WO2010145186A1 - Peptide deformylase inhibitor containing 2,5-dihydropyrrole and synthesis method thereof - Google Patents

Peptide deformylase inhibitor containing 2,5-dihydropyrrole and synthesis method thereof Download PDF

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WO2010145186A1
WO2010145186A1 PCT/CN2010/000268 CN2010000268W WO2010145186A1 WO 2010145186 A1 WO2010145186 A1 WO 2010145186A1 CN 2010000268 W CN2010000268 W CN 2010000268W WO 2010145186 A1 WO2010145186 A1 WO 2010145186A1
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胡文浩
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华东师范大学
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract

A peptide deformylase inhibitor containing 2,5-dihydropyrrole, its synthesis method and its use as antibacterial agent are disclosed. The peptide deformylase inhibitor containing 2,5-dihydropyrrole has the structure as formula (A). Wherein R1 is alkyl; R2 is H or alkyl; and R3 is alkyl, aryl, or heterocyclic group. The synthesized peptide deformylase inhibitor can inhibit the protein synthesis of bacteria, and thus kill bacteria. The incidence of drug resistance is very low.

Description

木領域 Wood field
25- 氫 的 抑制 及合成方法 涉及 25- Hydrogen suppression and synthesis methods
P F 抑制 一步涉及 抑制 的 各 。 于抗生 抗菌 物技木領域。 背景 木  P F inhibition one step involves inhibition of each. In the field of antibiotic antibacterial technology. Background
抗生素 在高稀釋度下 一些特 微生物 細菌、 、 立克 休、 文原休、 休和病毒等有 或抑制作用的微生物  Antibiotics At high dilutions, some microbes, bacteria, ricketts, primordial, hume, and viruses have inhibitory microorganisms.
。 929 者弗 首先在抗生素中 了 。 1940 弗 lFo ey和哉 Cha 在弗 的 上 了可供人 休注射用的 。 1944 Waks a 萬出 令人們 的 是 抗生素 有很強的抵抗作用 使 核病不再是 。 此 . 929 Fergu was first in antibiotics. 1940 弗 lFo ey and 哉 Cha in the shanghai for the injection of people. 1944 Waks a 10,000 people are antibiotics have a strong resistance so that nuclear disease is no longer. this
1947 、 新 1949 、 土 1950 )、 1952 、 1953 以及1959 -1961年以后出現的 合成 先 和 80年代 人工合成的 抗菌 5  1947 , New 1949 , 1950 ) , 1952 , 1953 , and 1959 - 1961 after the synthesis of the first and 80 's synthetic antibacterial 5
、氧 、 等迅速 泛用于 各 感染。現在 抗生素 的生力 看 的大半 江山。 目前 全球 感染 銷售 品銷售 的 5%左 位居全球  , oxygen, etc. are quickly used in various infections. Now the antibiotics are looking at most of the rivers. Currently, 5% of global sales of infected products are ranked worldwide.
銷售 的第二位。 但是大部分細菌都 已有的抗生素 。 休細胞和病菌合成蛋白的 程基本 似 兩者的起始 均力 但兩者有一介最大的 相 休細胞 病菌合成蛋白需要先 化 最 又 基化 再 而完成合成蛋白反的 人休細胞則沒有 化 - 的 。 于兩者的 Fe 1 的金 蛋白 的 P 的抑制 Fe 1 合作用 而 到 活的作用 抑制 的 作用 使 得細菌 而 擇性的抑制了病菌的蛋白合成 而不 休 胞的蛋白合成 。 The second place in sales. But most bacteria have antibiotics. The process of synthesizing proteins between the cells and the bacteria is basically the same as the initial force of the two, but the two of them have the largest synthetic protein of the phase-cell bacillus. However, the human resting cells that complete the synthesis of the protein are not chemicalized. The inhibition of Fe 1 by the Fe 1 gold protein in both of them inhibits the action of the action of the action, so that the bacteria selectively inhibit the protein synthesis of the bacteria without the synthesis of the protein.
抑制 是一 近 起來的一 抗菌  Inhibition is a near-antibacterial
己知的抗生素 作用 不同 因而能 那些 已有抗生 素有 性的細菌 抗菌 物的 了一 新道路 具有很好的 人們最早 的 抑制 是一 天然  The known antibiotics have different effects, so they have a new path of antibiotics that have antibiotics. The earliest inhibition is a natural
ac o Ac o
Figure imgf000004_0001
然而 天然 不具有休內的抗菌活性 因而 用力抗 菌 。
Figure imgf000004_0001
However, it does not naturally have antibacterial activity in Hugh and is therefore strongly antibacterial.
P F 是一 的金 蛋白 在細菌合成 蛋白的 中 看 鍵性的作用 P F 抑制 抑 制PDF在 的 的作用 而起到抑制細菌合成蛋白的 。因此 全新作用 制的P F抑制 提供了一 全新的抗生 可能 而且不全 到 生物的新陳代 。就目前的研究情況 看 細菌 P F抑制 生的 很小。 至今 有 -83698和 - P F抑制 了二期 。 2001 10 由 s oec 公司 出的 抑制 83698 一期 現在 二期 。 PF is a gold protein that plays a key role in the synthesis of proteins in bacteria. PF inhibits the role of PDF in inhibiting bacterial synthesis of proteins. . Therefore, the new role of PF inhibition provides a new anti-generation and not complete to the new generation of biology. As far as the current research is concerned, bacterial PF inhibition is very small. So far -83698 and - PF have suppressed the second phase. 2001 10 The first phase of the suppression of 83698 by s oec company.
Figure imgf000005_0001
Figure imgf000005_0001
2003 10 由Vc o 公司 的 B 415 D 一期 現在也已 二期 。 2003 10 The second phase of the B 415 D by Vc o is now also in the second phase.
Figure imgf000005_0002
Figure imgf000005_0002
內容 Content
本 的目的是提供 抑制 它是一 抗菌 它能 那些 已有抗生素有 性的細菌 本 的另 目的 是公升 抑制 的工 。 上 目的 本 抑制 含有2 5 二氧 含有2 5 二氧 的 抑制 具有以下 The purpose of the present invention is to provide a work which inhibits it as an antibacterial which can be used for those bacteria which have antibiotic properties. The above inhibition contains 2 5 dioxins containing 2 5 dioxins with inhibition
Figure imgf000006_0001
Figure imgf000006_0001
式中 ， H或 或芳香 或 。  Where, H or or aroma or .
5 本 的 2 5 二氧 的 抑制 的分子量是 于 300 500 可溶于 乙醇 N N二甲 、 二甲 室溫微 于甲苯、 、 加熱微溶解水 不 于石油 。 本 的 2 5 二氧 的 抑制 D 5 0 核 磁共振 氫 H NM 。 氯仿 周期20 32 表明 物的 是一 2 5 氧 的 衍生物的 抑制 。 The molecular weight of 5 of 2 2 - dioxin is determined to be 300 500 soluble in ethanol N N dimethyl , dimethyl at room temperature slightly in toluene, and heated to slightly dissolve water not in petroleum. This 2 5 dioxin inhibits D 5 0 nuclear magnetic resonance hydrogen H NM . The chloroform cycle 20 32 indicates inhibition of the derivative of a 25 oxygen.
本 的 2 5 氧 的 抑制 的 各 包括 先按照文 gan c p ocess esea ch& Deve op en 2006 10 78 93的方法 二乙 1 步驟 a 步驟 d合成得到 45) 3 2 ) 4千 2 5.  The inhibition of the 2 5 oxygen includes the following method according to the method of gan c p ocess esea ch & Deve op en 2006 10 78 93. The second step 1 step a is synthesized to obtain 45) 3 2 ) 4 thousand 2 5.
