CN114014874B - Preparation method of Mabalo Sha Wei intermediate - Google Patents
Preparation method of Mabalo Sha Wei intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of a Ma Balo Sha Wei intermediate, which comprises the following steps: i. condensing the compound of the formula II with chiral acid to generate a compound A; recrystallizing and filtering the compound A to obtain a filter cake and a filtrate, wherein the filter cake is a compound B, and hydrolyzing to obtain a critical intermediate compound of the formula I of the Mabalo Sha Wei; and (3) preparing a compound of a formula II from the filtrate which is a mixture of the compound B and the compound C or the compound C, repeating the steps I and II, and obtaining a key intermediate of the compound of the formula I of the Ma-ba-Luo Sha Wei from a filter cake. After the steps are circularly repeated, the compound of the formula II can be almost completely converted into the compound of the formula I theoretically, the reaction is simple, the operation is convenient, and the stable process production can be realized.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a key intermediate of Ma Balo Sha Wei.
Background
Marbalo Sha Wei (Baloxavir marboxil, trade name: xofluza) was developed by salt wild and Roche together and was first batched in Japan in month 2 of 2018 and batched in the United states in month 10 of the same year. Until now, marballo Sha Wei has been approved in various countries and regions worldwide and in japan for the treatment of infections caused by influenza a or b viruses; in the United states, singapore, thailand, hong Kong, taiwan, etc., are used to treat patients with acute and uncomplicated influenza of 12 years and older with symptoms of no more than 48 hours.
The compounds of formula (I) are key intermediates in the synthesis of marbalo Sha Wei. The literature reports that compounds of formula (I) are mainly obtained by resolution of racemic compounds of formula (II).
For example, CN107709321A reports a compound of formula (II) (R 1 =benzyl: 7- (benzyloxy) -3,4,12 a-tetrahydro-1H- [1,4]Oxazino [3,4-c]Pyrido [2,1-f][1,2,4]Triazine-6, 8-dione) and (R) -tetrahydrofuran-2-formic acid to obtain a pair of diastereoisomeric compounds A, and recrystallizing the compound A with a proper solvent to obtain a chiral compound B with a single configuration. The compound B is hydrolyzed to obtain a single-configuration key intermediate of the Mabalo Sha Wei compound (R) 1 =benzyl: (R) -7- (benzyloxy) -3,4,12 a-tetrahydro-1H- [1,4]Oxazino [3,4-c]Pyrido [2,1-f][1,2,4]Triazine-6, 8-dione).
The method uses a racemized compound of formula (II), and the racemized compound is condensed with chiral acid to generate a pair of diastereoisomeric compounds A, and then the compound of formula (I) with a single configuration is obtained through recrystallization and hydrolysis. The method has the defects that the resolution yield is very low, and only about 40 percent of resolution yield is calculated by the compound of the formula (II), and the rest about 60 percent of compound of the formula (II) is remained in mother liquor in the forms of B and C to be discarded, so that huge waste and pollution are caused, and the synthesis cost of the compound of the formula (I) is greatly increased.
Therefore, the improvement of the resolution efficiency of the compound of the formula (II) has great scientific significance and economic value.
Disclosure of Invention
The invention aims to provide a high-efficiency preparation/resolution method of a compound of a formula (II) or a hydrate or solvate thereof.
In a first aspect of the present invention there is provided a process for the preparation of a compound of formula (II) or a hydrate or solvate thereof, comprising the steps of:
(a) Directly preparing a compound of formula (II) or a hydrate or solvate thereof by taking a mixture of a compound B and a compound C or the compound C as a raw material;
or the preparation method comprises the following steps:
(b1) Preparing a mixture of a compound of formula (I) and a compound of formula (III) from a mixture of compound B and compound C; or preparing a compound of formula (III) from compound C;
(b2) Preparing a compound of formula (II) or a hydrate or solvate thereof from a mixture of a compound of formula (I) and a compound of formula (III) or from a compound of formula (III);
or the preparation method comprises the following steps:
(c1) Preparing a mixture of a compound of formula (I) and a compound of formula (III) from a mixture of compound B and compound C; or preparing a compound of formula (III) from compound C;
(c2) Preparing a compound of formula (IV) from a mixture of a compound of formula (I) and a compound of formula (III) or from a compound of formula (III);
(c3) Preparing a compound of formula (II) or a hydrate or solvate thereof from a compound of formula (IV);
in the formulae, R 1 Is hydrogen, benzyl, benzhydryl, trityl or C1-C8 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy;
R 2 selected from the group consisting of:
in another preferred embodiment, the weight ratio of compound B to compound C is 1:99 to 99:1, preferably 2 to 50:98 to 50, more preferably 5 to 20:95 to 80 or 6 to 15:94 to 85.
