CN106905100A - 手性胺类化合物的拆分方法及其中间体 - Google Patents
手性胺类化合物的拆分方法及其中间体 Download PDFInfo
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- CN106905100A CN106905100A CN201710221159.XA CN201710221159A CN106905100A CN 106905100 A CN106905100 A CN 106905100A CN 201710221159 A CN201710221159 A CN 201710221159A CN 106905100 A CN106905100 A CN 106905100A
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Abstract
本发明公开了一种手性胺类化合物的拆分方法及其中间体。本发明提供了一种手性胺类化合物的拆分方法及其中间体,所述拆分方法包括以下步骤:溶剂中,将手性胺类化合物与拆分剂进行成盐反应,即可;所述手性胺类化合物是指3‑(1‑氨基乙基)苯酚、(2R,3S)‑4‑氨基‑1,2,3‑环戊三醇或trans‑环己二胺;所述拆分剂为L‑α‑氨基酸、L‑α‑氨基酸衍生物、D‑α‑氨基酸或D‑α‑氨基酸衍生物;该方法可较好地对手性胺类化合物进行拆分,该方法收率高、成本低,适用于工业化生产。
Description
技术领域
本发明涉及手性胺类化合物的拆分方法及其中间体。
背景技术
在药物合成中,手性胺类化合物是一类应用非常广泛的医药中间体,手性拆分是一种可有效获得该类化合物的方法(手性药物-研究与应用:化学工业出版社,2004;Process Chem.Pharm.Ind.2008,137;Sci.Synth.2009,40,419;GreenChem.Pharm.Ind.2010,269;Chiral Drugs 2011,137.)。
对于手性胺类医药中间体,一般用手性酸进行拆分。常见的手性酸拆分剂有:酒石酸,苹果酸,樟脑酸,樟脑磺酸,双丙酮-L-古龙酸,扁桃酸,苯氧丙酸,氢化阿托酸及它们的衍生物等,其中,酒石酸及其衍生物、扁桃酸及其衍生物和樟脑磺酸及其衍生物是应用比较广泛的手性拆分试剂。
在制药工业中,通过拆分获得关键手性中间体的操作是一种可工业化的大规模生产方式;由于在工业中,手性试剂需要回收再利用,因此试剂的稳定性变得尤为重要;另外,由于在回收再利用过程中,手性试剂存在损失,因此试剂的价格也是制约其能否被广泛利用的一个重要因素。因此,如何选择具备廉价易得、性质稳定的拆分剂,是本领域技术人员迫切需要解决的问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中手性胺类化合物,如3-(1-氨基乙基)苯酚对映异构体、(2R,3S)-4-氨基-1,2,3-环戊三醇对映异构体及trans-环己二胺对映异构体拆分困难、拆分成本高,不适用于工业化生产等缺陷,而提供了一种手性胺类化合物的拆分方法及其中间体。本发明使用价格低廉的手性α-氨基酸或手性α-氨基酸衍生物作拆分剂,可以较好地对上述手性胺类化合物进行拆分,该方法收率高、成本低,适用于工业化生产。
本发明提供了一种手性胺类化合物的拆分方法,其包括以下步骤:溶剂中,将手性胺类化合物与拆分剂进行成盐反应;
所述手性胺类化合物是指3-(1-氨基乙基)苯酚、(2R,3S)-4-氨基-1,2,3-环戊三醇或trans-环己二胺;
所述3-(1-氨基乙基)苯酚为(S)-3-(1-氨基乙基)苯酚和(R)-3-(1-氨基乙基)苯酚的混合物;
所述(2R,3S)-4-氨基-1,2,3-环戊三醇为(1R,2R,3S,4S)-4-氨基-1,2,3-环戊三醇、(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇)、(1S,2R,3S,4S)-4-氨基-1,2,3-环戊三醇和(1R,2R,3S,4R)-4-氨基-1,2,3-环戊三醇中的至少一对对映异构体的混合物;
所述trans-环己二胺为(1R,2R)-环己二胺和(1S,2S)-环己二胺的混合物;
