位于上海外高桥保税区内的药明康德新药开发有限公司成

顺手牵羊来的新药研发秘密作者：潘文婕来源：《检察风云》2016年第23期生物医药行业的硕士研究生吴广，为了炫耀自己的研发能力，在老东家的保密电脑硬盘上“做手脚”后，获取了老东家开发的一大批保密的新药化合物信息，并私自以自己创办的公司名义公布到了互联网上。

最终，这个高级“搬仓鼠”被浦东新区检察院以侵犯商业秘密罪提起公诉，法院判处其有期徒刑三年六个月，并处罚金10万元。

注册在上海自由贸易试验区的上海药明康德新药开发有限公司在生物医药行业颇有名气，承接了多家国际医药行业巨头的研发订单，其中就包括知名跨国医药公司辉瑞制药公司。

2012年5月，辉瑞制药公司赫然发现，有人在两家国际知名化工网站“ACDFIND”和“SCIFINDER”上陆续发布了一批新药化合物结构式信息，总共89个。

这些新药化合物均是该公司委托上海药明康德新药开发公司斥巨资开发合成的主打产品，在医药行业处于领先地位，属于该公司的“商业秘密”。

是谁偷走了公司价值不菲的商业秘密？目标最终锁定在了上海药明康德新药开发公司已辞职的研究员吴广身上。

32岁的吴广毕业于某大学的生物医药专业，毕业后曾在药明康德新药开发公司担任合成研究员。

2010年年底，吴广工作合同期到后便辞职，并自立门户成立了一家名叫艾娜科的生物医药科技公司。

然后，他将重新编辑后的化合物结构式上传到“ACDFIND”和“SCIFINDER”两个国际知名化工网站之上，并留下艾娜科公司的信息作为这些化合物的权利人。

面对外国客户和上海药明康德新药开发公司的指控，吴广对自己的行为供认不讳。

吴广称，他之所以在网络上发布这些新药化合物结构式等信息，正是为了标榜自己的研发能力，一来给自家新成立的科技公司打广告，二来自己辞职后即使不开公司而另谋高就，也便于在应聘时增加筹码。

对于外国客户和上海药明康德新药开发公司来说，这些化合物结构式、合成信息被公之于众后，已然不能申请药品专利，前期所有的研发投入都“打了水漂”。

专利名称：3-氨基-4-哌啶酮及其相应衍生物的制备方法专利类型：发明专利
发明人：龚万本,朱晨江,郑宝江,尹云星,施一峰,马汝建,陈曙辉
申请号：CN200910057044.7
申请日：20090407
公开号：CN101857565A
公开日：
20101013
专利内容由知识产权出版社提供
摘要：本发明涉及一种3-氨基-4-哌啶酮及其相应衍生物的制备方法。

主要解决原制备过程中步数繁多以及收率偏低的技术问题。

本发明以1-R1-4-哌啶酮为起始原料，与盐酸羟胺在碱存在下反应生成1-R1-4-羟亚胺哌啶；1-R1-4-羟亚胺哌啶与对甲苯磺酰氯或甲基磺酰氯反应生成相应的1-R1-4-羟亚胺哌啶甲苯磺酸盐或甲基磺酸盐；1-R1-4-羟亚胺哌啶甲苯磺酸盐或甲基磺酸盐在醇钠存在下经过Neber重排(尼伯尔重排)，然后经酸处理后就可以得到1-R1-3-氨基-4-哌啶酮的氢卤酸盐或硫酸盐等。

本发明提供一种有效合成3-氨基-4-哌啶酮及其相应衍生物中间体的方法。

申请人：上海药明康德新药开发有限公司,天津药明康德新药开发有限公司
地址：200131 上海市浦东新区外高桥保税区富特中路288号
国籍：CN
代理机构：上海浦东良风专利代理有限责任公司
代理人：张劲风
更多信息请下载全文后查看。

经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写前言有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。