In another preferred embodiment, the weight ratio of the compound of formula (I) to the compound of formula (III) is from 1:99 to 99:1, preferably from 2 to 80:98 to 20, more preferably from 5 to 60:95 to 40 or from 6 to 50:94 to 50.
In another preferred embodiment, in step a, a mixture of compound B and compound C or compound C is reacted in a solvent in the presence of a base to give a compound of formula (II) or a hydrate or solvate thereof,
the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-Diisopropylethylamine (DIPEA), 1, 8-diazabicyclo undec-7-ene (DBU), pyridine, or a combination of two or more thereof;
the solvent is selected from the group consisting of: one or more mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water.
In another preferred embodiment, in the step a, the base is one or a combination of two of potassium carbonate and DBU.
In another preferred embodiment, in step a, the reaction is carried out at a temperature of from-20 to 100 ℃, preferably from 50 to 100 ℃.
In another preferred embodiment, in the step a, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
In a further preferred embodiment, in step B1 or C1, the mixture of compound B and compound C or compound C is reacted in a solvent in the presence of a base to obtain a mixture of compound (I) and compound (III) or compound (III),
the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof;
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water.
In another preferred embodiment, in the step b1 or c1, the base is one or a combination of two of potassium carbonate and DBU.
In another preferred embodiment, in said step b1 or c1, the reaction is carried out at a temperature of from-20 to 100 ℃, preferably from 50 to 100 ℃.
In another preferred embodiment, in the step b1 or c1, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
In another preferred embodiment, in step b2, the mixture of the compound of formula (I) and the compound of formula (III) or the compound of formula (III) is reacted in a solvent in the presence of a base to give the compound of formula (II) or a hydrate or solvate thereof,
the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof;
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water.
In another preferred embodiment, in the step b2, the base is one or a combination of two of potassium carbonate and DBU.
In another preferred embodiment, in step b2, the reaction is carried out at a temperature of from-20 to 100 ℃, preferably from 50 to 100 ℃.
In another preferred embodiment, in the step b2, the solvent is selected from: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
In another preferred embodiment, in the step c2, the mixture of the compound of formula (I) and the compound of formula (III) or the compound of formula (III) is reacted in a solvent with the addition of an oxidizing agent to give the compound of formula (IV),
the solvent is selected from the group consisting of: one or more mixed solvents selected from dichloromethane, chloroform, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and toluene;
the oxidant is selected from the group consisting of: one or more of 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ), tetrachlorobenzoquinone, tetrapropyl ammonium homoruthenate (TPAP), N-methylmorpholine oxide (NMO) and iodosobenzene.
In another preferred example, the oxidant is one or a combination of two of DDQ and tetrachlorobenzoquinone.
In another preferred embodiment, in step c2, the reaction is carried out at a temperature of from-20 to 100 ℃, preferably from 0 to 40 ℃.
In another preferred embodiment, in the step c2, the solvent is selected from: one or more mixed solvents selected from dichloromethane, chloroform, acetonitrile, ethyl acetate and toluene.
In another preferred embodiment, in the step c3, the compound of formula (IV) is reacted in a solvent with the addition of a reducing agent to obtain the compound of formula (II) or a hydrate or solvate thereof,
the solvent is selected from one or more than two mixed solvents of methanol, ethanol, isopropanol, dichloromethane, 1, 2-dichloroethane, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, isopropyl ether and methyl tertiary butyl ether;
the reducing agent is selected from the group consisting of: hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetyl borohydride, sodium cyanoborohydride, or a combination of two or more thereof.
In another preferred embodiment, the reducing agent is selected from the group consisting of: hydrogen, sodium borohydride, potassium borohydride, or a combination of two or more thereof.
