WO2017050092A1 - 一种制备奥当卡替中间体的方法 - Google Patents

一种制备奥当卡替中间体的方法 Download PDF

Info

Publication number
WO2017050092A1
WO2017050092A1 PCT/CN2016/097172 CN2016097172W WO2017050092A1 WO 2017050092 A1 WO2017050092 A1 WO 2017050092A1 CN 2016097172 W CN2016097172 W CN 2016097172W WO 2017050092 A1 WO2017050092 A1 WO 2017050092A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
metal
chloride
borohydride
Prior art date
Application number
PCT/CN2016/097172
Other languages
English (en)
French (fr)
Inventor
毛晖
陈国财
孙绍光
黄金昆
Original Assignee
江苏恒瑞医药股份有限公司
成都盛迪医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 成都盛迪医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201680003839.8A priority Critical patent/CN107001250B/zh
Publication of WO2017050092A1 publication Critical patent/WO2017050092A1/zh

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00Preparation of carboxylic acid nitriles
    • C07C253/30Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00Carboxylic acid nitriles
    • C07C255/45Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63Esters of sulfonic acids
    • C07C309/72Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/76Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton

Definitions

  • the present invention relates to a process for the preparation of an intermediate for the preparation of octopine.
  • Odantate ((2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[ 4'-(Methylsulfonyl)[1,1'-biphenyl]-4-yl]ethyl]amino]pentanamide, as shown in the following formula V) is a cathepsin K inhibitor, the indication of which is Osteoporosis in postmenopausal women. Its mechanism of action is to inhibit the activity of cathepsin K, thereby reducing bone resorption, improving bone density, and exerting anti-osteoporosis effects.
  • Odantine intermediate carboxylic acid dicyclohexylamine salt and 1-aminocyclopropane carbonitrile hydrochloride in N, N-dimethyl amide solution, EDCI as a coupling agent, pyridine as a base, The HOBT is used as an activator, and the condensation reaction gives Odantine (V).
  • CN1993314A describes in detail the synthesis technology of the middle-alloy carboxylic acid dicyclohexylamine salt of Odantine:
  • the intermediate of the imine carboxylate is not separated, and the metal borohydride prepared in an ether solvent is reduced to obtain an octacalcic intermediate carboxylic acid.
  • the metal borohydrides are calcium borohydride, magnesium borohydride, zinc borohydride and zirconium borohydride.
  • the ether solvent is tetrahydrofuran, diethyl ether, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dimethoxyethane or a mixture thereof.
  • the crystal of the octacarboxylate intermediate carboxylic acid in dimethylhexylamine in methyl tert-butyl ether solvent gives the Oducciti intermediate carboxylic acid dicyclohexylamine salt.
  • CN1993314A claims that reduction of the imine carboxylate by this method can result in higher levels of chiral isomers of the desired configuration for the preparation of octopine, whereas in practice the chirality of the desired configuration is prepared by this method.
  • the isomer content is low.
  • the method requires a preparation of a metal borohydride in an ether solvent, which is not only cumbersome to operate, but also requires a large amount of solvent to increase the amount of dissolution, and requires the addition of a co-solvent (for example, acetonitrile), so the solvent demand of the reaction is relatively high. Big.
  • a co-solvent for example, acetonitrile
  • the intermediate of the imine carboxylate is not separated, and is directly put into the next reaction, so that some impurities are brought into the subsequent reaction together, which makes the purification of the product more difficult.
  • zinc chloride is extremely easy to absorb water, and it is required to be carried out under anhydrous conditions in the preparation of borohydride, which is difficult to control at the time of amplification, making the preparation method difficult to apply to large-scale production.
  • the present invention relates to a process for the preparation of a compound of formula IA, comprising the step of reducing a compound of formula II to form a compound of formula IA,
  • the reduction is accomplished by adding a metal chloride and a metal borohydride to a solvent in which the compound of formula II is dissolved; wherein the metal chloride is selected from the group consisting of zinc chloride, calcium chloride, manganese chloride, magnesium chloride;
  • the metal borohydride is selected from the group consisting of lithium borohydride, sodium borohydride, and potassium borohydride;