然 按照文 Jou na O ed c na he s y 2006 49 2063 2076的方法 N 卻 二甲 6 步驟 e和步 驟 合成得到 氧基 8). 再按照文 Te ahed o sy e y 998 9 47 53的方法， N 氧 4R) L ( 2) 步驟 和步驟 k 合成得到2 2 2 碳酸 2 4. 特 是 However, according to the method of Jou na O ed c na he sy 2006 49 2063 2076 N but dimethyl 6 step e and the step synthesis to obtain an oxy group 8). According to the method of Te ahed o sy ey 998 9 47 53 , N oxy 4R) L ( 2) step and step k synthesize 2 2 2 carbonic acid 2 4.
步驟9 45) 3 2 3 氧基千氧 4 2嗎 9 的合成  Step 9 45) Synthesis of 3 2 3 Oxygen Oxygen 4 2
在氮 下 將 4 ) 3 2 4 Under nitrogen will be 4) 3 2 4
5和 氧基 8 以 1 2.38 比 混合 至50 反 24h 反 完全 降至室溫 化 得 5 and oxy 8 are mixed at a ratio of 1. 2.38 to 50 for 24h, and completely reduced to room temperature.
45 3 2 ) 3 氧基 氧 4 2 步驟h 2 ) 2 4 氧基 氧氨基) 0)的合成 將 45 3 2R) 3 氧基 氧 4 2 氧 水 1 33 34 比混合 至0 加入 3 氧水和氧氧化 水 46 比 溶液 45) 3 2 ) 3 氧基 氧 4 2 45 3 2 ) 3oxyoxy 4 2 Step h 2 ) 2 4 oxyoxyamino) 0) Synthesis 45 3 2R) 3 Oxygen Oxygen 4 2 Oxygen Water 1 33 34 Ratio Mix to 0 Add 3 Oxygen Water and Oxygen Oxidation Water 46 to Solution 45) 3 2 ) 3 Oxygen Oxygen 4 2
9) H L H= 2.31 1.16 比 下攪拌反 h 向 休 中加入 硫酸 溶液 升至室溫反 3 n 化她 得 黃 色 2 ) 2 4 氧基 氧氨基) 0  9) H L H= 2.31 1.16 ratio stirring anti h h to the rest of the sulfuric acid solution to rise to room temperature, 3 n to make her yellow 2 ) 2 4 oxy oxyamino) 0
步驟 2 2 4 氧基 氧基 氨基) ) 的 合成  Step 2 2 4 oxyoxyamino))
氮 下將 c H H 水 氧 5 30  Under nitrogen, c H H water oxygen 5 30
。  .
比混合 至50C反 2h 再 至0 再緩慢向上 休 中 步驟h的 2R) 2 (4 氧基 氧氨基 0)和 氧 1 60 比 的溶液控制 加速度 3 內 反 30m n 將 化她 得 黃色 2R 2 4 氧基 氧 基 氨基) ) ) 上 10 H H= 20 5 00 比 More than 50C, 2h, then 0, then slowly Step 2 of 2R) 2 (4 oxyoxyamino 0) and oxygen 1 60 ratio of the solution control acceleration 3 internal 30 m n will turn her yellow 2R 2 4 oxyoxy amino))) 10 HH = 20 5 00 ratio
步驟 25) 2 5 氧 2 碳酸 5 的合成  Step 25) Synthesis of 2 5 Oxygen 2 Carbonic Acid 5
將2 5 二氧 1 2 2 碳酸 1 2 4 和 以 1 40 比混合 醋酸 化合物 14 醋酸 16．6 比 室溫反 3 ns 反 以0 PH=7 8 2S 2 5二氧 2碳酸 5 直接投 入下一步  2 5 dioxo 1 2 2 carbonic acid 1 2 4 and 1 40 ratio mixed acetic acid compound 14 acetic acid 16.6 than room temperature reverse 3 ns reverse 0 PH = 7 8 2S 2 5 dioxy 2 carbonic acid 5 directly into the next step
步驟 m 25) 2 2 ( 4 氧基 氧基 氨基 2 5二氧 2  Step m 25) 2 2 ( 4 oxyoxyamino 2 5 dioxane 2
先將1 H B 和1 (3二甲氨基 ) 3 碳5 (ED )以 1 比 然 氮 下 加入 2R) 2 4 氧基 氧基 氨基 和 水 1 H B and 1 (3 dimethylamino ) 3 carbon 5 (ED ) are first added to 2R) 2 4 oxyoxyamino group and water under 1 specific nitrogen
1 20 比 的溶液 再加入N 再加入 25 2 5 二氧 2 碳酸 (15)的 物和 水 1 20 比 的溶液 H BT E NM 化合物( ) 化合物(15 1．1 . 2.2 1.0 ．0 比 室溫攪拌 反 8h 化她 得到 25) 1 2 ) 2 4 氧基 氧基) 氨基 ) 2 5 r 2 步驟 25) 2 ) 2 4 氧基 氧基) 氨基1 20 ratio of solution, then add N and then add 25 2 5 dioxane 2 carbonic acid (15) and water 1 20 ratio of solution H BT E NM compound ( ) compound (15 1.1 . 2.2 1.0 .0 than room temperature Stirring 8h to obtain 25) 1 2 ) 2 4 oxyoxy) amino) 2 5 r 2 Step 25) 2) 2 4oxyoxy)amino
) 2 5二氧 2 7)的合成  Synthesis of 2 5 dioxane 2 7)
將步驟m得到的 16 和1 4二氧 溶解以 50 比混 合 再加入氧氧化 和水以 250 比 的溶液 化合物(16) 氧化 ． 比 室溫反 h 反 以 萃取 水相以 和水溶液 PH 4 5 再以 萃取 有 相 水硫酸 得 25) 2 2 4 氧基 氧 基) 氨基 ) 2 5二氧 2 7)  The 16 and 14 dioxins obtained in step m are dissolved in 50 by mixing and then oxidized by oxygen and water is oxidized at 250 ratio of solution compound (16). The aqueous phase is extracted with respect to room temperature and the aqueous phase is extracted with an aqueous solution of PH 4 5 to obtain a phase of aqueous sulfuric acid to obtain 25) 2 2 4 oxy oxy) amino) 2 5 dioxo 2 7)
步驟 2 N 5 ) 2R 2 4 氧基 氧基 氨基) ) ) 2 5二氧 2 8)的合成  Step 2 Synthesis of N 5 ) 2R 2 4 oxyoxyamino)) ) 2 5 dioxo 2 8)
氮 下 加入步驟n得到的 17 和 水 氧 1， 。  Add 17 and water oxygen 1, obtained in step n under nitrogen.
50 比 的溶液 至 C 加入 水 50 to solution to C to add water
升至室溫反 h 加入2 氨基 5 和 水 氧 1 20 比 的溶液 上 7 水 2 氨基 5Raise to room temperature and add h to 2 amino 5 and water to oxygen 1 20 ratio on the solution 7 water 2 amino 5
1 1 1．2 比 室溫反 反 千 加入 稀釋 以 和 酸水溶液 再以 和碳酸 有 相 水硫酸 得到 25 N 5 2 1 1 1.2 is more than room temperature and is added to the aqueous solution of acid and aqueous acid to obtain 25 N 5 2
2 ) 2 4 氧基 氧基) 氨基) ) 2 5 二氧 21  2) 2 4 oxyoxy) amino)) 2 5 dioxane 21
步驟 2S N (5 1 氧 2 2 2 4 氧基 氧基 氨基 ) ) 2 5二氧 2 9)的合成  Synthesis of Step 2S N (5 1 Oxygen 2 2 2 4oxyoxyamino ) 2 2 Dioxane 2 9)
步驟。得到的 18 和 以 1 75 比混合 再加入 尿素 氧化氧 合物 三批加入卻 二甲 室溫反 反 以 硫酸 的水溶液 有 相再以 和碳酸 的水溶液 有 相 水硫酸 得到 25) N 5 氧 2 2 ) 2 ( 4 氧基 氧基 氨基)step. The obtained 18 is mixed with 1 75 ratio and then added with urea oxy-oxidate in three batches but the room temperature is reversed. The aqueous solution of sulfuric acid has a phase with water and sulfuric acid to obtain 25) N 5 Oxygen 2 2 ) 2 (4 Oxyoxyamino)
2 5二氧 2 9) 上 18 尿素 氧化氧 合 卻 二甲 = 3 3 比  2 5 dioxane 2 9) upper 18 urea oxidizing oxygen but dimethyl = 3 3 ratio
步驟 25) N 5 氧 2 ) 2 ) 2 氨基 ) 2 5二氧 2 20)的合成  Step 25) Synthesis of N 5 Oxygen 2 ) 2 ) 2 Amino ) 2 5 Dioxane 2 20)
在步驟 得到的 9 和 以 1 85 比混合 醋酸 室溫反 h 反 再以 稀釋 以 和碳酸 水溶液 至水相PH 8 9 水相再以 萃取 合井有 相 水硫酸 ( The 9 obtained in the step is mixed with acetic acid at room temperature and then diluted with water to the aqueous phase of PH 8 9 and then extracted with water.