In another preferred embodiment, in step c3, the reaction is carried out at a temperature of from-20 to 100 ℃, preferably from 0 to 70 ℃.
In another preferred embodiment, in step c3, the solvent is selected from one or more of methanol, ethanol, dichloromethane, ethyl acetate, DMF, and DMA.
In another preferred embodiment, R 1 Is benzyl, benzhydryl, trityl or C1-C6 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy.
In another preferred embodiment, R 2 Selected from the group consisting of:
in a second aspect of the invention, there is provided a process for the preparation of a compound of formula (I) intermediate marbaluo Sha Wei comprising the steps of:
(i) Condensing a compound of formula (II) or a hydrate or solvate thereof with a chiral acid to form a compound a;
(ii) Pulping or recrystallizing the compound A in a solvent, filtering to obtain a filter cake and filtrate,
the filter cake is a compound B, and is hydrolyzed to obtain a key intermediate of the Mabalo Sha Wei, namely a compound of the formula (I);
the filtrate is a mixture of the compound B and the compound C or the compound C,
the preparation method further comprises the steps of preparing a compound of formula (II) or a hydrate or solvate thereof by taking the filtrate as a raw material according to the method of the first aspect, repeating the steps I and II, obtaining a key intermediate of the compound of formula (I) of the Mabalo Sha Wei from a filter cake,
in the formulae, R 1 Is hydrogen, benzyl, benzhydryl, trityl or C1-C8 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy;
R 2 selected from the group consisting of:
in a preferred embodiment, once resolution is performed, the conversion efficiency of the compound of formula II to the compound of formula I is 37%, repeated resolution once can increase the conversion efficiency to 53%, and repeated resolution once can increase the conversion efficiency to 60%. In the present invention, repetition of steps I and II theoretically allows for nearly complete conversion of the compound of formula II to the compound of formula I.
In another preferred embodiment, R 1 Is benzyl, benzhydryl, trityl, C1-C6 alkyl or C1-C6 haloalkyl.
In another preferred embodiment, R 2 Selected from the group consisting of:
in another preferred embodiment, in the step (i), the compound of formula (II) or a hydrate or solvate thereof is reacted in a solvent with the addition of a condensing agent, a base and a chiral acid to obtain a compound of formula a, wherein,
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether and isopropyl ether;
the condensing agent is selected from the group consisting of: 2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-propylphosphoric anhydride (T) 3 P), 1-Hydroxybenzotriazole (HOBT), benzotriazole-N, N' -tetramethyluronium Hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), diphenyl azide phosphate (DPPA);
the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof;
the chiral acid is selected from: (R) -tetrahydrofuran-2-carboxylic acid, (S) -tetrahydrofuran-2-carboxylic acid, L-proline, D-proline, (S) -2-methylproproline, (R) -2-methylproproline, N-p-toluenesulfonate-L-proline, N-p-toluenesulfonate-D-proline.
In another preferred embodiment, the solvent is selected from the group consisting of: and one or more than two mixed solvents selected from ethyl acetate, acetonitrile, DMF and DMA.
In another preferred embodiment, the base is one or a combination of triethylamine and pyridine.
In another preferred embodiment, the condensing agent is selected from the group consisting of: HATU, T 3 P。
In another preferred embodiment, the chiral acid is selected from the group consisting of: (R) -tetrahydrofuran-2-carboxylic acid, (S) -tetrahydrofuran-2-carboxylic acid.
In another preferred embodiment, the reaction is carried out at 50 to 100 ℃, preferably at 55 to 65 ℃.
In another preferred embodiment, in step (ii), compound a is slurried or recrystallized in a solvent, filtered to obtain compound B, a mixture of compound B and compound C, or compound C, wherein,
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, isopropyl ether and methyl tertiary butyl ether.
In another preferred embodiment, the solvent is selected from the group consisting of: one or a combination of two of ethyl acetate and ethanol.
In a third aspect of the present invention, there is provided a process for the preparation of marbalo Sha Wei comprising the steps of:
obtaining a marbalo Sha Wei intermediate compound of formula (I) from the preparation process of the second aspect;
marbalo Sha Wei is prepared from a compound of formula (I) intermediate to Marbalo Sha Wei.