所述拆分剂为L-α-氨基酸、L-α-氨基酸衍生物、D-α-氨基酸或D-α-氨基酸衍生物;
所述L-α-氨基酸衍生物为L-α-氨基酸上的氨基上带有氨基保护基的化合物;
所述D-α-氨基酸衍生物为D-α-氨基酸上的氨基上带有氨基保护基的化合物;
通过上述拆分方法,即可实现将所述手性胺类化合物进行拆分,得到具有单一构型的胺类化合物,所述单一构型的胺类化合物是指所述胺类化合物中全部为单一构型或者以某种构型为主要优势构型存在,例如ee%大于95%。
本发明中,所述的手性胺类化合物优选为两种构型的对映异构体,进一步优选两种构型的异构体的摩尔比为1:1。
本发明中,所述的L-α-氨基酸、L-α-氨基酸衍生物、D-α-氨基酸和D-α-氨基酸衍生物中的所述氨基酸各自独立的选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、叔亮氨酸、苯丙氨酸、苯甘氨酸、色氨酸、酪氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、半胱氨酸和脯氨酸中的一种或多种。
本发明中,所述的L-α-氨基酸衍生物和所述D-α-氨基酸衍生物中所述的氨基保护基可为本领域常规的氨基保护基,本发明特别优选氧羰基类保护基(例如,甲氧羰基、乙氧羰基、叔丁氧羰基、烯丙氧羰基、苄氧羰基、芴甲氧羰基或三甲基硅乙氧羰基)、酰基类保护基(例如,乙酰基、三氟乙酰基、特戊酰基、苯甲酰基或邻苯二甲酰基)或磺酰基类保护基(例如,甲磺酰基、三氟甲磺酰基、苯磺酰基、对甲苯磺酰基、对甲氧基苯磺酰基、对硝基苯磺酰基或邻硝基苯磺酰基)。
本发明中,所述手性胺类化合物为3-(1-氨基乙基)苯酚时,所述拆分剂为N-叔丁氧羰基-L-缬氨酸。
本发明中,所述手性胺类化合物为(2R,3S)-4-氨基-1,2,3-环戊三醇时,所述拆分剂为N-乙酰基-L-异亮氨酸。
本发明中,所述手性胺类化合物为trans-环己二胺时,所述拆分剂为N-对甲苯磺酰基-L-天冬氨酸。
本发明中,所述溶剂优选选自水、醇类溶剂(例如,甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇和苯甲醇中的一种或多种)、醚类溶剂(例如,甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃和1,4-二氧六环中的一种或多种)、腈类溶剂(例如,乙腈、丙腈、正丁腈和异丁腈中的一种或多种)和酯类溶剂(例如,乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸叔丁酯、乙酸戊酯、乙酸异戊酯和乙酸新戊酯中的一种或多种)中的一种或多种。
本发明中,所述手性胺类化合物和所述拆分剂的摩尔用量比可参考本领域手性拆分时的常规用量,例如(10:1)~(1:10),本发明特别优选(5:3)~(20:11)。
本发明中,所述手性胺类化合物在所述溶剂中的摩尔体积比优选0.01~100mol/L,进一步优选0.5mol/L~2.7mol/L。
本发明中,所述成盐反应的温度优选60℃~100℃,同时,按照本领域常识,所述温度应不应超过溶剂的回流温度。
本发明中,所述成盐反应的时间可按照本领域技术人员的经验决定,例如是否有大量固体析出等,较佳的为4~12小时。
所述的成盐反应结束后还可进一步包括以下的后处理操作:冷却和过滤;所述冷却和过滤均和参照本领域常规操作方法。
较佳的,所述拆分方法还可将所述成盐反应制得的盐与碱反应,得到单一构型的胺类异构体即可。
所述碱的种类一般为可将所述成盐反应制得的盐中解离出来的碱的种类,优选无机碱;所述的无机碱优选MOH,M为碱金属离子,所述的碱金属优选锂、钠或钾;所述的无机碱一般以碱水溶液的形式参与反应;所述的碱水溶液的浓度可参照本领域常规进行选择,优选5%~10%;所述浓度为质量百分比。
所述盐与碱反应的反应温度可参照本领域的常规进行选择,优选-10℃~5℃。所述盐与碱反应的反应时间可参照本领域的常规进行选择,优选0.5~2小时。
所述盐与碱反应结束后还可包括后处理,如萃取和/或过滤。
本发明还提供了手性胺类化合物中间体,如下所示:
