阅读说明：本技术 异喹啉化合物的制备方法及其中间体 (The Preparation Method And Their Intermediate of isoquinoline compound ) 是由 郑旭春 张一平 于 2018-05-24 设计创作，主要内容包括：本发明公开了异喹啉化合物的制备方法及其中间体,所述的异喹啉化合物为罗沙司他,其中间体为化合物式2,本发明一化合物式2为原料发展了罗沙司他关键中间体9的两种新制备方法。方法一将化合物2与盐酸羟胺反应得到中间体化合物式3,再与膦试剂化合物式4反应得到罗沙司他关键中间体化合物式9；方法2将化合物式2制成酰氯后与氨基丙二酸酯衍生物7经缩合、脱羧反应后得到化合物式8,最后再得到关键中间体式9。两种方法收率较高而且避免了使用贵金属催化,极大地提高了路线效率,并降低了工艺成本,而且减少了副产物的生成,利于提高最终成品纯度；该路线操作简单,不仅总收率较高,得到的产品纯度也较高,适合放大生产,路线为：<Image he="347" wi="700" file="RE-DDA0001855388170000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(The invention discloses the Preparation Method And Their Intermediate of isoquinoline compound, the isoquinoline compound be Luo Shasi he, wherein mesosome is Formula 2, and an of the invention Formula 2 is two kinds of new preparation process that raw material has developed his key intermediate 9 of Luo Shasi.Method one reacts compound 2 with hydroxylamine hydrochloride to obtain intermediate compound of formula 3, then reacts with phosphonate reagent Formula 4 to obtain his key intermediate compound formula 9 of Luo Shasi；Formula 2 is made after acyl chlorides and obtains Formula 8 after condensation, decarboxylic reaction with amidomalonic acid ester derivant 7 by method 2, finally obtains key intermediate formula 9 again.Two methods yield is higher and avoids using precious metal catalyst, greatly improves route efficiency, and reduce process costs, and reduces the generation of by-product, is conducive to improve final finished purity；The route is easy to operate, and not only total recovery is higher, and obtained product purity is also higher, is suitble to amplification production, route are as follows: 。)

1. a kind of his key intermediate compound formula 2 of Luo Shasi, structure is as follows:

2. the preparation method of his intermediate compound of formula 2 of Luo Shasi as described in claim 1, it is characterised in that including walking as follows It is rapid:

Formula 1 is directly reacted to obtain Formula 2 with methyl Grignard；

3. the preparation method of his intermediate compound of formula 2 of Luo Shasi as claimed in claim 2, it is characterised in that in the step Methyl Grignard is selected from methyl-magnesium-chloride or methyl-magnesium-bromide；Reaction dissolvent is selected from methylene chloride, tetrahydrofuran, 2- methyl four Hydrogen furans or toluene；Reaction temperature is generally at -20~30 DEG C.

4. the preparation side of his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid ester compounds 9 of sieve sauce Method, it is characterised in that include the following steps:

(1) by Formula 2, in hydroxylamine hydrochloride, the reaction under alkali effect obtains intermediate formula 3；

(2) it is reacted Formula 3 and phosphonate reagent Formula 4 to obtain Formula 9；

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl.

5. his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin carboxylic of sieve sauce according to claim 4 The preparation method of ester compound 9, it is characterised in that in the reaction of the step (1), the alkali used be potassium carbonate, sodium carbonate, Potassium hydroxide or sodium hydroxide inorganic base；Reaction dissolvent selects methanol, ethyl alcohol, isopropanol, acetone, methylene chloride, bis- chloroethene of 1,2- Alkane, tetrahydrofuran, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；Reaction temperature is 0~110 DEG C.

6. his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin carboxylic of sieve sauce according to claim 4 The preparation method of ester compound 9, it is characterised in that in the reaction of the step (2), selection alkali is triethylamine, diisopropyl second Amine, pyridine, 2,6- lutidines, DBU or potassium tert-butoxide；The reaction dissolvent selected is N,N-dimethylformamide, N, N- bis- Methylacetamide, N-Methyl pyrrolidone, DMPU, toluene, dimethylbenzene or chlorobenzene；Reaction temperature is generally at 50~150 DEG C.