50 ) 得 2 N 5 氧 2 2 2 (( 氨基 2 5 氧 2 20) 上 19 醋酸 37．5 比。  50) to obtain 2 N 5 oxygen 2 2 2 ((amino 2 5 oxy 2 20) on 19 acetic acid 37.5 ratio.
背景 木相比 本 的有益效果  Background wood compared to the benefits of this
1． 由于本 的 2，5 氧 的 衍生物的  1. Due to the 2,5 oxygen derivative of this
抑制 的 P F 是一 的金 蛋白 抑 制細菌合成蛋白的 。 因此 不 提供了一 全新的抗生 可能 而且不余 到 生物的新陳代 同 研究表明細菌 PDF抑制 性的 很小。  The inhibition of P F is a gold protein that inhibits bacterial synthesis of proteins. Therefore, a new antibiotic possibility is not provided, and no new generation of biological studies have shown that bacterial PDF inhibition is small.
本 的 2 5 二氧 的 衍生物的 抑制 休外抗菌 表明 氧西林金黃色葡萄球菌 S 肺炎 球菌 P SP 和 球菌的最低抑制Inhibition of the antibacterial activity of this 2 5 dioxane derivative indicates oxycillin-resistant Staphylococcus aureus S pneumococcal P SP and cocci with minimal inhibition
0．03 8 g 表現出良好的 的抗菌性能 1。 0.03 8 g shows good antibacterial properties 1 .
1 最低抑制 C 羊 g/m 1 minimum inhibition C sheep g/m
2 3 4 45 nezo 2 3 4 45 nezo
4 8 4 4 4 8 4 4
球菌 2  Cocci 2
2 16 16 4 4 2 金黃色葡萄 0．5 0.25 0.25 0．5 0.25 2 球菌敏感 2 0.125 0.0 1 0.031 0.125 0.031 1 表皮葡萄球 0.125 0.0625 0.0625 0.125 0.0625 菌敏感 2 0.125 0.031 0.03 0.125 0.031 金黃色葡萄 0．5 0.125 0.125 0．5 0.125 2 球菌 2 0.25 0.125 0.125 0.25 0.25 2 表皮葡萄球 0.0625 0.031 0.0 0.0625 0.031 菌 2 0.25 0.125 0.125 0.25 .125 1 肺炎球菌 2 4 4 2 2  2 16 16 4 4 2 Golden yellow grapes 0.5 0.25 0.25 0.5 0.25 2 Cocci sensitive 2 0.125 0.0 1 0.031 0.125 0.031 1 Epidermal grape ball 0.125 0.0625 0.0625 0.125 0.0625 Bacterial sensitivity 2 0.125 0.031 0.03 0.125 0.031 Golden yellow grapes 0. 5 0.125 0.125 0.5 0.125 2 Cocci 2 0.25 0.125 0.125 0.25 0.25 2 Epidermal grape ball 0.0625 0.031 0.0 0.0625 0.031 Bacteria 2 0.25 0.125 0.125 0.25 .125 1 Pneumococcal 2 4 4 2 2
2 4 4 4 2 2 用的 L ezo d是 2000 批准上市 由 公司 的利奈 。  2 4 4 4 2 2 The L ezo d was approved for listing by the company of Lina.
上 4的 如下 The above 4 is as follows
1  1
Figure imgf000011_0001
Figure imgf000011_0001
2
Figure imgf000012_0001
2
Figure imgf000012_0001
3  3
Figure imgf000012_0002
Figure imgf000012_0002
4  4
Figure imgf000012_0003
Figure imgf000012_0003
2 背景 木 LBM 的合成 用卡 Bn NH 反 最終合成得到化合物LB 而此卡 于 的合 成 在 Bn 的 2 5 中的碳碳 也合 所以 得 1 4的 。 本 氧基 2 Background Synthesis of wood LBM The compound LB was finally synthesized by the card Bn NH and the resulting carbonic acid was also combined in the B 5 of Bn to obtain 14 . Oxyl
P B NH 替代 BnNH 以 TF H2 12 氧基 (P ) 不余 到 H2 Pd  P B NH replaces BnNH with TF H2 12 oxy (P ) without H2 Pd
敏感的基因 碳碳 上的N 而成功合成得到 1 4 休 方式 下 力本 的 1的
Figure imgf000013_0001
Sensitive gene N on carbon and successfully synthesized to obtain 1 4 The rest of the way
Figure imgf000013_0001
得上述 式的步驟如下 The steps of the above formula are as follows
EOOC COOE 1
Figure imgf000014_0001
EOOC COOE 1
Figure imgf000014_0001
Figure imgf000014_0002
P
Figure imgf000014_0003
Figure imgf000014_0002
P
Figure imgf000014_0003
Figure imgf000015_0001
上 1的各步驟 如下
Figure imgf000015_0001
The steps of the previous 1 are as follows
aB TBA 化 C  aB TBAization C
b a  b a
c C aq C 3C 22 C C  c C aq C 3C 22 C C
5 d 4E - C C 特 T -78C T -78C eP C 氧基 E □ -二甲5 d 4E - C C special T -78C T -78C eP C oxy E □ - dimethyl
Figure imgf000016_0001
Figure imgf000016_0001
95 C24 95 C24
T C Ac T T C Ac T
C PP A 偶氮二甲  C PP A azo
k)D 18- 氮 [5．4．0十 碳-7- 9 C TFA 醋酸 C C  k)D 18- nitrogen [5.4.0 ten carbon-7- 9 C TFA acetic acid C C
m T 1- E C 1-3-二甲氨基 -3- 碳5 - C C 18 m T 1- E C 1-3-dimethylamino-3-carbon 5 - C C 18
O 二氧  O dioxo
o)CC C C E T  o) CC C C E T
P)C )2 尿素 氧化氧 卻 二甲  P)C)2 urea oxidizing oxygen but dimethyl
qTF /C C qTF /C C
0 步驟a 二乙 2的合成 0 Step a Synthesis of diethylene 2
將 69 1．98 o 市售 二乙 3249 2．38mo) B B 229 .06mo) 化 TBA 33092.38mo)碳 酸鉀加入到 1 中。 至回流，反 18h。停止 加入5 m 水 使固休全部溶解。加入2 EA 。有 相 水硫酸 再用油泵 加裝 得 Add 69.98 o commercially available diethylene 3249 2.38mo) BB 229 .06mo) TBA 33092.38mo) potassium carbonate to 1. To reflux, reverse 18h. Stop adding 5 m The water dissolves all of the rest. Join 2 EA. There is phase water sulfuric acid and then oil pump installed
二乙 22009。 47% Second B 22009. 47%
R5 z,C C 64.74.22 4 3.30-3.32 .87- 5 .92 2 .28-.40 4 .25.28 7 6 0.89-0.92
Figure imgf000017_0001
R5 z, CC 64.74.22 4 3.30-3.32 .87- 5 .92 2 .28-.40 4 .25.28 7 6 0.89-0.92
Figure imgf000017_0001
步驟b 的合成  Synthesis of step b
將 12093mo a 加入到5 m 羊 中 加入250 水溶解。 11890．546 1步驟a的 2 。 至回流 攪拌0 反 至澄清 3 。 停止加熱 攪拌 至P 3 4 有大量白色固休析出 以2 m 萃取 。 再用 水硫酸 得 加入5 m石油 攪拌 析出 大量白色固休 合井兩批固休 共 789 3 90% Add 12093 mo a to 5 m sheep and dissolve in 250 water. 11890.546 1 step a 2 . To reflux, stir 0 to clarify 3 . Stop heating and stir until P 3 4 has a large amount of white solid precipitation and extract with 2 m. Then use water sulfuric acid to add 5 m of oil, stir and precipitate, a large amount of white solid rest, two batches of solid rest, 789 3 90%
5 CDC 67.85 .87b.s2 3.42-3.46 7 z, .94-.98m2 .35-.4 m4 0.89-0.94 7 z3 . 步驟c 2- 丙烯 4的合成  5 CDC 67.85 .87b.s2 3.42-3.46 7 z, .94-.98m2 .35-.4 m4 0.89-0.94 7 z3 . Step c 2- Synthesis of propylene 4
Z 加入789 0．487m 1 步驟 b得到的 3 二乙 75m 0．7 mo 百分比 37%的 78 10．974 o 1．50 乙醇。 加熱至回流 反 16 。 將 加入4 o 的 C  Z Add 789 0.487m 1 Step b to get 3 DiB 75m 0.7 mo Percent 37% 78 10.974 o 1.50 Ethanol. Heat to reflux reverse 16 . Will add 4 o C
P 3 4。 以400m 萃取 合井有 相 水硫酸 千 千得 黃色 2 丙烯 4529。 84% 5 z C C3 68.6 .98b.S 6．29s 5.65 s 2.302.33 8 z2 .46-.52 2 .34- 4 2 0.92-095 7 z3 . P 3 4. The extraction well with 400m has phase water sulfuric acid and thousands of yellow 2 propylene 4529. 84% 5 z C C3 68.6 .98b.S 6.29s 5.65 s 2.302.33 8 z2 .46-.52 2 .34- 4 2 0.92-095 7 z3 .