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明采用价格低廉的手性α-氨基酸或手性α-氨基酸衍生物作拆分剂,可以较好地对手性胺类化合物中的3-(1-氨基乙基)苯酚对映异构体、(2R,3S)-4-氨基-1,2,3-环戊三醇对映异构体或trans-环己二胺对映异构体进行拆分。该方法收率高、纯度好、成本低,适用于工业化生产。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例中,拆分后得到的某异构体的收率的计算方式为:拆分后得到某异构体的物质的量/该异构体的理论的物质的量*100%;
手性α-氨基酸及其衍生物在非环状手性胺类医药中间体拆分中的应用
实施例1
(1)向100mL异丙醇中加入N-叔丁氧羰基-L-缬氨酸2(6.5178g,30mmol),搅拌至全溶后,加入3-(1-氨基乙基)苯酚1((S)-3-(1-氨基乙基)苯酚:(R)-3-(1-氨基乙基)苯酚)=1:1)(6.8590g,50mmol);而后反应液加热至60℃,继续搅拌12小时后,反应液中生成大量白色固体;冷却,过滤,滤饼用异丙醇(2×25mL)洗涤后,得卡巴拉汀关键手性中间体(S)-3-(1-氨基乙基)苯酚的羧酸盐3(白色固体,8.1289g,23mmol);(2)冰盐浴下(约-10~-5℃),将羧酸盐3分批加入25ml饱和氢氧化钠水溶液中,而后该温度下继续搅拌1小时;反应结束后,反应液用二氯甲烷(3×25mL)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液旋干后得(S)-3-(1-氨基乙基)苯酚,收率97%,两步总收率89.24%,99.3%ee。拆分所得(S)-3-(1-氨基乙基)苯酚的表征数据与文献(J.Med.Chem.2004,47,2887)所报道数据一致;同时,(R)-3-(1-氨基乙基)苯酚亦可用该方法拆分获得,ee值可根据(R)-3-(1-氨基乙基)苯酚的ee值进行推算得知。
化合物3的鉴定数据
[α]25 D=+78.4,熔点111.3-113.7℃;
1H NMR(DMSO-d6,400MHz,ppm):δ8.16(s,1H),7.25-7.21(m,1H),7.08-7.02(m,4H),6.90-6.73(m,2H),5.49(s,1H),5.06(q,J=7.6Hz,1H),4.59(d,J=8.0Hz,1H),2.65(m,1H),2.05(d,J=7.2Hz,3H),1.45(s,9H),0.98(d,J=7.6Hz,6H)。
手性α-氨基酸及其衍生物在环状手性胺类医药中间体拆分中的应用
实施例2
反应式为:
(1)向200mL乙酸异丙酯中加入N-乙酰基-L-异亮氨酸5(9.5266g,55mmol),搅拌至全溶后,加入(2R,3S)-4-氨基-1,2,3-环戊三醇((1R,2R,3S,4S)-4-氨基-1,2,3-环戊三醇与(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇的比例为1:1)4(13.3150g,100mmol);而后反应液在回流状态下搅拌4小时,有大量白色固体生成;冷却,过滤,滤饼用乙酸异丙酯(3×25mL)洗涤后,得替格瑞洛手性中间体(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇的羧酸盐6(白色固体,14.7053g,48mmol);(2)将羧酸盐7溶于100ml甲醇中,冰水浴下(约0~5℃),向上述溶液中分批加入碳酸钠(5.8295g,55mmol),而后该温度下继续搅拌2小时;反应结束后,旋干甲醇,向残余物中加入50ml乙酸异丙酯,剧烈搅拌0.5小时后过滤,所得滤液旋干后即得(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇,收率98%,两步总收率94.08%,99.5%ee,拆分所得(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇苯酚的表征数据与文献(Chem.-Eur.J.1995,1,568)所报道数据一致。同时,(1R,2S,3R,4S)-4-氨基-1,2,3-环戊三醇亦可用该方法拆分获得,ee值可根据(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇的ee值进行推算得知。