7. the preparation side of his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid ester compounds 9 of sieve sauce Method, it is characterised in that include the following steps:

(1) compound 2 is reacted to obtain chloride compounds formula 6 with acylating reagent under N,N-dimethylformamide catalysis；

(2) chloride compounds formula 6 and Formula 7 are condensed, decarboxylic reaction obtains Formula 8；

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl；PG indicates amino protecting group, including but not It is only limitted to acetyl group, Boc, Cbz or p-toluenesulfonyl；

(3) Formula 8 is obtained into key intermediate compound 9 under acid or alkali effect；

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl；PG indicates amino protecting group, including but not It is only limitted to acetyl group, Boc, Cbz or p-toluenesulfonyl.

8. his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin carboxylic of sieve sauce according to claim 7 The preparation method of ester compound 9, it is characterised in that in the reaction of the step (1), acylating reagent is selected from phosphorus oxychloride, chlorination Sulfoxide or oxalyl chloride；The reaction dissolvent selected is methylene chloride, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran or toluene；Reaction Temperature is generally at 0~120 DEG C.

9. his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin carboxylic of sieve sauce according to claim 7 The preparation method of ester compound 9, it is characterised in that it is triethylamine, N that alkali is selected in the condensation reaction of the step (2), and N- bis- is different Propylethylamine or DBU；Selective chlorination magnesium is as additive；The reaction dissolvent selected is methylene chloride, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran or toluene；Reaction temperature is selected from -30~110 DEG C.

10. his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin carboxylic of sieve sauce according to claim 7 The preparation method of ester compound 9, it is characterised in that in the reaction of the step (3), selecting acid is hydrochloric acid, trifluoroacetic acid or right Toluenesulfonic acid, the alkali of selection are potassium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide；The reaction dissolvent selected is methanol, ethyl alcohol, Isopropanol, methylene chloride, 1,2- dichloroethanes, tetrahydrofuran or toluene；Reaction temperature is generally at -10~110 DEG C.

Technical field

The invention belongs to field of medicine and chemical technology, and in particular to different for treating chronic anaemia drug sieve sauce key intermediate The preparation method of quinoline acid compound and related intermediate.

Background technique

Luo Shasi his (Roxadustat, FG-4592) is small point of a kind of hypoxia inducible factor (HIF) prolyl hydroxylase Sub- inhibitor oral medication.The medicine be by Fei Buluogen company, the U.S. research and develop, after authorized by Astellas and AstraZeneca License, in III clinical trial phase is being carried out at present, for treating chronic kidney disease and the relevant anemia effect of end-stage renal disease Fruit is significant, great market prospects.

His chemical name of Luo Shasi are as follows: N- [(4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin) carbonyl] glycine, structure Formula is as follows:

PCT Patent WO2004108681A reports his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- of Luo Shasi Isoquinolinecarboxylic acid's tert-butyl ester and his synthetic route of Luo Shasi is prepared by the intermediate:

Yuan Yan company international monopoly WO2014014834A also improves his synthetic route of Luo Shasi, utilizes isoquinolin ring Intermediate and tetramethylmethane diamine reactant, then substitution reaction is completed with acetate, then palladium carbon adds hydrogen to complete isoquinolin ring again Methylation reaction obtain his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid's methyl esters of Luo Shasi, most Ammonolysis reaction, which is carried out, with glycine afterwards obtains product.

On the whole, the key for synthesizing his method of Luo Shasi is how quickly to prepare key intermediate 4- hydroxyl -1- Methyl -7- phenoxy group -3- isoquinolinecarboxylic acid's ester, but existing method general route is too long, and total recovery is low, in step on isoquinolin Introduce methyl to require using noble metal catalyst, the amplification of higher cost technique is difficult, it is still desirable to find process route it is simple, Method that is low in cost, being suitable for industrialized production.

Summary of the invention

In view of the deficiencies of the prior art, it is used to prepare the object of the present invention is to provide a kind of for his intermediate 2- of Luo Shasi His key intermediate isoquinoline compound 4- hydroxyl -1- methyl -7- of acetyl group -4- phenoxy benzoic acid compound 2 and Luo Shasi Two kinds of preparation methods of phenoxy group -3- isoquinolinecarboxylic acid ester compounds 9, preparation process route of the invention is simple, it is low in cost, It is suitable for industrialized production.

To realize goal of the invention, the invention adopts the following technical scheme:

The present invention provides a kind of his key intermediate compound formulas 2 of Luo Shasi, and structure is as follows:

The preparation method of his intermediate compound of formula 2 of Luo Shasi, includes the following steps:

Formula 1 is directly reacted to obtain Formula 2 with methyl Grignard；

Preferably, methyl Grignard is selected from methyl-magnesium-chloride or methyl-magnesium-bromide in the step；Reaction dissolvent choosing From methylene chloride, tetrahydrofuran, 2- methyltetrahydrofuran or toluene；Reaction temperature is generally at -20~30 DEG C.