  • M is an alkali metal, preferably selected from the group consisting of lithium, sodium, potassium, rubidium, and cesium.
  • Formula IA The compound can be used to further prepare Odakati.
  • the added metal chloride and metal borohydride are not treated in advance, for example, it is not necessary to first add the two to an ether solvent.
  • the metal chloride used in the present invention may be anhydrous or may be water with crystal water or may be metered in with water of crystallization.
  • the metal chloride and metal borohydride are added separately to the solvent.
  • the chloride is added first, followed by the metal borohydride.
  • the time interval between the addition of the metal chloride and the metal borohydride is from 5 minutes to 5 hours; preferably from 10 minutes to 2 minutes, more preferably from 15 minutes to 1 hour, most preferably 30 minutes.
  • the temperature of the reaction system is controlled to be 10 to 50 ° C, preferably 15 to 40 ° C, more preferably 20 to 40 ° C, most preferably 25 to 30 ° C; at this temperature for a while, then metal borohydride is added,
  • the system reaction temperature is controlled, for example, between -5 and 5 ° C according to the conditions described for the reduction.
  • the present invention utilizes an imide carboxylate to complexize with a metal chloride and then undergo a reductive amination reaction with a metal borohydride.
  • the solvent in which the compound of the formula II is dissolved is a C 1 -C 7 lower aliphatic alcohol, any one of acetonitrile or tetrahydrofuran or a combination thereof, preferably methanol, ethanol, isopropanol, more preferably methanol.
  • the preparation method of the present invention may further comprise the step of condensing a compound of the formula III with a compound of the formula IV to obtain a compound of the formula II,
  • R 1 is a C 1 -C 5 alkyl group
  • the condensation reaction can be carried out under basic conditions, and the basic medium can be potassium carbonate, potassium methoxide or potassium phosphate; preferably potassium carbonate.
  • the reaction solvent may be any one or a combination of methanol, ethanol, acetonitrile or tetrahydrofuran; methanol is preferred.
  • the reaction is carried out at a temperature of from 0 to 100 ° C; preferably at 50 ⁇ 5 ° C.
  • the present invention also relates to a process for the preparation of a compound of the formula IB or IB'. After the compound of the formula IA is prepared according to the aforementioned method, a salt is formed in an alkaline medium to give a formula IB or IB'.
  • the alkaline medium is selected from an inorganic base or an organic base selected from the group consisting of hydroxides, carbonates, and phosphates, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, and phosphoric acid. Potassium; the organic base is preferably selected from the group consisting of piperidine, morpholine, diethylamine, diisopropylamine, dicyclohexylamine, lower alkane-substituted pyridine, trimethylamine, triethylamine, tributylamine; more preferably diisopropylamine and More preferably, cyclohexylamine is dicyclohexylamine;
  • X in the formula IB is a metal ion in the inorganic base, and the metal ion is preferably selected from the group consisting of lithium, sodium, potassium, rubidium, and cesium;
  • X is the above-mentioned organic base.
  • the reaction can be carried out in a solvent selected from the group consisting of methyl tert-butyl ether, ethyl acetate, acetone, dichloromethane, cyclohexane, n-hexane and the like, preferably methyl tert-butyl ether.
  • the invention also provides a preparation method of octakatidine, which is prepared by the above method, and is obtained by condensation reaction with 1-aminocyclopropane carbonitrile hydrochloride to obtain Odarkate (Formula V).
  • the reaction can be carried out under the action of a base, an activator (or a coupling agent), which is DMF, DMAc, NMP, acetonitrile, THF or DMSO; preferably DMAc.
  • the base is N-methylmorpholine, TEA, DIPEA, 2,6-lutidine, 2,4,6-trimethylpyridine, 1-methylpiperidine, pyridine, etc.; DIPEA is preferred.
  • the activator is HATU, HBTU, TBTU, HOBT, etc.; preferably HATU.
  • the method of the invention has the advantages of short synthetic route, simple operation, easy separation and purification, low solvent dosage, low cost, safety and suitable for industrial production, and has significant social and economic benefits.
  • the invention solves the problem that zinc chloride is extremely easy to absorb water, and the main product obtained by the reductive amination reaction is the target product.
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • HBTU O-benzotriazole-tetramethylurea hexafluorophosphate