步驟 45-3-2 -4- -2 5的合成 在各有低溫溫度 和氮 的 250 中加入 g m 水 T F 再加入3.99 30.5 o 步驟。得到的 4 即至-78 。加入5.5r .m o 再緩慢加入3.8 .7 o1特 控制 加速度 保持反 休 溫度在-60 以下。 反 休 在-78 度下反 m 升至室溫反 2 再降溫至-78 。另一25 低溫溫度 氮 。加入90 水 氧 加入4.99 27.6 o S -4- -2- 即至-78 。 .2m 2.5 o 控制 加速度 升至室溫 反 。 將第二 反 中的溶液 加入 至-78 度的一 反 中 升至 室溫 反 。向休 加入4 m o/ 的 C 3溶液 反 。  Step 45-3-2 -4- -2 5 Synthesis Add g m water T F to each of 250 with low temperature and nitrogen and then add 3.99 30.5 o. The resulting 4 is up to -78. Add 5.5r.m o and then slowly add 3.8.7 o1 to control the acceleration and keep the reverse temperature below -60. Anti-happiness at -78 degrees, m is raised to room temperature, and then cooled to -78. Another 25 low temperature nitrogen. Add 90 water to oxygen to add 4.99 27.6 o S -4- -2- to -78. .2m 2.5 o Control acceleration rise to room temperature inverse. Add the solution from the second reaction to a temperature of -78 degrees and raise it to room temperature. Add 4 m o / C 3 solution to Hugh.
除去大部分 氧 加入 0 和 水  Remove most of the oxygen added to 0 and water
有 相 5 和食 水 水硫酸 于 得Have phase 5 and water, water, sulfuric acid
7． 9 快速 石油 61 得 加入 石油 15m1 攪拌 析出白色固休 得白色固休45-3-2 7. 9 fast oil 61 got added oil 15m1 stirred to precipitate white solid rest to get white solid rest 45-3-2
-4 -2- 55.59 63% -4 -2- 55.59 63%
5 zCDC3 67.29 5 5.40 d 7 2 4.44 4.22 2 3.37 2.82 2.39 2 .43 4 0.93 3 .  5 zCDC3 67.29 5 5.40 d 7 2 4.44 4.22 2 3.37 2.82 2.39 2 .43 4 0.93 3 .
步驟e 4- 氧基 苯甲 氧 卻 二甲 7的合成 向 5 中加入2690．16 o - 二甲 6及 259.16 o 氧基 C 加入53 10.37 o E 。 Step e Synthesis of 4-oxybenzyloxymethane 7 Add 5691.16 o - dimethyl 6 and 259.16 o oxy C to 5 and add 53 10.37 o E.
及 m F 得 溶液。 至 90C 反 4 s T C 。將反 倒入到 冰水中 充分攪拌15m s。 以400m 冰水 。 所得固休60 凡 得 黃色固休 4- 氧基 苯甲 氧 卻 二甲 309 68%And m F to get a solution. To 90C anti 4 s T C . Pour back into ice water and mix well for 15m s. Take 400m ice water. The obtained solid rest 60 has a yellow solid phase 4-oxybenzoic acid but dimethyl 309 68%
C Ct3 500 z 6 7.70-7.73m4 744 8.7 z2 6.87 d 8.7 z2 5 4 s2 3.79 s3 .  C Ct3 500 z 6 7.70-7.73m4 744 8.7 z2 6.87 d 8.7 z2 5 4 s2 3.79 s3 .
步驟 4- 氧基 苯甲 8的合成  Step 4-Alkylbenzene 8 Synthesis
將309 .106 o 步驟e的 4 300 e 加 入到 中 得 油液。 至60C 全 得淡黃色溶液 Add 4 300 e of 309.106 o step e to the medium oil. To 60C full yellowish solution
16m1 0．330mo 2 4. 2 1 s 至室溫 出現固休 加入 1 m 2 得 油液。 除去 eO 。 以 15 m J 萃取 水 a2S 4 得 139 黃色 休。 加入 m eO 6 C， 析出白色固休 以少量  16m1 0.330mo 2 4. 2 1 s to room temperature. Solid rest occurs. Add 1 m 2 of oil. Remove eO. The water a2S 4 was extracted at 15 m J to give 139 yellow hugh. Add m eO 6 C, precipitate white solids to a small amount
得15gP O 2. C。 所得固休 于8.4590．08 o C 3和 1 m 制的水溶液 以 1 m 萃取 有 相 水硫酸 除去 得 12.29 休 4- 氧基 苯甲 8 75% Get 15gP O 2. C. The obtained aqueous solution of 8.4590.08 o C 3 and 1 m is extracted with 1 m of phase water sulfuric acid to remove 12.29 oxiene 4-oxybenzene 8 75%
C C3 50 z 67.297.30d 8.5 2 6.89-6.9 d 8.5 z 2 5.34 s2 4.62 s2 3.8 s3 .  C C3 50 z 67.297.30d 8.5 2 6.89-6.9 d 8.5 z 2 5.34 s2 4.62 s2 3.8 s3 .