The present invention also provides his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid's esters of Luo Shasi Two kinds of preparation methods of compound 9.

Method one, his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid ester compounds 9 of Luo Shasi Preparation method, include the following steps:

(1) by Formula 2, in hydroxylamine hydrochloride, the reaction under alkali effect obtains intermediate formula 3；

(2) it is reacted Formula 3 and phosphonate reagent Formula 4 to obtain Formula 9:

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl.

Preferably, the alkali used is potassium carbonate, sodium carbonate, potassium hydroxide or hydroxide in the reaction of the step (1) The inorganic bases such as sodium；Reaction dissolvent selects methanol, ethyl alcohol, isopropanol, acetone, methylene chloride, 1,2- dichloroethanes, tetrahydrofuran, N, Dinethylformamide or DMAC N,N' dimethyl acetamide etc.；Reaction temperature is 0~110 DEG C.

Preferably, selection alkali is triethylamine, diisopropylethylamine, pyridine, 2,6- bis- in the reaction of the step (2) The alkali such as picoline, DBU or potassium tert-butoxide；The reaction dissolvent selected is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, DMPU, toluene, dimethylbenzene or chlorobenzene etc.；Reaction temperature is generally at 50~150 DEG C.

Method two, his key intermediate 4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolinecarboxylic acid ester compounds 9 of Luo Shasi Preparation method, include the following steps:

(1) compound 2 is reacted to obtain chloride compounds formula 6 with acylating reagent under N,N-dimethylformamide catalysis:

(2) chloride compounds formula 6 and Formula 7 are condensed, decarboxylic reaction obtains Formula 8:

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl；PG indicates amino protecting group, including But it is not limited only to acetyl group, Boc, Cbz or p-toluenesulfonyl.

(3) Formula 8 is obtained into key intermediate compound 9 under acid or alkali effect:

Wherein, R¹It indicates alkyl, includes but are not limited to methyl, ethyl or tert-butyl；PG indicates amino protecting group, including But it is not limited only to acetyl group, Boc, Cbz or p-toluenesulfonyl.

Preferably, acylating reagent is selected from phosphorus oxychloride, thionyl chloride or oxalyl chloride in the reaction of the step (1)；Choosing The reaction dissolvent selected is methylene chloride, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran or toluene etc.；Reaction temperature generally 0~ 120℃。

Preferably, it is triethylamine, n,N-diisopropylethylamine or DBU etc. that alkali is selected in the condensation reaction of the step (2)； Selective chlorination magnesium is as additive；The reaction dissolvent selected is methylene chloride, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran or Toluene etc..Reaction temperature is selected from -30~110 DEG C.

Preferably, selecting acid is hydrochloric acid, trifluoroacetic acid or p-methyl benzenesulfonic acid etc. in the reaction of the step (3), select Alkali be potassium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide etc.；The reaction dissolvent selected is methanol, ethyl alcohol, isopropanol, dichloro Methane, 1,2- dichloroethanes, tetrahydrofuran or toluene etc.；Reaction temperature is generally at -10~110 DEG C.

The present invention is to be with 4- phenoxy group phthalic anhydride formula 1 about the preparation method of his key intermediate 2 of Luo Shasi Starting material obtains intermediate compound of formula 2 after directly reacting with methyl Grignard.With 2 for raw material developed Luo Shasi he Two kinds of new preparation process of key intermediate 8.Method one reacts compound 2 with hydroxylamine hydrochloride to obtain intermediate compound of formula 3, React to obtain his key intermediate compound formula 9 of Luo Shasi with phosphonate reagent Formula 4 again；Acyl is made in Formula 2 by method 2 Formula 8 is obtained after condensation, decarboxylic reaction with amidomalonic acid ester derivant 7 after chlorine, finally obtains key intermediate again Formula 9.Two methods yield is higher and avoids using precious metal catalyst, greatly improves route efficiency, and reduce work Skill cost, and reduce the generation of by-product, it is conducive to improve final finished purity；The route is easy to operate, not only total recovery Higher, obtained product purity is also higher, is suitble to amplification production, route are as follows:

Specific embodiment

It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation Example.