The efficient preparation/resolution method of the compound of the formula (II) provided by the invention can enable the compound of the formula (II) to be almost 100% converted into the compound of the formula (I) after cyclic resolution, has simple reaction and convenient operation, and can realize stable process production.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Drawings
Figure 1 is a chiral HPLC profile of compound 4.
FIG. 2 is a single crystal plot of Compound 4
Figure 3 is a chiral HPLC profile of a mixture of compounds 5 and 4.
Figure 4 is a chiral HPLC profile of compound 5.
Figure 5 is a chiral HPLC profile of compound 1.
Figure 6 is a chiral HPLC profile of compound 1.
Figure 7 is a chiral HPLC profile of compound 1.
FIG. 8 is a 0.5 hydrate single crystal plot of Compound 1.
Figure 9 is a chiral HPLC profile of compound 1.
Figure 10 is a chiral HPLC profile of compound 1.
Detailed Description
The inventors of the present application have studied extensively and intensively to develop a method for preparing/resolving a compound of formula (II) or a hydrate or solvate thereof, wherein the compound of formula (II) or a hydrate or solvate thereof is condensed with chiral acid to form a pair of diastereoisomeric compounds a, the compound a can be recrystallized and filtered to obtain a filter cake (single configuration compound B) and a filtrate (mixture of compound B and compound C or compound C), and the mixture of compound B and compound C or compound C remaining in the crystallization mother liquor is chemically reacted to obtain a racemic compound of formula (II) or a hydrate or solvate thereof, and the newly obtained compound of formula (II) or a hydrate or solvate thereof can be repeatedly resolved to obtain a key intermediate of maralo Sha Wei as a compound of formula (I). In theory, this process may be carried out by continuous cycling such that almost 100% of the compound of formula (II) or a hydrate or solvate thereof is converted into the compound of formula (I). On this basis, the present invention has been completed.
Terminology
In the present invention, the halogen is F, cl, br or I.
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the term "C1-C4" means having 1,2, 3 or 4 carbon atoms, "C1-C8" means having 1,2, 3,4, 5,6, 7 or 8 carbon atoms, and so on.
In the present invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, for example the term "C1-C8 alkyl" refers to a straight or branched alkyl group having 1 to 8 carbon atoms, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" means an-O- (alkyl) group. For example, the term "C1-C4 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 4 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like.
The compounds of formula (II) of the present invention include solvated and unsolvated forms which may exist in unsolvated forms as well as solvated forms which comprise pharmaceutically acceptable solvents such as water, ethanol, and the like. The water-containing compound is a hydrate, such as 0.5 hydrate, monohydrate, dihydrate; the compound containing other solvents (such as ethanol, etc.) is solvate.
Preparation method
In the present invention, the following route is used to prepare the key intermediate compound of formula (I) for marbaluo Sha Wei.
The following describes in detail the examples of the present invention, which are implemented under the guidance of the technical solution/idea of the present invention, and give detailed embodiments and specific operation procedures, but the scope of the present invention is not limited to the following examples. Based on the scientific ideas and embodiments of the invention, one of ordinary skill in the art can combine existing known techniques or make minor improvements to the prior art or knowledge based on this technique to obtain all other embodiments without inventive effort, which fall within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The following is denoted by R 1 Is benzyl, R 2 Is that
The invention will be further described by way of example. />
Example 1 preparation of Compounds 2 ((S) -7- (benzyloxy) -12- ((R) -tetrahydrofuran-2-carbonyl) -3,4,12 a-tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione) and 3 ((R) -7- (benzyloxy) -12- ((R) -tetrahydrofuran-2-carbonyl) -3,4,12 a-tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione)
Compound 1 (7- (benzyloxy) -3,4,12 a-tetrahydro-1H- [1,4]Oxazino [3,4-c]Pyrido [2,1-f][1,2,4]Triazine-6, 8-dione) (20 g,61.1 mmol), 500mL ethyl acetate was added to the reaction flask, and 100mL T under argon 3 A50 wt% solution of P (1-propylphosphoric anhydride) in ethyl acetate was warmed to 65℃and triethylamine (49.46 g,488 mmol) and (R) -tetrahydrofuran-2-carboxylic acid (12.48 g,107.53 mmol) were slowly added dropwise and reacted for 12 hours. The mixture was cooled, concentrated to remove most of the ethyl acetate, 300mL of methylene chloride and 100mL of cold water were added, the aqueous layer was extracted three times with 200mL of methylene chloride, the organic layers were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The majority of the methylene chloride was concentrated off, and 200mL of ethanol was added to recrystallize twice, and 10.1g of pale yellow cake compound 3 (ee=99.9%) was obtained by filtration, the purity was 98.3%, the yield was 38.8%, the melting point was 187 to 188 ℃, and ESI-MS (m/z): 426.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.71(d,J＝7.8Hz,1H),7.55–7.47(m,2H),7.39–7.28(m,3H),6.30(d,J＝7.8Hz,1H),5.84–5.74(m,1H),5.14(q,J＝10.8Hz,2H),4.94(s,1H),4.35(d,J＝11.1Hz,1H),4.02(dd,J＝10.5,3.1Hz,1H),3.90–3.69(m,3H),3.55(t,J＝10.4Hz,1H),3.31(d,J＝22.8Hz,2H),2.03(s,2H),1.88(dq,J＝14.4,7.4,6.6Hz,2H).