Abstract

提供一种制备奥当卡替的中间体式IA化合物的方法,包括将式II化合物还原生成式IA化合物的步骤,其中所述还原通过在溶解了式II化合物的溶剂中加入金属氯化物和金属硼氢化物来完成。该制备方法成本低,操作简单,易于产品的分离纯化。

Description

一种制备奥当卡替中间体的方法 技术领域
本发明涉及一种用于制备奥当卡替的中间体的制备方法。
背景技术
奥当卡替((2S)-N-(1-氰基环丙基)-4-氟-4-甲基-2-[[(1S)-2,2,2-三氟-1-[4‘-(甲基磺酰基)[1,1'-联苯]-4-基]乙基]氨基]戊酰胺,如下式V所示)是一种组织蛋白酶K抑制剂,其适应症为绝经后妇女骨质疏松症。其作用机制为抑制组织蛋白酶K的活性,从而降低骨质吸收,改善骨密度,发挥抗骨质疏松的作用。
Figure PCTCN2016097172-appb-000001
US2013331597中记载了奥当卡替的一种合成方法,包括以下步骤:
1)、以2,2,2-三氟-1-(4'-(甲基磺酰基)联苯-4-基)乙酮和4-氟-L-亮氨酸酯为原料,通过合成得到亚胺羧酸盐的中间体;
2)、以氯化锌和硼氢化钠在醚类溶剂中制备硼氢化锌,还原亚胺羧酸盐的中间体得到奥当卡替中间体羧酸,并与二环己胺成盐得到奥当卡替中间体羧酸二环己胺盐。
3)、奥当卡替中间体羧酸二环己胺盐和1-氨基环丙烷甲腈盐酸盐在N,N-二甲酰胺溶液中,以EDCI为偶联剂、以吡啶做碱,以HOBT做活化剂,缩合反应得到奥当卡替(V)。
CN1993314A详细记载了奥当卡替中间体羧酸二环己胺盐的合成技术:
1)、以2,2,2-三氟-1-(4'-(甲基磺酰基)联苯-4-基)乙酮(III)和4-氟-L-亮氨酸酯(IV)为原料,通过合成得到亚胺羧酸盐的中间体;
2)、亚胺羧酸盐的中间体不被分离,用在醚类溶剂中制备的金属硼氢化物还原得到奥当卡替中间体羧酸。其中的金属硼氢化物为硼氢化钙、硼氢化镁、硼氢化锌和硼氢化锆。醚类溶剂是四氢呋喃、乙醚、二异丙醚、二丁醚、甲基叔丁基醚、二甲氧基乙烷或它们的混合物。奥当卡替中间体羧酸在甲基叔丁基醚溶剂中与二环己胺成盐得到奥当卡替中间体羧酸二环己胺盐。
CN1993314A声称通过该方法还原亚胺羧酸盐可以得到较高含量的所需构型的手性异构体用于制备奥当卡替,然而实际上通过该方法制备得到所需构型的手性异构体含量较低。另外该方法所得到的的由于需要在醚类溶剂中制备金属硼氢化物,不仅操作十分烦琐,还需要大量溶剂增加溶解量,并需要加入助溶剂(例如乙腈),所以反应的溶剂需求量较大。同时,亚胺羧酸盐的中间体不被分离,直接投入下一步反应,使得一些杂质一起带入后续反应,加大产品纯化难度。另外,氯化锌极易容易吸水,而在制备硼氢化物的时候需在无水条件下进行,在放大的时候很难控制,使得其制备方法很难适用于大生产。
发明内容
为了克服现有技术的不足,本发明的目的在于提供一种简单、经济、安全的制备奥当卡替中间体羧酸或其盐的方法,适于工业化大规模生产。
本发明涉及一种制备式IA所示化合物的制备方法,包括式II化合物经还原生成式IA所示化合物的步骤,
Figure PCTCN2016097172-appb-000002
其中,所述还原通过在溶解了式II化合物的溶剂中加入金属氯化物和金属硼氢化物来完成;其中所述金属氯化物选自氯化锌、氯化钙、氯化锰、氯化镁;所述的金属硼氢化物选自硼氢化锂、硼氢化钠、硼氢化钾;M为碱金属,优选选自锂、钠、钾、铷、铯。所述的式IA化 合物可以用于进一步制备奥当卡替。
在该反应中,加入的金属氯化物和金属硼氢化物不需事先处理,例如,不需要先将二者加入到醚类溶剂中处理。
本发明中所使用的金属氯化物可以是无水的,也可以是带结晶水的或者按照结晶水定量加入水。