化合物6结构鉴定数据:[α]25D=+135.9;熔点102.8~104.1℃;
1H NMR(DMSO-d6,400MHz,ppm):δ8.05(s,1H),7.02(s,3H),4.56(m,1H),3.98(m,1H),3.67-3.58(m,4H),3.40-3.32(m,2H),2.50-2.45(m,1H),2.23-2.12(m,2H),1.88(s,3H),1.60(m,2H),1.09(d,J=7.2Hz,3H),0.92(t,J=7.6Hz,3H)。
手性α-氨基酸及其衍生物在手性二胺类医药中间体拆分中的应用
实施例3
反应式为:
(1)向75mL水中加入trans-环己二胺7((1R,2R)-环己二胺:(1S,2S)-环己二胺=1:1)(22.8380g,200mmol),搅拌至全溶后,加入N-对甲苯磺酰基-L-天冬氨酸8(31.6019g,110mmol)的乙腈(75mL)溶液;而后反应液在70℃下继续搅拌6小时,接着缓慢降低温度至25℃(约6小时),有大量白色固体生成;过滤,滤饼用冰的乙腈(2×25mL)洗涤后,得米铂手性中间体(1R,2R)-环己二胺的羧酸盐9(白色固体,38.1406g,95mmol);(2)冰盐浴下(约-10~-5℃),将羧酸盐11分批加入50ml饱和氢氧化钠水溶液中,而后该温度下剧烈搅拌1小时;反应结束后,反应液用乙醚(3×50mL)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液旋干后得(1R,2R)-环己二胺,收率92%),两步的总收率为87.4%,99.0%ee,拆分所得(1R,2R)-环己二胺的表征数据与文献(Org.Lett.2008,10,4755)所报道数据一致。同时,(1S,2S)-环己二胺亦可用该方法拆分获得,ee值可根据(1R,2R)-环己二胺的ee值进行推算得知。
化合物9的结构鉴定数据:[α]25 D=-57.3,熔点98.2~99.6℃,
1H NMR(DMSO-d6,400MHz,ppm):δ7.92(s,1H),7.70(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),5.18(s,6H),3.69(t,J=7.2Hz,1H),3.08(dd,J=14.4,6.8Hz,1H),2.83(m,3H),2.38(s,3H),1.79-1.70(m,2H),1.56-1.48(m,2H),1.21-1.11(m,4H)。
Claims (10)
1.一种手性胺类化合物的拆分方法,其特征在于,包括以下步骤,溶剂中,将手性胺类化合物与拆分剂进行成盐反应,即可;
所述手性胺类化合物是指3-(1-氨基乙基)苯酚、(2R,3S)-4-氨基-1,2,3-环戊三醇或trans-环己二胺;
所述3-(1-氨基乙基)苯酚为(S)-3-(1-氨基乙基)苯酚和(R)-3-(1-氨基乙基)苯酚的混合物;
所述(2R,3S)-4-氨基-1,2,3-环戊三醇为(1R,2R,3S,4S)-4-氨基-1,2,3-环戊三醇、(1S,2R,3S,4R)-4-氨基-1,2,3-环戊三醇)、(1S,2R,3S,4S)-4-氨基-1,2,3-环戊三醇和(1R,2R,3S,4R)-4-氨基-1,2,3-环戊三醇中的至少一对对映异构体的混合物;
所述trans-环己二胺为(1R,2R)-环己二胺和(1S,2S)-环己二胺的混合物;
所述拆分剂为L-α-氨基酸、L-α-氨基酸衍生物、D-α-氨基酸或D-α-氨基酸衍生物;
所述L-α-氨基酸衍生物为L-α-氨基酸上的氨基上带有氨基保护基的化合物;
所述D-α-氨基酸衍生物为D-α-氨基酸上的氨基上带有氨基保护基的化合物。
2.如权利要求1所述的拆分方法,其特征在于,所述手性胺类化合物为两种构型的对映异构体,优选两种构型的异构体的摩尔比为1:1。
