CN116589383A - 一种沙库比曲中间体的制备工艺 - Google Patents
一种沙库比曲中间体的制备工艺 Download PDFInfo
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- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical class CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
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- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- 239000004299 sodium benzoate Substances 0.000 claims description 3
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- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 3
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- 235000010334 sodium propionate Nutrition 0.000 claims description 3
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- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
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- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
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- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
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- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
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- YDNMHDRXNOHCJH-UHFFFAOYSA-N 3-aminopyrrolidine-2,5-dione Chemical compound NC1CC(=O)NC1=O YDNMHDRXNOHCJH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000736026 Sarcandra Species 0.000 description 1
- -1 Tributyl phosphine Carbon tetrachloride Chemical compound 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
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- YVWGMAFXEJHFRO-UHFFFAOYSA-N halopropane Chemical compound FC(F)C(F)(F)CBr YVWGMAFXEJHFRO-UHFFFAOYSA-N 0.000 description 1
- 229950000188 halopropane Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 229960004699 valsartan Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
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- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
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- C07C67/00—Preparation of carboxylic acid esters
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
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Abstract
本发明公开了一种沙库比曲中间体的制备工艺,以4‑卤代联苯和(R)‑环氧卤代丙烷为原料对接,接入酯基,发生Appel反应将羟基卤代,再经过氨化,接入Boc保护基等步骤,最终合成沙库比曲中间体;本发明的制备方法与已有方法比,工序更简单,反应更容易,并且降低了原料成本。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种沙库比曲中间体的制备工艺。