The two recrystallization mother liquors were combined and concentrated to give 13.8g of a mixture of compounds 2 and 3 in 53.1% yield, compound 2: compound 3=91.7:8.3 (chiral HPLC peak area ratio)).
ESI-MS(m/z):426.2[M+H] +
EXAMPLE 2 preparation of Compound 4 ((R) -7- (benzyloxy) -3,4,12 a-tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione)
Compound 3 (10.1 g,23.8 mmol), 75mL of ethyl acetate and 1mL of methanol were added to the reaction flask, DBU (1, 8-diazabicyclo undec-7-ene) (1.09 g,7.15 mmol) was added and stirred overnight at room temperature. Filtration gave 7.4g of pale yellow cake compound 4 (chiral HPLC pattern shown in FIG. 1, single crystal pattern shown in FIG. 2). Purity 99.9%, yield 95.2%, ee value 99.9%, melting point 202-203 ℃, ESI-MS (m/z): 350.2[ M+Na ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.71(d,J＝7.7Hz,1H),7.61–7.52(m,2H),7.40–7.28(m,4H),6.23(d,J＝7.6Hz,1H),5.08(d,J＝1.5Hz,2H),4.81(ddd,J＝12.8,9.9,4.6Hz,1H),4.15(dd,J＝13.8,2.8Hz,1H),4.04(td,J＝10.5,9.7,4.3Hz,2H),3.44(td,J＝11.9,3.1Hz,1H),3.14(dd,J＝11.4,10.0Hz,1H),2.96(ddd,J＝14.2,12.4,4.3Hz,1H).
EXAMPLE 3 preparation of a mixture of Compound 5 ((S) -7- (benzyloxy) -3,4,12 a-tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione) and Compound 4
To a mixture of compounds 2 and 3 (mixture obtained by resolution of mother liquor in example 1, 10g,23.5 mmol) was added 80mL ethyl acetate, DBU (3.5 mL,23.5 mmol), and reacted at 70℃for 10h. Filtration gave 6.6g of a mixture of compounds 5 and 4 as pale yellow solids (chiral HPLC profile shown in fig. 3), wherein compound 5: compound 4=91.7:8.3 (chiral HPLC peak area ratio), purity 98.99%, yield 85.8%.
ESI-MS(m/z):350.2[M+Na] + 。
EXAMPLE 4 preparation of Compound 5
To compound 2 (1 g,2.4 mmol) was added 10mL ethyl acetate, DBU (0.36 g,2.4 mmol), and reacted at 70℃for 10h. Filtration gave 0.63g of compound 5 as a white solid (chiral HPLC profile shown in fig. 4) with a purity of 99.8% and a yield of 81.8%.
Melting point 202-204 deg.c. ESI-MS (m/z): 350.2[ M+Na ]] +
1 H NMR(400MHz,DMSO-d 6 )δ7.71(d,J＝7.6Hz,1H),7.62–7.48(m,2H),7.44–7.17(m,4H),6.22(d,J＝7.6Hz,1H),5.07(d,J＝1.7Hz,2H),4.80(ddd,J＝12.8,9.9,4.5Hz,1H),4.14(dd,J＝13.9,2.8Hz,1H),4.03(ddd,J＝13.3,9.1,4.3Hz,2H),3.43(td,J＝12.0,3.1Hz,1H),3.13(dd,J＝11.4,10.0Hz,1H),3.03–2.89(m,1H).