3.如权利要求1所述的拆分方法,其特征在于,所述的L-α-氨基酸、L-α-氨基酸衍生物、D-α-氨基酸和D-α-氨基酸衍生物中的所述氨基酸各自独立地选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、叔亮氨酸、苯丙氨酸、苯甘氨酸、色氨酸、酪氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、丝氨酸、苏氨酸、半胱氨酸和脯氨酸中的一种或多种;所述氨基保护基为氧羰基类保护基、酰基类保护基或磺酰基类保护基。
4.如权利要求3所述的拆分方法,其特征在于,所述的氧羰基类保护基为甲氧羰基、乙氧羰基、叔丁氧羰基、烯丙氧羰基、苄氧羰基、芴甲氧羰基或三甲基硅乙氧羰基;所述酰基类保护基为乙酰基、三氟乙酰基、特戊酰基、苯甲酰基或邻苯二甲酰基;所述磺酰基类保护基为甲磺酰基、三氟甲磺酰基、苯磺酰基、对甲苯磺酰基、对甲氧基苯磺酰基、对硝基苯磺酰基或邻硝基苯磺酰基。
5.如权利要求1所述的拆分方法,其特征在于,
所述手性胺类化合物为3-(1-氨基乙基)苯酚时,所述拆分剂为N-叔丁氧羰基-L-缬氨酸;
和/或,所述手性胺类化合物为(2R,3S)-4-氨基-1,2,3-环戊三醇时,所述拆分剂为N-乙酰基-L-异亮氨酸;
和/或,所述手性胺类化合物为trans-环己二胺时,所述拆分剂为N-对甲苯磺酰基-L-天冬氨酸;
和/或,所述溶剂选自水、醇类溶剂、醚类溶剂、腈类溶剂和酯类溶剂中的一种或多种;
和/或,所述手性胺类化合物和所述拆分剂的摩尔用量比为(10:1)~(1:10);
和/或,所述手性胺类化合物在所述溶剂中的摩尔体积比为0.01~100mol/L;
和/或,所述成盐反应的温度为60℃~100℃;
和/或,所述成盐反应的时间为4~12小时;
和/或,所述成盐反应结束后包括后处理,所述后处理包括冷却和过滤。
6.如权利要求5所述的拆分方法,其特征在于,所述手性胺类化合物和所述拆分剂的摩尔用量比为(5:3)~(20:11);和/或,所述手性胺类化合物在所述溶剂中的摩尔体积比为0.5mol/L~2.7mol/L。
7.如权利要求1所述的拆分方法,其特征在于,还包括将所述成盐反应制得的盐与碱反应,得到单一构型的胺类异构体即可。
8.如权利要求7所述的拆分方法,其特征在于,所述碱为无机碱;所述的无机碱为MOH,M为碱金属离子,所述的碱金属为锂、钠或钾;所述的无机碱以碱水溶液的形式参与反应;所述的碱水溶液的浓度优选5%~10%;所述浓度为质量百分比;
和/或,所述盐与碱反应的反应温度为-10℃~5℃;
和/或,所述盐与碱反应的反应时间为0.5~2小时;
和/或,所述盐与碱反应结束后还包括后处理,所述后处理包括萃取和/或过滤。
9.手性胺类化合物中间体,结构如下所示:
10.如权利要求9所述的手性胺类中间体的制备方法,其特征在于,其制备方法和条件如权利要求1-8任一项中所述。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110256261A (zh) * | 2019-02-20 | 2019-09-20 | 常州大学 | 一种用于制备左旋2-氨基-1-丁醇的手性拆分方法 |
CN111763150A (zh) * | 2019-12-27 | 2020-10-13 | 上虞京新药业有限公司 | 一种手性盐酸舍曲林的制备方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1874992A (zh) * | 2003-10-28 | 2006-12-06 | 辉瑞产品公司 | 3-氨基烷基腈的拆分 |
CN101538242A (zh) * | 2009-04-27 | 2009-09-23 | 浙江工业大学 | 一种贝那普利关键中间体s-氨基物的合成方法 |
CN101613292A (zh) * | 2009-07-29 | 2009-12-30 | 上海医药(集团)有限公司 | (s)-3-(1-二甲氨基乙基)苯酚的制备方法 |
CN102329241A (zh) * | 2011-09-09 | 2012-01-25 | 诚达药业股份有限公司 | 1,2-环己二胺的化学拆分方法 |