步驟 9 45-3- 2R-3- 氧基 氧 -2- 4 -2- 9的合成 各有 管的 0 在氮 。加入7.89 27. o 步驟 d得到的 5 和 g 64.6 mo 步驟 的 8 至 50 反 24 。 反 完全 降至室溫 加入32 稀釋 再加入20.g9 1 .m o 甲苯磺酸溶解于 26m 溶液 5 1．5 少量 。 將有 相 加入 185 甲 室溫下 攪拌 以少量水 和的 Step 9 Synthesis of 45-3- 2R-3-oxyoxy-2- 4 -2- 9 Each tube has 0 in nitrogen. Add 7.89 27. o Step d to get 5 and g 64.6 mo steps 8 to 50 anti 24 . Reverse completely to room temperature, add 32 dilutions and then add 20.g9 1 .mo toluenesulfonic acid dissolved in 26m solution 5 1.5 small amount. Add a phase to the 185 A stirring at room temperature with a small amount of water and
得白色固休9．69加入33 和 水溶解加入0.819 7．6mmo 碳酸 溶解于15r 水中 反 15m 。 水相 15 萃取 合井有 相 15 水  White solid rest 9.69 added 33 and water dissolved into 0.819 7.6mmo carbonic acid dissolved in 15r water anti 15m. Water phase 15 extraction well well phase 15 water
10 得 45-3- 2R-3- 氧基 氧 -Z- 410 gave 45-3- 2R-3-oxyloxy-Z- 4
2 96.49。 58% 2 96.49. 58%
C C 5 z 67.23-7.32m5 7 7-7.g 8.52 6.806.82d 8.52 5.75b 4.58-463 3 4.07-4.4 3 3.7053 3.323.36 m 3.2-3.20 2 2.38-2.43m .63-.75m .35 .55 15 26.3 m4 0.87-0.89 7 z3 .  CC 5 z 67.23-7.32m5 7 7-7.g 8.52 6.806.82d 8.52 5.75b 4.58-463 3 4.07-4.4 3 3.7053 3.323.36 m 3.2-3.20 2 2.38-2.43m .63-.75m .35 .55 15 26.3 m4 0.87-0.89 7 z3 .
步驟 2R-2- 4- 氧基 氧氨基 0的合成 在1 m 中 將4.39 9．8mmo 步驟9的 9 于26 氧 和6 水中 即至0 緩慢加入6.9 22.6 mo130% 氧水和9．5m .2 o/1 氧化 溶液 下攪拌反 1 。 向休 中 20 加入35m 的 o/ 硫酸 溶液 升至室溫反 3 。 將有  Step 2R-2-4-oxyoxyamino0 synthesis In a 1 m, 4.39 9.8 mmo 9 of 9 is slowly added to 6.9 22.6 mo 130% oxygen water and 9.5 m.2 in 26 oxygen and 6 water to 0. o/1 Stir the reverse 1 under oxidizing solution. Add 35 m of o/sulfuric acid solution to Hugh 20 and raise to room temperature. will have
水相 1 萃取6 水相 mo/1的  Aqueous phase 1 extraction 6 aqueous phase mo/1
至 3-4 2 m 萃取 有 相 水硫酸  To 3-4 2 m extraction with phase water sulfuric acid
， 得 黃色 2R-2 4 氧基 氧氨基 019 34% CDc 50 z 67.26-7.28d 7 z2 6.87-6.88 d 7 z2 4.624.68m2 3.80s3 306-3.4m2 2.7 2.72 .66-.70 .49.53 .26-.33m4 0.88-0.9 7 z 3 . , yellow 2R-2 4 oxyoxyamino 019 34% CDc 50 z 67.26-7.28d 7 z2 6.87-6.88 d 7 z2 4.624.68m2 3.80s3 306-3.4m2 2.7 2.72 .66-.70 .49.53 .26-.33m4 0.88-0.9 7 z 3 .
步驟 2 -2- 4- 氧基 氧基 氨基 的合成 5 5 m 氮 下加入 25 m 水 氫 再加入 10.4 108 o 和25r 54 m o 至50 反 2 再 至0 。 向上 休 中 1595．3 o 步驟 的 0 和 25 氫 的溶液 控制 加速度 內 反 3 m 。 將 加入 5 m 和 50 水分 有 相 5 m 和食 水 水硫酸  Step 2 -2- 4-oxyoxyamino group synthesis 5 5 m Nitrogen is added to 25 m of water and then hydrogen is added to 10.4 108 o and 25 r 54 m o to 50 anti 2 to 0. Upward rest 1595.3 o Steps of the 0 and 25 hydrogen solutions control the acceleration within the inverse 3 m. Will add 5 m and 50 moisture with phase 5 m and water sulfuric acid
得 1．59。 純化  Got 1.59. Purification
PEEA 31 21 得  PEEA 31 21
黃色 2R-2- 4 氧基 氧基 氨基 Yellow 2R-2- 4oxyoxyamino
1.9 60%  1.9 60%
15 C C3 50 z 68.0gb 7.26-7.35 8.5 2 6.88-6.90 8.5 z2 4.72-4.76m2 3.8 s3 3.79-3.82 2 2.73-2.76 .56-.66m .43.53m .25-.40m4 0.87090 7 ,3 . 15 C C3 50 z 68.0gb 7.26-7.35 8.5 2 6.88-6.90 8.5 z2 4.72-4.76m2 3.8 s3 3.79-3.82 2 2.73-2.76 .56-.66m .43.53m .25-.40m4 0.87090 7 ,3 .
步驟 氧碳 4 - 3的合成  Step Synthesis of Oxygen Carbon 4 - 3
20 250m 加入5.0g 2 m o - 氧碳 -4R- 2 6.39 24m o 三苯基 PP 60m 水 氧 氮 4.99 24m o 偶氮二甲 A 和 2 m 水 氧 的溶液 再 3.49 24mmo C 31和2 m 水 氧 組成的溶 ， 室溫反 。 反 石油 ， 10 1 得6．5g - 氧碳 -4- - - 3 90%20 250m Add 5.0g 2 mo - Oxygen carbon-4R- 2 6.39 24m o Triphenyl PP 60m Nitrous oxide 4.99 24m o Azodimethyl A and 2 m water oxygen solution 3.49 24mmo C 31 and 2 m water oxygen The composition of the solution, the room temperature is reversed. Anti-oil, 10 1 get 6.5g - oxygen carbon-4- - - 3 90%
c c3 500 z 6 4.204.28 8 z 4.00-4. m2 372 s3 3.64-3.68 2.84-2.88m 232-2.37 .40.46 sg . 步驟 2 5-二氧 - 2- 2S 碳酸 - 2- 4 的合成  c c3 500 z 6 4.204.28 8 z 4.00-4. m2 372 s3 3.64-3.68 2.84-2.88m 232-2.37 .40.46 sg . Step 2 Synthesis of 5-dioxy-2 - 2S carbonic acid - 2 - 4
250m 加入8.49 23.7mmo 步驟 3 4.0m 26mmo 18- 氮 5．4．0十一碳-7- 15 m 甲苯。加熱 至80 90 反 至室溫 攪拌 的 完全析出。  250m added 8.49 23.7mmo Step 3 4.0m 26mmo 18- Nitrogen 5.4.0 Eleven-7- 15 m Toluene. Heat to 80 90 and then to room temperature. Stirring is completely precipitated.
石油 30 1 得 2 5二氧 - 2- 2S - 碳酸 - 2- 43.79 68% Oil 30 1 to get 2 5 dioxo - 2 2S - carbonic acid - 2- 43.79 68%
R C C 50 z 65.925.98 5.69-5.74m 494-5.03 m 4.20-4.30m,2 3.72 s3 42 47 s9 ．  R C C 50 z 65.925.98 5.69-5.74m 494-5.03 m 4.20-4.30m, 2 3.72 s3 42 47 s9 .
步驟1 2S -25-二氧 -2-碳酸 5的合成 Step 1 Synthesis of 2S-25-dioxy-2-carbonic acid 5
1 m 加入3.79 16.3mmo 步驟k得到的 4 使其 于40 2 27 o 醋酸TFA 室溫反 s。反 以 P 7 8。 2S -25-二氧 -2-碳酸 5 直接投入下一步 100% 。  1 m was added to 3.79 16.3mmo. Step 4 obtained in step k was allowed to react at 40 2 27 o acetic acid TFA at room temperature. Against P 7 8. 2S -25-Dioxy-2-carbonic acid 5 is directly put into the next step 100%.