为了提高大家的工作效率，因此化学合成部需要一份《经典合成反应标准操作》。

在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。

同时每种反应的标准操作，均可作为模板套用于书写客户的final report，这样可以大大节省研究人员书写final report的时间，也相应减少在报告中的文法错误。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-28目录1.胺的合成a)还原胺化b)直接烷基化c)腈的还原d)酰胺的还原e)硝基的还原f)叠氮的还原g)Hoffman降解h)羧酸通过Cris 重排2.羧酸衍生物的合成a)酰胺化的反应b)酯化反应c)腈转化为酯和酰胺d)钯催化的插羰反应e)酯交换为酰氨3.羧酸的合成a)醇氧化b)酯水解c)酰胺的水解d)腈的水解e)有机金属试剂的羰基化反应f)芳香甲基的氧化4.醛酮的合成a)Weinreb 酰胺合成醛酮b)醇氧化c)酯的直接还原d)有机金属试剂对腈加成合成酮5.脂肪卤代物的合成a)醇转化为脂肪溴代物通过PBr3 转化通过PPh3 与CBr4 转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b)醇转化为脂肪氯代物通过SOCl2转化通过PPh3 与CCl4 转化HCl直接交换c)醇转化为脂肪碘代物通过PPh3 与I2 转化通过相应的氯代物或磺酸酯与NaI交换6.芳香卤代物的合成a)Sandermyyer 重氮化卤代b)直接卤代c)杂环的酚羟基或醚的卤代7.醇的合成a)羧酸或酯的还原b)醛酮的还原c)卤代烃的水解d)吡啶的氧化转位8.酚的合成a)Sandermayer 重氮化反应b)醚的水解c)Bayer-vigerlar 氧化d)硼酸的氧化9.腈的合成a)磺酸酯或卤代烃的取代b)酰胺的脱水c)芳卤代烃的氰基取代10.硝化反应11.醚的合成a)芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu 芳香醚化Buckwald芳香醚化b)脂肪醚的合成醇的醚化12.脲的合成a)胺与异腈酸酯的反应b)用三光气合成脲c)羰基二咪唑（CDI）合成脲d)对硝基苯酚碳酰胺合成脲13.烯烃的合成a)Wittig 反应b)羟基的消除c)Wittig-Horner 反应合成α,β-不饱和酯14.磺酸及磺酰氯的合成a)氯磺化反应合成磺酰氯b)从硫醇合成磺酰氯c)磺化反应15.氨基酸的合成a)Streck 反应合成b)手性氨基酸的合成16.偶联反应a)Suzuki Couplingb)Buckwald 芳胺化，芳酰胺化、c)Heck 反应17.Mitsunobu 反应a)醇的反转b)胺的取代18.脱羟基反应19.酮还原为亚甲基20.氨的保护及脱保护策略a)用碳酰胺作保护基b)苄基保护21.醇的保护及脱保护策略a)用硅醚进行保护b)其他醚类保护22.羧基的保护格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2 Suzuki coupling-------------------------------------------------------------------------------------------------2磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4 n-BuLi------------------------------------------------------------------------------------------------------------4 LiAlH4还原-----------------------------------------------------------------------------------------------------4 POCl3的杂环氯代----------------------------------------------------------------------------------------------5 NaH---------------------------------------------------------------------------------------------------------------5 NBS---------------------------------------------------------------------------------------------------------------5m-CPBA ----------------------------------------------------------------------------------------------------------6EDC ---------------------------------------------------------------------------------------------------------------6用三光气成脲---------------------------------------------------------------------------------------------------7芳卤用n-BuLi 处理后与Weinreb 酰胺成酮-----------------------------------------------------------------7Boc 上保护OHH 2NHO OOOOOO OHN HO OHO O ABTo a solution of A (2.72 g, 13.9 mmol) and tetramethylammonium hydroxide pentahydrate (5.62 g, 31.0 mmol) in acetonitrile (270 mL) was added di-tert-butyldicarbonate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitioned between Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCl3 (3.x.100 mL). The organic extracts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc 脱保护OON HOOOOH 2NTert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) in dichloromethane (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1, 40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88percent yield) as a light yellow solid.Return格氏反应NCNNOA stirred mixture of magnesium turnings (23.6 g, 0.98 mol) and Et2O (200 mL) under nitrogen is treated with a crystal of iodine and about 5percent of a solution of bromoethane (56.3 ml, 0.75 mol) in Et2O (375 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. To this solution of ethylmagnesium bromide was slowly added a solution of 4-cyanopyridine (39 g, 0.375 mol) in Et2O (750 ml). The reaction mixture was warmed at reflux for 12 hours, treated with concentrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portion was made basic (PH 9) with 15percent NaOH solution and extracted five times with 250 ml portions of Et2O. The combined Et2O extracts were dried (MgSO4), and the solvent was removed under reduced pressure to afford a brown oil (48.4 g, 95percent).Return还原胺化OHO H 2N+HON HA solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), andp-toluenesulfonic acid (0.05 g) in methanol (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After addition was completed, the mixture was stirred at room temperature for 30 min and concentrated under vacuum. The residue was then subjected to column chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous methanol) yielded 450 mg (22percent) of analytically pure product.Return卤化反应O2N O2NBrTo a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCl4 (150 ml) heated to 60°C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the reaction mixture was poured into saturated NaHCO3 solution, and the layers were separated. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was recrystallized from ethanol and the mother liquors were concentrated and then flash chromatographed on silica, eluding hexanes:ethyl acetate (12: 1).ReturnSuzuki couplingBrBOO NH+NH To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and3-bromobenzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 ml of water).The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °Coil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%yield) of 4-phenyl-1H-indole as a colorless liquid.Return磺化反应NOFFFNOFFFSOClOChlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml). The resulting solution is stirred at 0°C for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product is purified by column chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).Return酯化反应HOHO O HOO OA mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2SO4(2 ml) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应OO OHOA solution of 1-Methyl-naphthalene-2-carboxylic acid methyl ester (7.20g, 35mmol) and 2N sodium hydroxide (35ml) in tetrahydrofuran (130ml) was stirred under reflux for 18 hours. The mixture was neutralised using 2N hydrochloric acid, and extracted with dichloromethane (3x). The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g, 47.8%yield).Return硝化反应NO 2To a cold (0°C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate: hexane (5: 95) and recrystallized from methanol to give yellow needles (0.22g, 33% yield).Returnn-BuLiEtOCF 3O CF 3O NCTo a dry three-necked round-bottomed flask with an addition funnel and at -78°C under inert atmosphere was charged with anhydrous THF (500 ml). A solution of n-butyllithium (2.5 M in hexane, 88ml, 220 mmol) was added dropwise followed by addition of a solution of acetonitrile (10.43 ml, 200 mmol) in anhydrous THF (100 ml). The internal temperature was maintained below -70°C during the entire addition process. After 2 hr at -78°C a solution of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. To the mixture was added acetic anhydride to quench the reaction. The reaction mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step without purification.ReturnLiAlH4还原HOHO O OHOHOA solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed to 50° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.ReturnPOCl3的杂环氯代NN HOOHN NClClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimethylaniline (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 °C for 3 hours. After this time, the starting material completely dissolved indicating that the reaction was completed.The reaction mixture was cooled and then poured slowly onto ice to quench the POCl3(caution[exothermic]). A precipitate formed, which was filtered and washed with ice-cold water. The precipitate was dried under high vacuum overnight to yield 2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.ReturnNaHHSH 2N Cl +SNH 2Sodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwise at 0 °C under a nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml). After 0.5 h, benzyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solution was stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The solid obtained was ground in pentane (19.3 g, 90% yield).ReturnNBSNN FCl ClNBSN N FCl ClBrA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g ， 0.14mol), AIBN (1.32 g) and n-bromosuccinimide (27.02 g ， 0.152mol) in CH2Cl2 (170 ml) was refluxed under a nitrogen atmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The combined organic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by column chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6% yield).Return氢化反应O ONH OONH2Cl ClA mixture of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride (25g, 0.1 mol) and 10percent Pd-C (2g) in 250 ml of dried alcohol was hydrogenated under 55 psi H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide an amber oil which gradually crystallized upon standing (18 g, 100% yield).Returnm-CPBAS NH2SNH2OA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at –5 –0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). The mixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 solution, 10% NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. The solid was ground in pentane (19 g, 95% yield).ReturnEDCNH2OHNOO+HOHOHNOOTo a 0°C mixture of Boc-L-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) in methylene chloride (30 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.53 g, 9.9 mmol). Thewhite mixture is stirred at 0°C for 5 min and at room temp for 23 hrs. The resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarbonate (25 ml). The organic phase is dried over magnesium sulfate and concentrated to a foam (1.84 g, 72.4%yield), sufficiently pure to carry into the next step. An analytical sample is obtained by HPLC.Return三光气成脲NH 2ONO 2Si O Cl Cl ClO O Cl Cl ClO 2NHN H NO OHOHNO 2+To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml) triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours, then cooled to room temperature. Then more 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70 °C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield).Return芳卤用n-BuLi处理后与Weinreb酰胺成酮N FFFFNOO+FFFO NFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon was added n-butyllithium (54.0 ml, 2.5M in hexane, 0.135 mole), followed after 5 min by dropwise a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mole) in THF (20 ml). After stirring for 15 min at –78°C, a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirring for more 5 min, the reaction was allowed to warm to 0°C and quenched by pouring into water (400 ml) and ethyl acetate (400 ml). The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20percent ethyl acetate in hexane to give 21.6 g of 2-(2-Fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanone (84.8%yield).Return。