在本发明优选的实施方案中,所述金属氯化物和金属硼氢化物分开加入溶剂中。例如,先加入氯化物,然后加入金属硼氢化物。在本发明优选的实施方案中,加入金属氯化物和金属硼氢化物的时间间隔为5分钟至5小时;优选10分钟至2分钟,更优选15分钟至1小时,最优选30分钟。
加入金属氯化物后,控制反应体系温度10~50℃,优选15~40℃,更优选20~40℃,最优选25~30℃;在该温度下持续一段时间,再加入金属硼氢化物,根据还原所述的条件,再控制体系反应温度,例如-5~5℃之间。
按照前述方法的加入顺序,本发明利用亚胺羧酸盐与金属氯化物先络合反应,然后与金属硼氢化物进行还原氨化反应。
所述溶解了式II化合物的溶剂是C1-C7的低级脂肪醇,乙腈或四氢呋喃中的任一种或其组合,优选甲醇,乙醇,异丙醇,更优选甲醇。
本发明所述的制备方法还可包括式III化合物与式IV化合物缩合得到式II化合物的步骤,
Figure PCTCN2016097172-appb-000003
其中,R1为C1-C5烷基;
所述的缩合反应可以在碱性条件下进行,碱性介质可以是碳酸钾、甲醇钾或磷酸钾;优选碳酸钾。反应溶剂可以是甲醇,乙醇,乙腈或四氢呋喃的任一种或其组合;优选甲醇。所述的反应在温度在0-100℃进行;优选50±5℃进行。
本发明还涉及一种式IB或IB’化合物的制备方法,在根据前述方法制备得到IA所示化合物后,在碱性介质中成盐,得到式IB或IB’ 化合物,
Figure PCTCN2016097172-appb-000004
所述的碱性介质选自无机碱或有机碱,所述无机碱选自氢氧化物、碳酸盐、磷酸盐,优选氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾;有机碱优选选自哌啶,吗啡啉,二乙胺,二异丙胺,二环己胺,低级烷烃取代的吡啶,三甲胺,三乙胺,三丁胺;更优选二异丙胺和二环己胺更优选二环己胺;
其中,式IB中X为所述无机碱中的金属离子,所述金属离子优选选自锂、钠、钾、铷、铯;
式IB’中,X为所述的有机碱。
所述反应可以在溶剂中进行,溶剂选自甲基叔丁基醚、乙酸乙酯、丙酮、二氯甲烷、环己烷、正己烷等,优选甲基叔丁基醚。
本发明还提供了一种奥当卡替的制备方法,通过上述方法制备得到式IB或IB’化合物后,与1-氨基环丙烷甲腈盐酸盐缩合反应得到奥当卡替(式V)
Figure PCTCN2016097172-appb-000005
所述反应可在碱、活化剂(或加偶联剂)的作用下进行,所述的溶剂为DMF、DMAc、NMP、乙腈、THF或DMSO;优选DMAc。所述的碱为N-甲基吗啉、TEA、DIPEA,2,6-二甲基吡啶、2,4,6-三甲基吡啶、1-甲基哌啶、吡啶等;优选DIPEA。所述的活化剂为HATU、HBTU、TBTU、HOBT等;优选HATU。
本发明方法具有合成路线短,操作简单,易于分离和纯化,溶剂用量少,成本低、安全并适合工业化生产等特点,具有显著的社会效益和经济效益。本发明解决了氯化锌极易吸水的问题,且还原氨化反应得到的主产物是目标产物。
除非有相反陈述,在说明书和权利要求书中使用的英文缩写具有下述含义。
TEA:三乙胺
DMF:N,N-二甲基甲酰胺
DMAc:N,N-二甲基乙酰胺
NMP:N-甲基吡咯烷酮
THF:四氢呋喃
DMSO:二甲基亚砜
DIPEA:N,N-二异丙基乙胺
HATU:2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
HBTU:O-苯并三氮唑-四甲基脲六氟磷酸酯
TBTU:O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸
HOBT:1-羟基苯并三唑