步驟 m 25 - 2R-2- 4- 氧基 氧基 氨基 Step m 25 - 2R-2- 4-oxyoxyamino
25-二氧 -2-碳酸 6的合成  Synthesis of 25-dioxo-2-carbonic acid 6
在5 中加入0.69 4．4mmo)1- OBT 0.8494.4m o 1-3-二甲氨基 3- 碳  Add 0.69 4.4mmo) 1- OBT 0.8494.4m o 1-3-dimethylamino 3-carbon to 5
(E C)氮 加入 1.239 396m o 步驟 得到的 和 m 水 的溶液。加入0.97 1 8．8mm o - 加入由 g 4．4 o 步驟1得到的 5 的 物和5 1 水 組成的 溶液 室溫攪拌 反 。 反 以 和 酸水溶液 (EC) nitrogen Add a solution of 1.239 396 m o and m water. Add 0.97 1 8.8 mm o - Add the solution of the 5 obtained from step 3.4 of g 4.4 o and the mixture of 5 1 water at room temperature with stirring. Anti-acid solution
5 再以 和碳酸 有 相 水硫酸 5 and with carbonic acid, phase water sulfuric acid
得到 1．49 25- - 2 -2- 4- 氧基 氧基 氨基 Yield 1.49 25- - 2 -2- 4-oxyoxyamino
-25-二氧 -2-碳酸 6 85% -25-dioxy-2-carbonic acid 6 85%
R C C 500 z 6 7.868.07s 724-7.25d 5 z2 6.88-6.89 d 5 z2 5.88-596 5.72-5.82m 5.08-5.2 m 4.644.86 2 4.304.40 2 3.8 s3 3.72 3 2.8 -3.0 m .60.75 m .42-.58m .20-.42 m4 0.89-0.92 7 z3 .  RCC 500 z 6 7.868.07s 724-7.25d 5 z2 6.88-6.89 d 5 z2 5.88-596 5.72-5.82m 5.08-5.2 m 4.644.86 2 4.304.40 2 3.8 s3 3.72 3 2.8 -3.0 m .60.75 m . 42-.58m .20-.42 m4 0.89-0.92 7 z3 .
步驟 仍5- - 2 -2- 4- 氧基千氧基 氨基 Step Still 5-- 2 -2- 4-oxyloxyamino
25二氧 -2- 7的合成  Synthesis of 25 dioxo-2- 7
5 中加入 1.49 3．4 o 步驟m得到的 6 15m5 的 14-二氧 溶解 再加入(0.149 3．4m o 一水合氧氧化 的 15m 水溶液。 室溫反 h 反 以2 m 萃取 水相以  5 Add 1.49 3.4 o Step 15 obtained 6 15m5 of 14-diox dissolved and then add (0.149 3.4m o 15m aqueous solution oxidized by oxygen. Room temperature anti-h reverse 2 m extraction of water phase
和水溶液 P 4 5 再以2 萃取 有 相 水硫 酸 得1359 25 2 -2- 4- 氧基 氧基 氨基 -25-二氧 -2- 7 0% And the aqueous solution P 4 5 is further extracted with 2 phase water sulfuric acid to obtain 1359 25 2 -2- 4-oxyoxyamino-25-dioxo-2- 7 0%
0 CDC3 500 z 6 7.89792S 7.237.24d 7 z2 6.88-6.89 d 7 z2 589-6.0 m2 5.30-5.33 4.72-4.95 m2 4.30-4.48 2 3.8 s3 2.90-3.00 .60.75 .48-.62m .20.30 4 0.86-0.89 7 z3 . 0 CDC3 500 z 6 7.89792S 7.237.24d 7 z2 6.88-6.89 d 7 z2 589-6.0 m2 5.30-5.33 4.72-4.95 m2 4.30-4.48 2 3.8 s3 2.90-3.00 .60.75 .48-.62m .20.30 4 0.86- 0.89 7 z3 .
步驟 25) 5- 2 2R)-2- 4 氧基 氧基 氨基5 -25-二氧 -2- 5 氮 下 加入 9 2．5m o 步驟 得到的 7 和 水 氫 銅 的溶液 至 C 加入0.36m1 2．5m o 水 0.24 1 2． oStep 25) 5- 2 2R)-2- 4oxyoxyamino 5 -25-dioxy-2- 5 Add 92.5m o to the solution of 7 and copper hydrogen hydride to nitrogen. Add 0.36m1 2.5m o water 0.24 1 2. o
CC C C 升至室溫反 。加入0.349 3 o 2-氨基-5- 的 5m1 水 氧 溶液 室溫反 反 加入 15m 稀釋 以 和 酸水溶液 再以 CC C C rises to room temperature. Add 0.349 3 o 2-amino-5- in 5m1 water and oxygen solution at room temperature, add 15m dilution and acid solution
m 和碳酸 有 相 水硫酸  m and carbonic acid have phase water sulfuric acid
得到 1． 9Get 1. 9
25- -5- -2- - - 2 -2- 4 氧基 氧基 氨基 -25-二氧 -2- 8 81% 25- -5- -2- - - 2 -2- 4 oxyoxyamino -25-dioxo-2- 8 81%
C C3 50 z 68.36-8.5 m 8.4-8.7m 7.868.07 d 7.37-7.42m 7.24-7.25d 5 z2 6.88-6.89 d 5 z2 6.04-6.2 5.95-6.02m 5.56-5.62m 473-4.82m 4.434.50 m 3.88-4.0 m 3.8 s3 3.4 -3.5 m 3.4-3.23m .60-.75m .42.58 .20.42m4 0.890.92 7 z3 .  C C3 50 z 68.36-8.5 m 8.4-8.7m 7.868.07 d 7.37-7.42m 7.24-7.25d 5 z2 6.88-6.89 d 5 z2 6.04-6.2 5.95-6.02m 5.56-5.62m 473-4.82m 4.434.50 m 3.88-4.0 m 3.8 s3 3.4 -3.5 m 3.4-3.23m .60-.75m .42.58 .20.42m4 0.890.92 7 z3 .
步驟 P 25- -5- - -氧2- - - 2R-2- 4 氧基 氧基 氨基 -2,5-二氧 -2- 9的合成  Step P 25- -5- - - Oxy 2 - - 2R-2- 4 Oxyoxy Amino - 2,5-Dioxy-2- 9 Synthesis
25m 中加入( . g 2mmo)步驟。得到的 8 將 于 15m 再加入(0. 6mmo)尿素 氧化氧 合物 C ． 三批加入(0.899 6 mo 卻 二甲 室溫反 反 以 1.249 1 o 硫酸 的 m 水溶液  Add ( . g 2mmo) step to 25m. The obtained 8 will be added to the (0. 6mmo) urea oxy-oxide C at 15m. Three batches of (0.899 6 mo but dimethyl room temperature reversed with 1.249 1 o sulfuric acid in m aqueous solution
有 相再以 和碳酸 的水溶 有 相 水硫酸 There is phase and water soluble in carbonated water.
得 .939 2S- -5 - 氧-2 - 2 2 4- 氧基 氧基 氨基 -25-二氧 2- 9 得得·939 2S- -5 - Oxygen-2 - 2 2 4- Oxyoxyamino-25-dioxo 2- 9
90%90%
C C , 50 z 68.36-8.5 8.4-8.7  C C , 50 z 68.36-8.5 8.4-8.7
7.86-8.07 d 7.24-7.25d 5 z2 7.0-7.20 6.88-6.89 d 5 z2 6.04-6.2 5.95-6.02 5.565.62m 4,73-4.82 4.43-4.50 3.88-4.0 3.8 s3 3.4 3.5 m 3.4-3.23m, .60-.75 .42-.58m .20-.42 4 ,0.89-0.92 7 z3 . 7.86-8.07 d 7.24-7.25d 5 z2 7.0-7.20 6.88-6.89 d 5 z2 6.04-6.2 5.95-6.02 5.565.62m 4,73-4.82 4.43-4.50 3.88-4.0 3.8 s3 3.4 3.5 m 3.4-3.23m, . 60-.75 .42-.58m .20-.42 4 , 0.89-0.92 7 z3 .