上海药明康德新药开发有限公司班车路线表（2007.4.18.）常日班班车（星期一至星期五）现车号上班行车路线下班行车路线备注1号车怒江路金沙江路（7:40AM）- 曹杨八村新浪酒店（7:45AM）- 中宁路·石泉路（8:00AM）- 公司按原路返回（17：15公司发车）2号车阳泉路·共康东路（8:10AM）- 车站南路·水电路（8:15AM）- 逸仙路·纪念路（8:17AM）- 国定路·武川路口（8:30AM）- 公司按原路返回（17：15公司发车）3号车民星路(8：15AM) - 包头路•国顺东路（8:20AM）- 松花江路•双阳路（8:25AM）-中环入口处站（拖拉机内燃机公司门口）（8:35AM）-公司按原路返回（17：15公司发车）4号车712路田林新苑站（谭火锅门口）（7:20AM）- 万体馆·零陵路（7:35AM）- 东安路（7:45AM）- 南车站路（8:05AM）- 公司按原路返回（17：15公司发车）5号车三林城东明路（华联超市门口）（7:40AM）- 杨高南路·农工商超市车站（8:10AM）- 东锦江（经南浦大桥8:15AM）- 杨高路·家乐福（8:30AM）- 公司按原路返回（17：15公司发车）6号车沪南路·北中路（北蔡镇政府公交站）（7:50AM）- 白杨路龙东路车站（靠近龙阳路地铁站）（7:58AM）-锦绣路科技馆地铁站6号出口（8:15AM）- 公司按原路返回（17：15公司发车）7号车张江路·紫薇路（8:10AM）- 公司按原路返回（17：15公司发车）8号车莘庄地铁北广场（碧秀路肯德鸡门口）（7:50AM）- 莲花路站（南方商城对面）（7:55AM）-锦江乐园大门口（8:00AM）- 公司按原路返回（17：15公司发车）9号车七街坊（8:38AM）- 公司按原路返回（17：15公司发车）10号车东方路·崂山东路（靠近紫金山大酒店）（8:10AM）- 张杨路·福山路口车站（小学门口。