背景技术
沙库必曲是一种NEP抑制剂,IC50值为5nM,是治疗心力衰竭药物LCZ696的一个组分,可以与缬沙坦联合使用的抗高血压药物,其制备过程中的一个重要中间体结构式如下:
专利CN105026361中报道一种制备方法,主要步骤如下:
该方法在构建氨基过程中丁二酰亚胺会与氯原子反应对接,形成杂质,造成产品收率纯度下降,有一定缺陷。
发明内容
为解决上述问题,本发明公开了一种沙库比曲中间体的制备工艺,以4-卤代联苯和(R)-环氧卤代丙烷为原料对接,接入酯基,发生Appel反应将羟基卤代,再经过氨化,接入Boc保护基等步骤,最终合成沙库比曲中间体;本发明引用酯基保护端位羟基,减少端位氨基杂质的产生,三废排放少,对环境友好,同时利用Appel反应构建特定目标手性中心原子,再通过氨取代卤素,简单条件下获得目标产物,反应条件条件更温和,生产成本低。
为达到上述目的,本发明的技术方案如下:
一种沙库比曲中间体的制备工艺,其合成路线如下:
其中:X、Y、Z是卤素,R是H或C1~C7的烷基或芳基。
具体制备步骤如下:
(1)以4-卤代联苯与(R)-环氧卤代丙烷为原料,通过格式反应合成化合物1;
(2)将步骤(1)制得的化合物1与烷基酸盐对接酯化合成化合物2;
(3)将步骤(2)制得的化合物2发生Appel反应将羟基卤代合成化合物3;
(4)将步骤(3)制得的化合物3再通过氨化合成化合物4;
(5)将步骤(4)制得的化合物4通过Boc酸酐保护氨基合成化合物5。
作为本发明的一种改进,所述步骤(1)中,4-卤代联苯与环氧卤代丙烷的摩尔比为1:1~2,格式反应的催化剂为卤代亚铜。
作为本发明的一种改进,所述步骤(2)中,烷基酸盐为乙酸钠、乙酸钾、丙酸钠、丙酸钾、丁酸钠、苯甲酸钠、苯甲酸钾中的任一种。
作为本发明的一种改进,所述步骤(2)中,化合物1与烷基酸盐的摩尔比为1:1~1.5。
作为本发明的一种改进,所述步骤(3)中,化合物2、有机膦、卤化碳的摩尔比为1:1~3:1~3。
作为本发明的一种改进,所述步骤(3)中,Appel反应在有机膦和卤化碳存在下反应。
作为本发明的一种改进,所述步骤(3)中Appel反应的有机膦试剂为三苯基膦、三丁基膦、三乙基膦中的任一种,卤化碳为四氯化碳或四溴化碳。
作为本发明的一种改进,所述步骤(4)中,化合物3与氨气的摩尔比为1:1~3。
作为本发明的一种改进,所述步骤(5)中,化合物4与Boc酸酐的摩尔比为1:1~2。
本发明的有益效果为:
(1)本发明引入引用酯基保护端位羟基,减少端位氨基杂质的产生,三废排放少,对环境友好。
(2)本发明利用Appel反应构建特定目标手性中心原子,再通过氨取代卤素,简单条件下获得目标产物。
实施方式
下面结合具体实施方式,进一步阐明本发明,应理解下述具体实施方式仅用于说明本发明而不用于限制本发明的范围。
实施例1:化合物1的合成
向反应器中加入11.6g 0.05mol 4-溴联苯、28.8g 1.2mol镁粉与50mL四氢呋喃搅拌混合,加入0.1g碘粒引发,补加200mL四氢呋喃。控温40~45℃,向反应器中滴加221.4g0.95mol 4-溴联苯和300mL四氢呋喃混合溶液,滴加完毕后保温反应3h。反应结束后,降温至0℃,加入2g碘化亚铜,降温至-15~-10℃,滴加92.5g 1mol(R)-环氧氯丙烷和100mL四氢呋喃混合溶液,保温反应2h。
反应结束,升至室温,向反应液中加入4M盐酸调酸,体系分层,有机相回收溶剂,向残余物中加入乙醇和水重结晶,干燥后得到化合物1(231g,0.936mol),收率93.6%。
实施例2:化合物2的合成
向反应器中依次投入123.4g 0.5mol化合物1、6g三乙胺,加入300mL乙醇搅拌溶解,向体系中加入200mL 45.1g 0.55mol乙酸钠的水溶液,升温至65~70℃搅拌反应1h。
反应结束后,向体系中加入300mL乙酸乙酯萃取两次,加300mL水洗涤有机层两次,有机层回收干溶剂后,得到化合物2(126g,0.466mol),收率93.2%。
实施例3:化合物3的合成
向反应器中投入121.65g 0.45mol化合物2,随后加入138.44g 0.9mol四氯化碳、236.06g0.9mol三苯基膦,再加入250mL乙腈搅拌混合,保持25~35℃,反应16h。
反应完全后减压回收干溶剂,向残余物中加入300mL乙醇,升温搅拌溶解,缓慢降至5~10℃,析晶3h,过滤干燥后得到化合物3(113.77g,0.394mol),收率87.6%。
实施例4:化合物4的合成
向反应器中加入153.28g 0.45mol 5%氨甲醇溶液,将250mL含有86.63g 0.3mol化合物3的甲醇溶液滴加到反应器中,0~5℃下搅拌反应2h。
反应结束后,减压浓缩干溶剂,加入200mL乙酸乙酯和200mL水,萃取分液后,再用200mL乙酸乙酯萃取水层,合并有机层,有机层减压回收干乙酸乙酯,得到化合物4(62.28g,0.274mol),收率91.2%。
实施例5:化合物5的合成
向反应器中加入58.83g 0.25mol化合物4、50g三乙胺、300mL四氢呋喃搅拌混合,再向其中分批加入65.47g 0.3mol(Boc)2O,保持40~45℃,搅拌反应4小时。
向体系中加入200mL水,搅拌洗涤3次,有机层减压回收干,向残余物中加入150mL乙醇,升温至全溶,降温至0~5℃,搅拌析晶2小时,过滤后滤饼干燥,得到化合物5(78.58g,0.24mol),收率96%。