Example 5: preparation of Compound 6 (7- (benzyloxy) -3, 4-dihydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione)
A mixture of compound 5 and compound 4 (chiral HPLC peak area ratio=91.7:8.3) (1 g,3.1 mmol) was dissolved in 7mL of methylene chloride, DDQ (2, 3-dichloro-5, 6-dicyanobenzoquinone) (0.83 g,3.7 mmol) was added under ice bath, and the mixture was reacted at room temperature for 30 minutes. 5mL of saturated aqueous sodium bicarbonate solution was added, the mixture was extracted three times with 15mL of methylene chloride, the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, slurried with 5mL of methanol, and filtered to give 0.68g of Compound 6 as a white solid, yield 68% and purity 96.4%.
ESI-MS(m/z):326.2[M+H] + 。
EXAMPLE 6 preparation of Compound 6
Compound 5 (1 g,3.1 mmol) was dissolved in 7mL of dichloromethane, DDQ (0.83 g,3.7 mmol) was added under ice bath, and reacted at room temperature for 30 minutes. 5mL of saturated aqueous sodium bicarbonate solution was added, the mixture was extracted three times with 15mL of methylene chloride, the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, slurried with 5mL of methanol, and filtered to give 0.71g of Compound 6 as a white solid in 71% yield and 97.3% purity.
Melting point is 232-233 ℃. ESI-MS (m/z): 326.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d6)δ8.07(d,J＝7.8Hz,1H),7.59(d,J＝7.3Hz,2H),7.38(t,J＝7.3Hz,2H),7.32(t,J＝7.1Hz,1H),6.56(d,J＝7.8Hz,1H),5.11(s,2H),4.52(s,2H),4.03(t,J＝5.5Hz,2H),3.72(t,J＝5.5Hz,2H).
EXAMPLE 7 preparation of Compound 1
A mixture of compounds 2 and 3 (chiral HPLC peak area ratio=91.7:8.3) (1 g,2.4 mmol), potassium carbonate (0.3 g,2.4 mmol) and 10mL ethanol were added to the reaction flask and reacted at 80℃for 11 hours. Concentrated, 10mL of water was added, extracted three times with 15mL of dichloromethane, the organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, slurried with 10mL of ethyl acetate, filtered to give 0.64g of compound 1 (chiral HPLC profile as shown in fig. 5) as a white solid, 99.4% pure, 82.7% yield, enantiomer compound 5: compound 4=52.1:47.9 (chiral HPLC peak area ratio).
ESI-MS(m/z):350.2[M+Na] + 。
EXAMPLE 8 preparation of Compound 1
To the reaction flask was added compound 2 (1 g,2.4 mmol), DBU (1.1 g,7.2 mmol) and 10mL ethanol, which were reacted at 80℃for 11 hours. Concentrated, 10mL of water was added, extracted three times with 15mL of dichloromethane, the organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, slurried with 10mL of ethyl acetate, filtered to give 0.64g of compound 1 (chiral HPLC profile as shown in fig. 6) as a white solid, 99.3% pure, 83.2% yield, enantiomer compound 5: compound 4=51.0:49.0 (chiral HPLC peak area ratio).
ESI-MS(m/z):350.2[M+Na] + 。
EXAMPLE 9 preparation of 0.5 hydrate of Compound 1
A mixture of compound 5 and compound 4 (chiral HPLC peak area ratio=91.7:8.3) (1 g,3.1 mmol), potassium carbonate (0.42 g,3.1 mmol) and 10mL ethanol were added to a reaction flask and reacted at 80℃for 2h. Filtration, recrystallization by adding 10mL of water to the filtrate, filtration gave 0.82g of 0.5 hydrate of white solid compound 1 (chiral HPLC profile shown in fig. 7, single crystal profile shown in fig. 8), yield 79.8%, purity 99.8%, enantiomer compound 5: compound 4=50.2: 49.8 (chiral HPLC peak area ratio).