专利名称：一种1－R－2,3－二氢－1H－喹啉－4－酮的合成方法
专利类型：发明专利
发明人：蒋剑峰,楼良,马汝建,陈曙辉,李革
申请号：CN200710094205.0
申请日：20071106
公开号：CN101429159A
公开日：
20090513
专利内容由知识产权出版社提供
摘要：本发明涉及一种1－R－2，3－二氢－1H－喹啉－4－酮的合成方法。

主要解决目前合成方法中原料不易放大，路线较长，反应操作不便等技术问题。

一种1－R－2，3－二氢－1H－喹啉－4－酮的合成方法，其特征是：包括以下步骤：a.以4－羟基喹啉为原料，在溶剂中与烷基卤代物、苄基卤代物或烷基的磺酸酯反应生成烯酮；b.将烯酮溶入溶剂中，加入还原剂得到相应的醇；c.将溶于溶剂的相应醇加入氧化剂经氧化后得到1－R－2，3－二氢－1H－喹啉－4－酮。

申请人：上海药明康德新药开发有限公司
地址：200131 上海市浦东新区外高桥保税区富特中路288号1号楼
国籍：CN
代理机构：上海浦东良风专利代理有限责任公司
代理人：张劲风
更多信息请下载全文后查看。

天津药明康德新药开发有限公司、汝磊劳动争议二审民事裁定书【案由】民事劳动争议、人事争议其他劳动争议、人事争议【审理法院】天津市第三中级人民法院【审理法院】天津市第三中级人民法院【审结日期】2020.10.12【案件字号】(2020)津03民辖终246号【审理程序】二审【审理法官】刘俊闫萍武伟【审理法官】刘俊闫萍武伟【文书类型】裁定书【当事人】天津药明康德新药开发有限公司;汝磊;无锡药明康德新药开发股份有限公司【当事人】天津药明康德新药开发有限公司汝磊无锡药明康德新药开发股份有限公司【当事人-个人】汝磊【当事人-公司】天津药明康德新药开发有限公司无锡药明康德新药开发股份有限公司【代理律师/律所】崔佩玲天津卓纳律师事务所;朱美珍天津卓纳律师事务所;戴庆博北京炜衡(天津)律师事务所【代理律师/律所】崔佩玲天津卓纳律师事务所朱美珍天津卓纳律师事务所戴庆博北京炜衡(天津)律师事务所【代理律师】崔佩玲朱美珍戴庆博【代理律所】天津卓纳律师事务所北京炜衡(天津)律师事务所【法院级别】中级人民法院【终审结果】二审维持原判【原告】天津药明康德新药开发有限公司【被告】汝磊;无锡药明康德新药开发股份有限公司【本院观点】《最高人民法院关于审理劳动争议案件适用法律若干问题的解释》第八条规定：“劳动争议案件由用人单位所在地或者劳动合同履行地的基层人民法院管辖，劳动合同履行地不明确的，由用人单位所在地的基层人民法院管辖。