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
MeOH:甲醇
K2CO3:无水碳酸钾
EA:乙酸乙酯
ZnCl2:无水氯化锌
NaBH4:硼氢化钠
LiBH4:硼氢化锂
MTBE:甲基叔丁基醚
DCHA:二环己胺
HCl:盐酸
具体实施方式
以下将结合具体实例详细地解释本发明,使得本专业技术人员更 全面地理解本专利,具体实例仅用于说明本发明的技术方案,并不以任何方式限定本发明。
实施例1:奥当卡替中间体(IA或IB’)
Figure PCTCN2016097172-appb-000006
步骤1)、制备亚胺羧酸盐中间体(II)
将2,2,2-三氟-1-(4’-(甲基磺酰基)联苯-4-基)乙酮(III)9.1g(26.2mmol,1eq)、4-氟-L-亮氨酸乙酯(IV)4.9g(27.5mmol,1.05eq)加入到甲醇中,搅拌溶解,加入9.0g(65.2mmol,2.5eq)无水碳酸钾。将反应体系加热至50±5℃反应4~5小时。冷却至25~30℃,滤去不溶物。滤液浓缩,残留物中加入乙酸乙酯100mL打浆1小时。过滤,滤饼用乙酸乙酯50mL洗涤,干燥得到亚胺羧酸盐中间体(黄色固体)13.7g。
步骤2)、制备奥当卡替中间体羧酸(IA)
实验条件A
将亚胺羧酸盐中间体(II)2.0g(4mmol,1eq)加入到20mL甲醇中,加入无水氯化锌1.1g(8mmol,2eq),25~30℃搅拌反应30分钟。反应体系降温至-5~0℃,加入硼氢化钠0.3g(8mmol,2eq),控制体系反应温度在-5~5℃之间反应2~3小时。1N盐酸淬灭反应,调节pH至1~2,乙酸乙酯萃取(20mL*2),饱和盐水洗涤(10mL*2),无水硫酸钠干燥。过滤,滤液浓缩得到产物奥当卡替中间体羧酸1.0g(收率54.1%)。
1HNMR:(CDCl3)
δ8.04(d,2H),7.78(d,2H),7.65(d,2H),7.53(d,2H),4.28(q,1H),3.65(dd,1H),3.11(s,3H),2.20(ddd,1H),1.99(ddd,1H),1.48(d,6H)。
MS(M+1):462.14;(S,S):(S,R)=77.6:22.4
实验条件B
将亚胺羧酸盐中间体(II)2.0g(4mmol,1eq)加入到20mL甲醇中,加入无水氯化锌1.1g(8mmol,2eq)以及水0.6g(33.3mmol,8eq),25~30℃搅拌反应30分钟。反应体系降温至-5~0℃,加入硼氢化钠0.6g(16mmol,4eq),控制体系反应温度在-5~5℃之间反应2~3小时。1N盐酸淬灭反应,调节pH至1~2,乙酸乙酯萃取(20mL*2),饱和盐水洗涤(10mL*2),无水硫酸钠干燥。过滤,滤液浓缩得到产物奥当卡替中间体羧酸1.1g(收率59.5%)。
MS(M+1):462.14;(S,S):(S,R)=78.0:22.0
实验条件C
将亚胺羧酸盐中间体(II)2.0g(4mmol,1eq)加入到20mL甲醇中,加入无水氯化锌1.1g(8mmol,2eq)以及水0.6g(33.3mmol,8eq),25~30℃搅拌反应30分钟。反应体系降温至-5~0℃,加入硼氢化锂0.4g(16mmol,4eq),控制体系反应温度在-5~5℃之间反应2~3小时。1N盐酸淬灭反应,调节pH至1~2,乙酸乙酯萃取(20mL*2),饱和盐水洗涤(10mL*2),无水硫酸钠干燥。过滤,滤液浓缩得到产物奥当卡替中间体羧酸1.2g(收率64.9%)。
MS(M+1):462.14;(S,S):(S,R)=84.2:15.8
步骤3)、制备奥当卡替中间体羧酸二环己胺盐(IB’)