CN104151176A (zh) * | 2014-08-29 | 2014-11-19 | 大连韦德生化科技有限公司 | 一种卡巴拉汀手性中间体及其制备方法 |
KR20160101554A (ko) * | 2015-02-17 | 2016-08-25 | (주)아모레퍼시픽 | N-[4-(1-아미노에틸)-페닐]-메탄술폰아미드 유도체의 카이랄 분할 방법 |
-
2017
- 2017-04-06 CN CN201710221159.XA patent/CN106905100B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1874992A (zh) * | 2003-10-28 | 2006-12-06 | 辉瑞产品公司 | 3-氨基烷基腈的拆分 |
CN101538242A (zh) * | 2009-04-27 | 2009-09-23 | 浙江工业大学 | 一种贝那普利关键中间体s-氨基物的合成方法 |
CN101613292A (zh) * | 2009-07-29 | 2009-12-30 | 上海医药(集团)有限公司 | (s)-3-(1-二甲氨基乙基)苯酚的制备方法 |
CN102329241A (zh) * | 2011-09-09 | 2012-01-25 | 诚达药业股份有限公司 | 1,2-环己二胺的化学拆分方法 |
CN104151176A (zh) * | 2014-08-29 | 2014-11-19 | 大连韦德生化科技有限公司 | 一种卡巴拉汀手性中间体及其制备方法 |
KR20160101554A (ko) * | 2015-02-17 | 2016-08-25 | (주)아모레퍼시픽 | N-[4-(1-아미노에틸)-페닐]-메탄술폰아미드 유도체의 카이랄 분할 방법 |
Non-Patent Citations (1)
Title |
---|
刘宏民主编: "《药物合成技巧与策略》", 31 December 2016 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110256261A (zh) * | 2019-02-20 | 2019-09-20 | 常州大学 | 一种用于制备左旋2-氨基-1-丁醇的手性拆分方法 |
CN110256261B (zh) * | 2019-02-20 | 2022-06-24 | 常州大学 | 一种用于制备左旋2-氨基-1-丁醇的手性拆分方法 |
CN111763150A (zh) * | 2019-12-27 | 2020-10-13 | 上虞京新药业有限公司 | 一种手性盐酸舍曲林的制备方法 |
CN111763150B (zh) * | 2019-12-27 | 2024-03-08 | 上虞京新药业有限公司 | 一种手性盐酸舍曲林的制备方法 |
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Address after: 317016 No.3, Donghai 8th Avenue, linhaitoumengang New District, Taizhou City, Zhejiang Province Patentee after: Lianhua Angjian (Zhejiang) Pharmaceutical Co.,Ltd. Country or region after: China Address before: 317016 south end of Nanyang 1st Road, medical and chemical park, Duqiao Town, Linhai City, Taizhou City, Zhejiang Province Patentee before: LIANHE CHEMICAL TECHNOLOGY (TAIZHOU) Co.,Ltd. Country or region before: China |
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