【权责关键词】无效撤销合同合同约定管辖权异议合同履行地诉讼请求【指导案例标记】0【指导案例排序】0【本院认为】本院经审查认为，《最高人民法院关于审理劳动争议案件适用法律若干问题的解释》第八条规定：“劳动争议案件由用人单位所在地或者劳动合同履行地的基层人民法院管辖，劳动合同履行地不明确的，由用人单位所在地的基层人民法院管辖。

”本案中，汝磊向一审法院起诉请求：1.判决天津药明公司向汝磊支付违法解除劳动合同经济赔偿金413206.5元；2.判决天津药明公司向汝磊支付未休年假工资7431.72元；3.判决天津药明公司向汝磊支付报销费用98元；4.判决天津药明公司向汝磊支付年终奖差额32086.2元；5.判决天津药明公司、无锡药明公司连带赔偿汝磊2018年限制性股票损失174686.4元，2019年限制性股票损失378672元；6.判决天津药明公司、无锡药明公司连带赔偿汝磊千人项目激励奖金损失420000元。

专利名称：1-取代-3,8-二氮杂双环[3.2.1]辛烷衍生物及制备方法
专利类型：发明专利
发明人：张鹏,彭宣嘉,胡利红,房顺大,董径超,吴颢,马汝建,陈曙辉
申请号：CN201010219408.X
申请日：20100702
公开号：CN102311439A
公开日：
20120111
专利内容由知识产权出版社提供
摘要：本发明涉及1-取代-3，8-二氮杂双环[3.2.1]辛烷取代衍生物及制备方法，主要解决目前的3，8-二氮杂双环[3.2.1]辛烷结构的桥环化合物在空间结构延伸受到限制以及化合物水溶性差的技术问题。

化学结构式如下：X和Y为取代官能团或氨基的保护基，选自H、C1～C10直链或含有取代基侧链的烷基、苄基、叔丁氧羰基、烷酰基、磺酰基、脲、硫脲中的一种；Z为亚烃基或羰基中的一种。

当Z为羰基时，G为羟基、氨基、或烷氧基中的一种，当Z为亚烃基时，G为羟基或卤素中的一种。

申请人：上海药明康德新药开发有限公司,天津药明康德新药开发有限公司
地址：200131 上海市浦东新区外高桥保税区富特中路288号
国籍：CN
代理机构：上海浦东良风专利代理有限责任公司
代理人：张劲风
更多信息请下载全文后查看。

专利名称：4－(3－碘－2－吡啶基)哌嗪类化合物的合成方法专利类型：发明专利
发明人：林道广,王小平,彭作中,廖文胜,陈曙辉
申请号：CN200810043775.1
申请日：20080911
公开号：CN101671297A
公开日：
20100317
专利内容由知识产权出版社提供
摘要：本发明涉及一种改进的4－(3－碘－2－吡啶基)哌嗪类化合物的合成方法。

主要解决现有制备方法存在的反应条件苛刻，有副反应生成，分离困难，总收率低，不易于大规模生产的技术问题。

制备步骤：以2－氯－3－硝基吡啶为起始原料，与N－叔丁氧羰基哌嗪和碱在有机溶剂中进行N－烷基化反应得到1－叔丁氧羰基－4－(3－硝基－2－吡啶基)哌嗪(11)；在还原剂作用下，化合物(11)中的硝基被还原后得到1－叔丁氧羰基－4－(3－氨基－2－吡啶基)哌嗪(12)；化合物(12)经重氮化碘代反应得到1－叔丁氧羰基－4－(3－碘－2－吡啶基)哌嗪(8)；化合物(8)酸性条件下去保护得到4－(3－碘－2－吡啶基)哌嗪(7)。

本发明主要用于大规模化制备4－(2－吡啶基)哌嗪类化合物。

申请人：上海药明康德新药开发有限公司,上海合全药业有限公司
地址：200131 上海市浦东新区外高桥保税区富特中路288号
国籍：CN
代理机构：上海浦东良风专利代理有限责任公司
代理人：张劲风
更多信息请下载全文后查看。