将奥当卡替中间体羧酸1.1g(2.4mmol,1eq)溶于20mLMTBE中,加入二环己胺0.6g(3.3mmol,1.4eq),25~30℃搅拌反应2小时,析出白色固体。过滤,滤饼用MTBE洗涤,干燥得到奥当卡替中间体羧酸二环己胺盐1.0g(收率65.3%)。(S,S):(S,R)=94.1:5.9。
实施例2:制备奥当卡替(V)
Figure PCTCN2016097172-appb-000007
步骤1)、制备亚胺羧酸盐中间体(II)
将2,2,2-三氟-1-(4’-(甲基磺酰基)联苯-4-基)乙酮(III)41.8g(128mmol,1eq)、4-氟-L-亮氨酸乙酯(IV)23.7g(134mmol,1.05eq)加入到200mL甲醇中,搅拌溶解,加入44.0g(319mmol,2.5eq)无水碳酸钾。将反应体系加热至50±5℃反应4~5小时。冷却至25~30℃,滤去不溶物。滤液浓缩,残留物中加入乙酸乙酯1000mL打浆1小时。过滤,滤饼用乙酸乙酯200mL洗涤,干燥得到亚胺羧酸盐中间体(黄色固体)65.0g。
步骤2)、制备奥当卡替中间体羧酸(IA)
将亚胺羧酸盐中间体(II)65.0g(128mmol,1eq)加入到300mL甲醇中,加入无水氯化锌35.0g(256mmol,2eq)以及水18.4g(1.02mol,8eq),25~30℃搅拌反应30分钟。反应体系降温至-5~0℃,加入硼氢化锂11.3g(512mmol,4eq),控制体系反应温度在-5~5℃之间反应2~3小时。1N盐酸淬灭反应,调节pH至1~2,乙酸乙酯萃取(300mL*2),饱和盐水洗涤(100mL*2),无水硫酸钠干燥。过滤,滤液浓缩得到产物奥当卡替中间体羧酸38.4g(收率64.9%)。
步骤3)、制备奥当卡替中间体羧酸二环己胺盐(IB’)
将奥当卡替中间体羧酸(IA)38.0g(82.4mmol,1eq)溶于200mLMTBE中,加入二环己胺20.9g(115.4mmol,1.4eq),25~30℃搅拌反应2小时,析出白色固体。过滤,滤饼用MTBE洗涤,干燥得到奥当卡替中间体羧酸二环己胺盐34.0g(收率64.3%)。
步骤4)、制备奥当卡替(V)
将奥当卡替中间体羧酸二环己胺盐(IB’)34.0g(53.0mmol,1eq)与1-氨基环丙烷甲腈盐酸盐7.5g(63.6mmol,1.2eq)在150mL DMAc中搅拌溶解,加入HATU 24.2g(63.6mmol,1.2eq)。将体系降温至0~5℃,滴加DIPEA 20.5g(159mmol),维持体系温度在0~10℃。缓慢升温至室温反应3-4小时。反应完毕后将反应液加入到450mL水中,搅拌析出固体,过滤。滤饼用水洗涤,烘干得到22.8g奥当卡替粗品(收率82.0%)。
[根据细则91更正 09.09.2016] 
1HNMR(CD3OD):δ8.02(d,2H),7.92(d,2H),7.73(d,2H),7.54(d,2H),4.26(d,1H),3.46(t,1H),3.16(s,3H),1.95(m,2H),1.38(m,9H),0.96(dd,1H),0.78(dd,1H)。
13CNMR(DMSO-d6):
δ174.51,144.44,139.78,138.84,135.27,129.20,127.85,127.63,127.22,120.42,95.90,94.27,61.96,61.68,57.99,43.92,43.59,27.69,27.45,26.35,26.10,19.36,15.37,15.17。
MS(M+1):526.29。
由于已根据其特殊的实施方案描述了本发明,某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。