步驟 25- -5- - -氧-2- - - 2 -2- 氨基 Step 25- -5- - Oxo-2- - 2 -2-Amino
25二氧 -2- 20的合成  Synthesis of 25 dioxol-2- 20
25m1 中加入0.939 1．8mmo 步驟 p得到的 9 和 m 的溶液 5m 67.5m o 醋酸TFA  Add 0.939 1.8mmo to 25m1 Step p and get 9 and m solution 5m 67.5m o acetic acid TFA
室溫反 。 反 再以 稀釋 以 和碳酸 水溶液 至水相P 8 9。 水相再以 m 萃取 合井有 相 水硫酸 千 Room temperature is reversed. Dilute again with an aqueous solution of carbonic acid to the aqueous phase P 8 9 . The aqueous phase is extracted by m, and the well has a phase of sulfuric acid.
50 1 得0．39 2S -5- - -氧-2- - - 2 2 氨基 -25二氧 -2- 20 42% 50 1 yields 0.39 2S -5- - -oxy-2- - - 2 2 amino -25 dioxo-2- 20 42%
cDC 50 z 6 0.5 s 8.36-8.5 m 8.4-8.7 6.046.2m 5.95-6.02 5.56-5.62 473-4.82 4.43-4.50 m 3.884.0 m 3.4 -3.5 m ) 3.43.23m .60.75m .42.58m 20.42m4 0.890.92 7 z3 .  cDC 50 z 6 0.5 s 8.36-8.5 m 8.4-8.7 6.046.2m 5.95-6.02 5.56-5.62 473-4.82 4.43-4.50 m 3.884.0 m 3.4 -3.5 m ) 3.43.23m .60.75m .42.58m 20.42m4 0.890 .92 7 z3 .
上 涉及的所有原料 均力市售的 。 All the raw materials involved are commercially available.
2 除了步驟。將原料由 2-氨基-5- 替換 2-氨基-5 。 其他集 不 得 25- -5 -2- - 2 -2- 4 氧基 氧基 氨基 25-二氧 -2- 。然 直接 步驟q 得到 25- -5- -2- - 2 -2- 氨基2 In addition to the steps. The starting material was replaced by 2-amino-5- with 2-amino-5. Other sets may not be 25- -5 -2- - 2 -2- 4 oxyoxyamino 25-dioxo-2-. However, directly step q gives 25- -5- -2- 2 -2-amino
25二氧 -2- 。 其余 1相同。 25 dioxane-2-. The remaining 1 are the same.
C C3 50 z 67.64s 5.935.97m2 5.725.75 4.954.97m 4.35-4.38 Z 4.05-4.09m 4.35-4.38m 3.6-3.9 m 2.29s3 83-.85 .55-.57 .40-.44 4 0.940.97 7 z3 . C C3 50 z 67.64s 5.935.97m2 5.725.75 4.954.97m 4.35-4.38 Z 4.05-4.09m 4.35-4.38m 3.6-3.9 m 2.29s3 83-.85 .55-.57 .40-.44 4 0.940. 97 7 z3 .
3  3
除了步驟。將原料由2-氨基-5- 替換 硝基 其他集 不 得到25- -4-硝基苯基 - 2 4- 氧基 氧基 氨基 In addition to the steps. Substituting the starting material from 2-amino-5- to the nitro other set does not give 25--4-nitrophenyl-2-4-oxyoxyamino
-25-二氧 -2- 。 然 接 步驟 q得到 -25-dioxo-2-. Then step q gets
25 4-硝基苯基- - 2 -2- 氨基 -25-二氧 2 。 其余 1相同。 25 4-Nitrophenyl-2 --2-amino-25-dioxo 2 . The remaining 1 are the same.
CDC3 500 z 6 8.09-8. d z2 7.607.62 z2 6.02-6.04 5.955.97m 5.53-5.55m 4.774.80 4.43-4.46 3.88-3.94 3.40-3.43m 3.83.22 .66-.70 .5 .55m .25-.40m4 0.870.9 7 z3 . 除了步驟。得到了 25- -5- 2 - 2 -2- 4- 氧基 氧 基 氨基 25-二氧 -2- 8 不 步驟p 直接 步驟q  CDC3 500 z 6 8.09-8. d z2 7.607.62 z2 6.02-6.04 5.955.97m 5.53-5.55m 4.774.80 4.43-4.46 3.88-3.94 3.40-3.43m 3.83.22 .66-.70 .5 .55m . 25-.40m4 0.870.9 7 z3 . In addition to the steps. 25- -5- 2 - 2 -2- 4-oxyoxyamino 25-dioxo-2- 8 is obtained. Step p Direct Step q
得到 25 5 -2 - 2R 2 氨基 Obtaining 25 5 -2 - 2R 2 amino
25-二氧 2- 。 其余 1相同。 - - - - - - - - - - - C Cb500 z 59.48 s 8.98.23m 8.028.05m 7.677.69m 73774 m 6.026.04 5.965.98m 5.525.54m 4.734.76m 4.4 4.44m 3.883.94m 3.4 3.44m 3.203.23m .66.70m .5 .55m .25.40m4 0.870.90 7 z3 . 25-dioxene 2-. The remaining 1 are the same. - - - - - - - - - - - C Cb500 z 59.48 s 8.98.23m 8.028.05m 7.677.69m 73774 m 6.026.04 5.965.98m 5.525.54m 4.734.76m 4.4 4.44m 3.883.94m 3.4 3.44m 3.203. 23m .66.70m .5 .55m .25.40m4 0.870.90 7 z3 .

Claims

要求 Claim
1． 25- 氧 的 抑制 其特 在于  1. 25- Oxygen suppression is characterized by
抑制 具有以下  Inhibition
Figure imgf000028_0001
Figure imgf000028_0001
式中 比 或 或芳香 或 。 Where the ratio is or aroma or .
2 要求1的 25-二氧 的 抑制 的 各方 法制各 包括  2 Requirement 1 of the 25-dioxo inhibition of the parties
先伙 二乙 1 步驟a到步驟d合成得 4S 3 First partner, two B, 1 step a to step d, 4S 3
-4-千 -2- 5  -4- thousand -2- 5
然 - 卻 二甲 6 步驟e和步驟 合成 再 - 氧碳 -4R- - - 12 步驟 和 步驟 合成得到2 5-二氧 - 2- 2S 碳酸 2 4 特 是  However - but dimethyl 6 step e and step synthesis re-oxycarbon -4R- - - 12 steps and steps to synthesize 2 5-dioxo-2 - 2S carbonic acid 2 4
步驟9 45-3- 2 -3- 氧基 氧 -2- 4 2 9的合成  Step 9 Synthesis of 45-3- 2 -3-oxyoxy-2- 4 2 9
在氮 下 將45-3-2 -4-千 -2- 5和 氧基 8 以 12.38 比 混合 至50 反 24h 反 完全 降至室溫 化她 得Mix 45-3-2 -4-千-2- 5 and oxy 8 at a ratio of 12.38 to 50 Å under nitrogen 24h, completely reduced to room temperature, she got
45-3- 2 -3 氧基 氧 2 -4- -2 9 步驟 2 -2- 4- 氧基 氧氨基 0的合成， 將 45 3 2R-3 氧基 氧 2- 4- 2- 5 9 氫 水 33 34 比混合 即至0 加 入30 氧水和氧氧化 水 46 比 溶液 45 3- 2 -3- 氧基千氧 -2- -4-千 -2- 9 45-3- 2 -3oxyoxy 2 -4- -2 9 Step 2 -2- 4-oxyoxyamino 0 synthesis, 45 3 2R-3oxyoxy 2- 4- 2- 5 9 hydrogen Water 33 34 is mixed to 0. Add 30 Oxygen water and Oxygen Oxidation Water 46 to solution 45 3- 2 -3- Oxide Oxygen-2- -4-K-2- 9
2.31 1.16 比 下 反 1 向休 中加入 硫 酸 溶液 升至室溫反 m 化她 得 黃色 2.31 1.16 ratio, reverse 1 to the rest, add sulfuric acid solution, raise it to room temperature, and m
2R 2- 4- 氧基 氧氨基 0  2R 2- 4-oxyoxyamino 0
步驟 2 -2- 4- 氧基 氧基 氨基 的合成 氮 下將 Ac COO 水 氧 1 5 30  Step 2 -2- 4-oxyoxyamino group Synthesis Nitrogen Ac COO Water Oxygen 1 5 30
。  .