实施例6-8:化合物1的合成
其他条件同实施例1,改变4-卤代联苯与环氧卤代丙烷的不同摩尔比值,实施例1及实施例6-8的反应条件和收率详见表1。
表1实施例1、实施例6-8不同条件与结果
实施例 | 4-卤代联苯:环氧卤代丙烷 | 总收率/% |
1 | 1:1 | 93.6 |
6 | 1:2 | 92.5 |
7 | 1:2.5 | 88.3 |
8 | 1:0.8 | 74.6 |
实施例9-12:化合物2的合成
其他条件同实施例2,改变化合物1与烷基酸盐的摩尔比以及烷基酸盐的种类,实施例2及实施例9-12的反应条件和收率详见表2。
表2实施例2、实施例9-12的不同条件与结果
实施例 | 化合物1:烷基酸盐 | 烷基酸盐种类 | 总收率/% |
2 | 1:1.1 | 乙酸钠 | 93.2 |
9 | 1:1 | 乙酸钠 | 92.9 |
10 | 1:1.5 | 乙酸钠 | 92.4 |
11 | 1:1.1 | 丙酸钠 | 86.9 |
12 | 1:1.1 | 苯甲酸钠 | 88.3 |
实施例13-16:化合物3的合成
其他条件同实施例3,改变化合物2、有机膦、卤化碳的摩尔比以及有机膦种类、卤化碳的种类(R为甲基),实施例3及实施例13-16的反应条件和收率详见表3。
表3实施例3、实施例13-16的不同条件与结果
实施例 | 化合物1:有机膦:卤化碳 | 有机膦种类 | 卤化碳种类 | 收率/% |
3 | 1:2:2 | 三苯基膦 | 四氯化碳 | 87.6 |
13 | 1:1:1 | 三苯基膦 | 四氯化碳 | 85.3 |
14 | 1:3:3 | 三苯基膦 | 四氯化碳 | 86.9 |
15 | 1:2:2 | 三丁基膦 | 四氯化碳 | 84.3 |
16 | 1:2:2 | 三苯基膦 | 四溴化碳 | 85.7 |
实施例17-18:化合物4的合成
其他条件同实施例4,改变化合物3与氨气的摩尔比(R为甲基,Z为Cl),实施例4与实施例17-18的反应条件和结果详见表4。
表4实施例4、实施例17-18的不同条件与结果
实施例 | 化合物3:氨气 | 收率/% |
4 | 1:1.5 | 91.2 |
17 | 1:1 | 89.3 |
18 | 1:3 | 88.6 |
实施例19-20:化合物5的合成
其他条件同实施例5,改变化合物4与Boc酸酐的摩尔比,实施例5与实施例19-29的反应条件和结果详见表5。
表5实施例5、实施例19-20的不同条件与结果
实施例 | 化合物4:Boc酸酐 | 收率/% |
5 | 1:1.2 | 96 |
19 | 1:1 | 94.4 |
20 | 1:2 | 94.7 |
需要说明的是,上述仅仅是本发明的较佳实施例,并非用来限定本发明的保护范围,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,在上述实施例的基础上还可以做出若干改进和润饰,这些改进和润饰均落入本发明权利要求书的保护范围之内。
Claims (9)
1.一种沙库比曲中间体的制备工艺,其特征在于,包括以下步骤:
(1)以4-卤代联苯与(R)-环氧卤代丙烷为原料,通过格式反应合成化合物1;
(2)将步骤(1)制得的化合物1与烷基酸盐对接酯化合成化合物2;
(3)将步骤(2)制得的化合物2发生Appel反应将羟基卤代合成化合物3;
(4)将步骤(3)制得的化合物3再通过氨化合成化合物4;
(5)将步骤(4)制得的化合物4通过Boc酸酐保护氨基合成化合物5;
其中:X、Y、Z是卤素,R是H或C1~C7的烷基或芳基。
2.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(1)中,4-卤代联苯与环氧卤代丙烷的摩尔比为1:1~2,格式反应的催化剂为卤代亚铜。
3.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(2)中,烷基酸盐为乙酸钠、乙酸钾、丙酸钠、丙酸钾、丁酸钠、苯甲酸钠、苯甲酸钾中的任一种。
4.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(2)中,化合物1与烷基酸盐的摩尔比为1:1~1.5。
5.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(3)中,化合物2、有机膦、卤化碳的摩尔比为1:1~3:1~3。
6.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(3)中,Appel反应在有机膦和卤化碳存在下反应。
7.根据权利要求6所述的一种沙库比曲中间体的制备工艺,其特征在于:所述有机膦试剂为三苯基膦、三丁基膦、三乙基膦中的任一种,所述卤化碳为四氯化碳或四溴化碳。
8.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(4)中,化合物3与氨气的摩尔比为1:1~3。
9.根据权利要求1所述的一种沙库比曲中间体的制备工艺,其特征在于:所述步骤(5)中,化合物4与Boc酸酐的摩尔比为1:1~2。
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