ESI-MS(m/z):350.2[M+Na] + 。
EXAMPLE 10 preparation of Compound 1
Compound 5 (1 g,3.1 mmol), potassium carbonate (0.42 g,3.1 mmol) and 10mL ethanol were added to the reaction flask and reacted at 80℃for 2h. Filtration, concentration of the filtrate, beating with 10mL of ethyl acetate, filtration gave 0.8g of compound 1 (chiral HPLC profile as shown in fig. 9) as a white solid in 80% yield, 99.9% purity, enantiomer compound 5: compound 4=51.1: 48.9 (chiral HPLC peak area ratio).
ESI-MS(m/z):350.2[M+Na] + 。
EXAMPLE 11 preparation of Compound 1
To the reaction flask was added compound 6 (0.7 g,2.2 mmol), 10mL of methanol, and potassium borohydride (0.23 g,4.3 mmol) in an ice bath, and the reaction was refluxed for 20h. 10mL of water was added, extracted three times with 30mL of dichloromethane, the organic layers were combined, washed three times with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and slurried with 10mL of ethyl acetate to give 0.41g of compound 1 (chiral HPLC pattern as in FIG. 10) as a yellow solid in 58.6% yield, 93% purity, enantiomer compound 5: compound 4=49.3: 50.7 (chiral HPLC peak area ratio).
Melting point: ESI-MS (m/z) 350.2[ M+Na ]] + 。
1 H NMR(400MHz,DMSO-d6)δ7.71(d,J＝7.7Hz,1H),7.56(dt,J＝6.1,1.4Hz,2H),7.40–7.33(m,2H),7.33–7.26(m,2H),6.22(d,J＝7.6Hz,1H),5.07(d,J＝1.7Hz,2H),4.81(ddd,J＝12.4,9.9,4.5Hz,1H),4.15(dd,J＝13.8,2.8Hz,1H),4.03(td,J＝10.4,9.3,4.3Hz,2H),3.43(td,J＝12.0,3.1Hz,1H),3.13(dd,J＝11.4,10.0Hz,1H),3.01–2.89(m,1H).
EXAMPLE 12 preparation of Compound 4
Compound 1 (20 g,61.1 mmol) was resolved according to the procedure in example 1 and example 2 to give 7.4g of Compound 4 in 37% yield in two steps. The resulting resolution filtrate was subjected to the procedure of example 7 to obtain 8.8g of compound 1, and the obtained 8.8g of compound 1 was resolved again to obtain 3.2g of compound 4, and the two cycles were repeated to obtain 10.6g of compound 4 in total yield 53%, and the three cycles were repeated to obtain 11.2g of compound 4 in total yield 60.1%.
Next, R is used 1 Is n-hexyl, R 2 Is that
The invention will be further described by way of example.
Wherein, the liquid crystal display device comprises a liquid crystal display device, the compounds 8 ((S) -6, 8-dioxan-12- ((S) -tetrahydrofuran-2-carbonyl) -3,4,6,8,12 a-hexahydro-1H- [1,4] oxazinyl [3,4-c ] pyrido [2,1-f ] [1,2,4] triazin-7-yl hexanoate), 9 ((S) -6, 8-dioxa-12- ((S) -tetrahydrofuran-2-carbonyl) -3,4,6,8,12 a-hexahydro-1H- [1,4] oxazinyl [3,4-c ] pyrido [2,1-f ] [1,2,4] triazin-7-yl hexanoate) were prepared in analogy to examples 1-6 compound 10 ((R) -6, 8-dioxo-3, 4,6,8,12 a-hexahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazin-7-yl hexanoate), compound 11 ((S) -6, 8-dioxo-3, 4,6,8,12 a-hexahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazin-7-yl hexanoate) and compound 12 7- (hexyloxy) -3, 4-dihydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazin-6, 8-dione.
EXAMPLE 13 preparation of Compound 7
A mixture of compounds 8 and 9 (chiral HPLC peak area ratio=90.1:9.9) (1 g,2.4 mmol) and 10mL ethanol, potassium carbonate (0.33 g,2.4 mmol) were added to the reaction flask and reacted at reflux for 10 hours. Concentrated, 10mL of water was added, extracted three times with 30mL of dichloromethane, the combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, slurried with 10mL of ethyl acetate, filtered to give 0.68g of compound 7 as a white solid in 88.7% yield, 98.9% purity, enantiomer compound 11: compound 10=50.5: 49.5 (chiral HPLC peak area ratio).