比混合 至50C反 2 再 即至0 再緩慢向上 休 中 步驟h的 2 2- 4- 氧基 氧氨基 0和 氫 Ratio to 50C, reverse 2, then to 0, then slowly upward, rest, step 2, 2 2- 4-oxyoxyamino 0 and hydrogen
5 1 60 比 的溶液 控制 加速度 3 m 內 反 3 m 將 化她 得 黃色 2 2 4- 氧基 氧基 氨基 上 10 C 20 100 比 5 1 to 60 ratio of the solution to control the acceleration within 3 m and the inverse of 3 m will give her a yellow 2 2 4-oxyoxyamino group on the 10 C 20 100 ratio
步驟1 仍S-2，5二氧 2-碳酸 5的合成 Step 1 Synthesis of still S-2,5-dioxy 2-carbonate 5
0 將2 5-二氧 -1 2- 2S 碳酸1 2- 4 和 以 1 40 比混合 醋酸 化合物 14 醋酸 16．6 比 室溫反 m s 反 以 P 7 8 2S-25-二氧 -2-碳酸 5 直接投入下 步 0 2 2 dioxo-1 2- 2S carbonate 1 2- 4 and 1 40 ratio mixed acetic acid compound 14 acetic acid 16.6 than room temperature inverse ms P 7 8 2S-25-dioxo-2-carbonate 5 directly into the next step
步驟 25- - 2 -2- 4- 氧基千氧基 氨基 Step 25- - 2 -2- 4-oxyloxyamino
-25-二氧 -2-碳酸 6的合成，  Synthesis of -25-dioxy-2-carbonic acid 6,
5 先將 1- O T 和 1-3-二甲氨基 3- 碳5 first 1- O T and 1-3-dimethylamino 3-carbon
E C)以 1 1 比 然 氮 下 加入2 2 4- 氧基千氧基 氨基 和 水 1 20 比 組成的溶液 再加入 - M 4 再加入2S 25-二氧 2 碳酸 5的 物和 水 1 20 比 的溶液 O T E C 化合物 11 化合物 15 11 1 . 1．0 比 室溫 反 18h 純化她 得到 25- - 2 -2- 4- 氧基千氧基 氨基 -25二氧
Figure imgf000030_0001
EC) Add a solution of 2 2 4-oxyloxyamino group and water 1 20 ratio under a nitrogen ratio of 1 1 and then add -M 4 and then add 2S 25-dioxy 2 carbonic acid 5 and water to 1 20 ratio. Solution OTEC Compound 11 Compound 15 11 1 . 1.0 Purified at room temperature for 18 h to obtain 25- - 2 -2- 4-oxyloxyamino-25 dioxo
Figure imgf000030_0001
步驟 25- - 2 -2- 4- 氧基千氧基 氨基 Step 25- - 2 -2- 4-oxyloxyamino
5 -25二氧 -2- 7的合成 Synthesis of 5 -25 dioxol-2- 7
將步驟m得到的 16 和14-二氧 溶解以 1 50 比混 合 再加入氧氧化 和水以1 250 比 的溶液 化合物 16 氧 氧化 1．1 比 室溫反 h 反 以 萃取 水 相以 和水溶液 P 4 5 再以 萃取 有 相0 水硫酸 得 25 2 -2- 4 氧基 氧基 氨基 -25-二氧 -2 7  The 16 and 14-dioxane obtained in step m are dissolved at a ratio of 1 50 and then added with oxygen oxidation and water at a ratio of 1 to 250. Compound 16 Oxygen is oxidized 1.1 Reversal at room temperature anti-h to extract aqueous phase and aqueous solution P 4 5 and then extracting phase 0 water sulfuric acid to obtain 25 2 -2-oxyoxyamino-25-dioxo-2 7
步驟 25- -5- 2 - - 2R 2 4 氧基 氧基 氨基
Figure imgf000030_0002
氮 下 加入步驟 得到的 17 和 水 氧 1 。 Step 25- -5- 2 - - 2R 2 4oxyoxyamino
Figure imgf000030_0002
Add nitrogen under the step of adding 17 and water oxygen 1 .
50 比 的溶液 至 C 加入 水 50 to solution to C to add water
升至室溫反 加入2-氨基-5- 和 水 氧 1 20 比組成的溶液 上 17 水 2-氨基-5- 1 1 1．2 比 室溫反 反 加入 稀釋 以 和 酸水溶液 再以 和碳酸 有 相 水硫酸 得到 2S- -5- 2 - 2 2 4- 氧基 氧基 氨基 -25-二氧 -2 8 Raise to room temperature and add 2-amino-5- and water-oxygen 1 20 to the composition of the solution. 17-water 2-amino-5- 1 1 1.2 Add the dilution to the aqueous solution and the aqueous solution. Phase water sulfuric acid gives 2S- -5-2 - 2 2 4-oxyoxyamino-25-dioxo-2 8
步驟 P -5 - -氧2- - 2 -2- 4- 氧基 氧基 氨基 25-二氧 -2 9的合成  Step P -5 - - Oxygen 2- - 2 -2- 4-oxyoxyamino 25-diox - 2 9 Synthesis
步驟。得到的 18 和 以 1 75 比混合 再加入 尿素 氧化氧 合物 三批加入卻 二甲 室溫反 反 以 硫酸 的水溶液 有 相再以 和碳酸 的水溶液 有 相 水硫酸 千 得到 2S 5 - - 氧-2 - - 2 2 4- 氧基千氧基 氨基 -25-二 氧 2- 9 上 18 尿素 氧化氧 合物 卻 二甲 1 3 3 比  step. The obtained 18 is mixed with the ratio of 1 75 and then added with urea oxy-oxide. The three batches are added, but the room temperature of the dimethyl sulfate is reversed, and the aqueous solution of sulfuric acid is further phased with aqueous solution of carbonic acid to obtain 2S 5 - - oxygen - 2 - - 2 2 4-oxyloxyamino-25-dioxo 2- 9 on 18 urea oxidized oxygen but dimethyl 1 3 3 ratio
步驟 仍5- -5 -氧-2- 2R-2- 氨基 Step still 5-5-oxy-2- 2R-2-amino
-25-二氧 -2 20的合成  Synthesis of -25-dioxo-220
在步驟p得到的 9 和 以 1 85 比混合 醋酸 室溫反 h 反 再以 稀釋 以 和碳酸 水溶液 至水相 P 8 9 水相再以 萃取 合井 有 相 水硫酸9 obtained in step p and mixed with acetic acid at room temperature of 1 85 to dilute to dilute with aqueous solution of carbonic acid to the aqueous phase P 8 9 and then extract well Phase water sulfuric acid
50 1 得 2S -5 - 氧-2- - - 2 -2- 氨基 50 1 gave 2S -5 -oxo-2- - 2-2-amino
-25二氧 -2- 仍0 上 19 ， 醋酸 1 37．5 比。  -25 dioxane-2- still 0 on 19, acetic acid 1 37.5 ratio.
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EP2684039A4 (en) * 2011-03-09 2015-03-11 Glaxosmithkline Ip No 2 Ltd Peptide deformylase inhibitors

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