Claims (10)

  1. 一种式IA所示化合物的制备方法,包括式II化合物经还原生成式IA所示化合物的步骤,
    Figure PCTCN2016097172-appb-100001
    其中,所述还原通过在溶解了式II化合物的溶剂中加入金属氯化物和金属硼氢化物来完成;其中所述金属氯化物选自氯化锌、氯化钙、氯化锰、氯化镁;所述的金属硼氢化物选自硼氢化锂、硼氢化钠、硼氢化钾;M为碱金属,优选选自锂、钠、钾、铷、铯。
  2. 根据权利要求1所述的制备方法,其中所述金属氯化物为氯化锌,所述金属硼氢化物为硼氢化锂;优选所述氯化锌为无水氯化锌。
  3. 根据权利要求1所述的制备方法,其中所述金属氯化物和金属硼氢化物分开加入溶剂中。
  4. 根据权利要求3所述的制备方法,其特征在于先加入氯化物,然后加入金属硼氢化物。
  5. 根据权利要求3或4所述的制备方法,其特征在于加入金属氯化物和金属硼氢化物的时间间隔为5分钟至5小时;优选10分钟至2小时,更优选15分钟至1小时,最优选30分钟。
  6. 根据权利要求4所述的制备方法,其特征在于加入氯化物和金属硼氢化物的时间间隔内,控制反应体系温度10~50℃,优选15~40℃,更优选20~40℃,最优选25~30℃。
  7. 根据权利要求1所述的制备方法,其特征在于所述溶剂是选自C1-C7的低级脂肪醇,乙腈或四氢呋喃中的任一种或其组合,优选甲醇,乙醇,异丙醇,更优选甲醇。
  8. 根据权利要求1所述的制备方法,其特征在于还包括式III化合物与式IV化合物缩合得到式II化合物的步骤,
    Figure PCTCN2016097172-appb-100002
    其中,R1为C1-C5烷基。
  9. 一种式IB或IB’化合物的制备方法,其特征在于通过权利要求1-8任意一项所述的制备方法制备得到IA所示化合物后,在碱性介质中成盐,得到式IB或IB’化合物
    Figure PCTCN2016097172-appb-100003
    所述的碱性介质选自无机碱或有机碱,所述无机碱选自氢氧化物、碳酸盐、磷酸盐,优选氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾;有机碱优选选自哌啶,吗啡啉,二乙胺,二异丙胺,二环己胺,低级烷烃取代的吡啶,三甲胺,三乙胺,三丁胺;更优选二异丙胺和二环己胺更优选二环己胺;
    其中,式IB中X为所述无机碱中的金属离子,所述金属离子优选选自锂、钠、钾、铷、铯;
    式IB’中,X为所述的有机碱。
  10. 一种奥当卡替的制备方法,其特征在于,通过权利要求9所 述的制备方法制备得到式IB或IB’化合物后,与1-氨基环丙烷甲腈盐酸盐缩合反应得到奥当卡替;优选所述综合反应在在溶剂中,碱、活化剂的作用下进行,所述的溶剂选自DMF、DMAc、NMP、乙腈、THF或DMSO;优选DMAc;所述的碱选自N-甲基吗啉、TEA、DIPEA,2,6-二甲基吡啶、2,4,6-三甲基吡啶、1-甲基哌啶、吡啶,优选DIPEA;所述的活化剂选自HATU、HBTU、TBTU、HOBT,优选HATU。
PCT/CN2016/097172 2015-09-23 2016-08-29 一种制备奥当卡替中间体的方法 WO2017050092A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680003839.8A CN107001250B (zh) 2015-09-23 2016-08-29 一种制备奥当卡替中间体的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510614170.3 2015-09-23
CN201510614170 2015-09-23

