えば対イオンとしてのテトラフルオロボレートの存在下で、ペンタメチニウム塩とほとんど定量的に反応してN−置換3−アセチルピリジニウム誘導体が得られることが分かっている。
好ましくは、アミノアルコール類はあらゆる天然存在アミノ酸またはあらゆる商業的に入手できる非天然アミノ酸に由来する。好ましくは、そのアミノアルコール類は、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(オルニチンから)、2,6−ジアミノ−1−ヘキサノール(リシンから)からなる群から選択される。
ベータ−D−リボフラノシルアミン類、2−デオキシリボフラノシルアミン、または2,3−ジデオキシ−リボシルフラノシルアミンのようなフラノシルアミン類のカルバ類似体であるシクロペンチルアミン類、すなわち(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、(1S,3R,4R)−3−アミノ−4−ヒドロキシ−シクロ−ペンタンメタノール、または(1R−シス)−3−アミノ−シクロペンタン−メタノールも好ましい。
((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)−カルバミン酸 9H−フルオレン−9−イルメチルエステルの合成
((3aS,4R,6R,6aR)−6−ヒドロキシメチル−2,2−ジメチル−テトラヒドロ−シクロペンタ[1,3]ジオキソール−4−イル)−カルバミン酸 9H−フルオレン−9−イルメチルエステルの合成
((1R,2S,3R,4R)−2,3−ジヒドロキシ−4−ホスホノ−オキシメチル−シクロペンチル)−カルバミン酸 9H−フルオレン−9−イルメチルエステルの合成
(1R,2S,3R,5R)−3−アミノ−5−[(ホスホノ−オキシ)メチル]−1,2−シクロ−ペンタンジオール ジアンモニウム塩の合成
ピリジニウム テトラフルオロボレートの合成
5−ジメチルアミノ−4−アセチル−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
3−アセチル−1−[(1R,2S,3R,4R)−2,3−ビスヒドロキシ−4−(ホスホノオキシ)メチル−シクロペンチル]−ピリジニウム ジイソプロピルエチルアンモニウム塩の合成
アセチルcNADの(酵素的)合成
アセチルcNAD、cNAD、cNADPの酵素還元
アセチルcNADHおよび比較のためにcNAD、cNADPを、GlucDH mut 2(WO2010/094632)を用いることにより、以下の条件を用いて還元した:
化学物質:
NaCl(Merck.1.02406.0080)
トリス(708 976、Rocheから)
D(+)−グルコース一水和物 p.a.(Merck 8342)
アセチル−cNAD(遊離酸)
再蒸留水(Bidest. water)(Millipore)
HCl 1N(Merck 1.09973.0001)
希釈緩衝液(NaCl 0.2mol/l;トリス0.1mol/l;pH8.5)を以下のように調製した:
11.7gのNaClおよび12.1gのトリス(=トリス(ヒドロキシエチル)アミン)を900mlの再蒸留水中で溶解させ、そのpHをHCL(1N)の添加によりpH8.5に調節し、再蒸留水を加えて1.00 lにした。
2.00gのD(+)−グルコース一水和物を10.0mlの再蒸留水中で溶解させた。その溶液は室温で2時間後に使用の用意ができている。
10.0mgのその酵素(Lyo)を1.00mlのトリス緩衝液中で溶解させた。
アセチルcNAD溶液(15mmol/l)の還元:
9.90mgのアセチルcNAD(分子量=659.47g/mol)を1.00mlの再蒸留水中で溶解させた。
cNADP(15mmol/l)の還元:
10μlのGlucDH2ストック溶液を0.99mlの希釈緩衝液中で溶解させた。100μlのこの溶液を0.40mlの希釈緩衝液中で溶解させた(希釈因子=500)。
10μlのGlucDH2ストック溶液を0.99mlの希釈緩衝液中で溶解させた。100μlのこの溶液を0.30mlの希釈緩衝液中で溶解させた(希釈因子=400)。
この実験から、アセチルcNADはデヒドロゲナーゼのための補酵素の役目も果たすことは明らかである。
Claims (10)
- 以下の工程:
a)式Iに示すペンタメチニウム塩を提供する工程、
X−は対イオンであり、
R1はC1〜C10アルキル、C6〜C30アリールおよび6〜30原子を有するヘテロアリールからなる群から選択され、そして
R2〜R5は独立してメチルまたはエチルであり、
b)工程(a)のペンタメチニウム塩を式IIの第1級アミンと反応させる工程、
c)それにより式IIIのN−置換ピリジニウム化合物を得る工程、
を含む、N−置換3−アルキルカルボニル、3−アリールカルボニルまたは3−ヘテロアリールカルボニルピリジニウム化合物の合成方法。 - R1がメチル、エチル、プロピル、ブチルまたはイソプロピルである、請求項1に記載の方法。
- R2〜R5がメチルである、請求項1または2に記載の方法。
- 式IIに示す第1級アミンが3−アミノ−5−[(ホスホノオキシ)メチル]−1,2−シクロ−ペンタンジオールである、請求項1〜3のいずれかに記載の方法。
- 式IIに示す第1級アミンが(1R,2S,3R,5R)−3−アミノ−5−[(ホスホノ−オキシ)メチル]−1,2−シクロ−ペンタンジオールである、請求項1〜4のいずれかに記載の方法。
- 式IIに示す第1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1〜5のいずれかに記載の方法。
- R1がC1〜C10アルキルである、請求項7に記載の化合物。
- R1がメチル、エチル、プロピル、ブチルおよびイソプロピルからなる群から選択される、請求項7または8に記載の化合物。
- R1がメチルである、請求項9に記載の化合物。
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US4411995A (en) | 1981-09-28 | 1983-10-25 | Massachusetts Institute Of Technology | Synthesis of nicotinamide cofactors |
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US6716596B2 (en) * | 2001-03-12 | 2004-04-06 | The Regents Of The University Of California | Agents for replacement of NAD+/NADH system in enzymatic reactions |
HUP0104831A2 (hu) * | 2001-10-19 | 2003-08-28 | Torrent Pharmaceuticals Ltd. | Készítmény és eljárás piridíniumszármazékok gyógyászati alkalmazására |
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