Publications (1)

Publication Number Publication Date
WO2017050092A1 true WO2017050092A1 (zh) 2017-03-30

Family

ID=58385832

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/097172 WO2017050092A1 (zh) 2015-09-23 2016-08-29 一种制备奥当卡替中间体的方法

Country Status (3)

Country Link
CN (1) CN107001250B (zh)
TW (1) TW201711993A (zh)
WO (1) WO2017050092A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108912020A (zh) * 2018-06-05 2018-11-30 上海博志研新药物技术有限公司 奥当卡替及其中间体的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108558699A (zh) * 2018-04-28 2018-09-21 杭州师范大学 一种骨质疏松新药奥丹卡替关键中间体动态动力学拆分合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1993314A (zh) * 2004-08-04 2007-07-04 默克公司 非对映异构选择性还原胺化方法
WO2012148555A1 (en) * 2011-03-02 2012-11-01 Merck Sharp & Dohme Corp. Amidation process
US20120282267A1 (en) * 2011-05-02 2012-11-08 Virobay, Inc. Cathepsin inhibitors for the treatment of bone cancer and bone cancer pain
WO2015000076A1 (en) * 2013-07-02 2015-01-08 Alectos Therapeutics Inc. Photochemical process for the fluortnation of an organic compound having an unactivated sp3 c-h bond

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1922069A2 (en) * 2005-08-08 2008-05-21 Nitromed, Inc. Nitric oxide enhancing angiotensin ii antagonist compounds, compositions and methods of use
WO2015000108A1 (en) * 2013-07-01 2015-01-08 Mediatek Singapore Pte. Ltd. An improved texture merging candidate in 3dvc
CN113272545A (zh) * 2019-01-15 2021-08-17 V3科技有限公司 用于模块化放大风力发电系统的集成协同式多涡轮、多叶片阵列

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1993314A (zh) * 2004-08-04 2007-07-04 默克公司 非对映异构选择性还原胺化方法
WO2012148555A1 (en) * 2011-03-02 2012-11-01 Merck Sharp & Dohme Corp. Amidation process
US20120282267A1 (en) * 2011-05-02 2012-11-08 Virobay, Inc. Cathepsin inhibitors for the treatment of bone cancer and bone cancer pain
WO2015000076A1 (en) * 2013-07-02 2015-01-08 Alectos Therapeutics Inc. Photochemical process for the fluortnation of an organic compound having an unactivated sp3 c-h bond

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108912020A (zh) * 2018-06-05 2018-11-30 上海博志研新药物技术有限公司 奥当卡替及其中间体的制备方法

Also Published As

Publication number Publication date
TW201711993A (zh) 2017-04-01
CN107001250A (zh) 2017-08-01
CN107001250B (zh) 2018-12-21

Similar Documents

Publication Publication Date Title
CN111423452B (zh) 瑞卢戈利的中间体及其制备方法和应用
US11952341B2 (en) Method of preparing high chiral purity lactam intermediate and brivaracetam
JP2013532164A (ja) トロンビン特異的インヒビターを調製する方法
CA3061713C (en) Method for preparing intermediate of 4-methoxypyrrole derivative
WO2019019795A1 (zh) 一种沙库必曲中间体的制备方法
TW201311629A (zh) 用於製備前列腺素醯胺之新穎方法
TW201429924A (zh) 經精製之胺化合物的製造方法
CN103554031B (zh) 阿齐沙坦中间体的制备方法
WO2017050092A1 (zh) 一种制备奥当卡替中间体的方法
US8809581B2 (en) Method of making 6-aminocaproic acid as active pharmaceutical ingredient
CN110803980B (zh) 一锅法制备4-正丁基间苯二酚的方法
JP3440129B2 (ja) グルタミン誘導体の製造法
CN109836412A (zh) 一种甲磺酸达比加群酯的制备方法
CN111349045A (zh) 乐伐替尼的合成方法及新的中间体
JP6781030B2 (ja) L−カルノシン誘導体またはその塩、及びl−カルノシンまたはその塩の製造方法
CN105777581A (zh) 一种顺-1-腈基-4-甲氧基环己基-2-(2,5-二甲基苯基)乙酰胺及其制备方法和应用
CN109810052B (zh) 一种高选择性的阿帕替尼的简便制备方法
WO2015184798A1 (zh) N-取代苯基甘氨酸的制备方法
KR20150041280A (ko) 미티글리니드 칼슘 이수화물의 제조방법
CN102212034B (zh) 替米沙坦杂质b的制备方法
CN108658961A (zh) 一种阿齐沙坦的制备方法
CN112174798B (zh) 一种沙库巴曲缬沙坦钠lcz696的合成方法
WO2015163446A1 (ja) イミダゾール化合物の製造方法
JP4675234B2 (ja) 光学活性なキノロンカルボン酸誘導体の製造中間体およびその製造法
TWI565696B (zh) 2-Amino-6-methylnicotinic acid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16847974

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16847974

Country of ref document: EP

Kind code of ref document: A1