ESI-MS(m/z):344.3[M+Na] + 。
EXAMPLE 14 preparation of Compound 7
Compound 8 (5.8 g,13.8 mmol) and 58mL of ethanol, potassium carbonate (3.82 g,37.6 mmol) were added to the reaction flask and reacted at reflux for 10 hours. Concentrating, adding 30mL of water, extracting three times with 90mL of dichloromethane, washing the combined organic layers with saturated aqueous sodium chloride solution, drying the combined organic layers with anhydrous sodium sulfate, adding 20mL of ethyl acetate for pulping after concentrating, and filtering to obtain 3.9g of white solid compound 7, with the yield of 87.8% and the purity of 99.1%, and enantiomer compound 11, wherein the compound 10=50.3: 49.7 (chiral HPLC peak area ratio).
ESI-MS(m/z):344.3[M+Na] + 。
EXAMPLE 15 preparation of Compound 7
A mixture of compounds 11 and 10 (chiral HPLC peak area ratio=90.1:9.9) (1 g,3.1 mmol), DBU (47 mg,0.31 mmol) and 10mL ethanol were added to a reaction flask and reacted at 80℃for 5h. 10mL of ethyl acetate was added to the mixture and the mixture was slurried and filtered to obtain 0.85g of compound 7 as a white solid in 85% yield and 99.2% purity, and enantiomer compound 11, compound 10=52.0:48.0 (chiral HPLC peak area ratio).
ESI-MS(m/z):344.3[M+Na] + 。
EXAMPLE 16 preparation of Compound 7
Compound 11 (1 g,3.1 mmol), DBU (47 mg,0.31 mmol) and 10mL ethanol were added to the reaction flask and reacted at 80℃for 5h. 10mL of ethyl acetate was added and the mixture was slurried and filtered to give 0.88g of compound 7 as a white solid in 88% yield and 99.2% purity, enantiomer compound 11: compound 10=51.3: 48.7 (chiral HPLC peak area ratio).
ESI-MS(m/z):344.3[M+Na] + 。
EXAMPLE 17 preparation of Compound 7
To the reaction flask was added compound 12 (0.7 g,2.2 mmol), 10mL of methanol, and potassium borohydride (0.23 g,4.3 mmol) in an ice bath, and the reaction was refluxed for 20h. 10mL of water was added, extracted three times with 30mL of methylene chloride, the organic layers were combined, washed three times with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and slurried with 10mL of ethyl acetate to give 0.51g of compound 7 as a white solid in 72.9% yield, 96% purity, enantiomer compound 11: compound 10=50.9: 49.1 (chiral HPLC peak area ratio).
ESI-MS(m/z):344.3[M+Na] + 。
1 H NMR(400MHz,DMSO-d6)δ7.64(d,J＝7.6Hz,1H),7.23(d,J＝12.6Hz,1H),6.13(dd,J＝7.6,0.7Hz,1H),4.80(ddd,J＝12.8,9.9,4.5Hz,1H),4.11(dd,J＝14.0,2.8Hz,1H),4.06–3.96(m,3H),3.93(dt,J＝8.6,6.8Hz,1H),3.41(td,J＝12.0,3.1Hz,1H),3.10(dd,J＝11.4,10.0Hz,1H),2.94(dd,J＝13.3,4.1Hz,1H),1.71–1.58(m,2H),1.42–1.32(m,2H),1.32–1.19(m,4H),0.91–0.81(m,3H).
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (40)
1. A process for the preparation of a compound of formula (II) or a 0.5 hydrate thereof, comprising the steps of:
(a) Reacting a mixture of compound B and compound C or compound C in a solvent in the presence of a base at-20 to 100 ℃ to obtain a compound of formula (II) or a 0.5 hydrate thereof, wherein the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-Diisopropylethylamine (DIPEA), 1, 8-diazabicyclo undec-7-ene (DBU), pyridine, or a combination of two or more thereof; the solvent is selected from the group consisting of: one or more mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water;
or the preparation method comprises the following steps:
(b1) Reacting a mixture of a compound B and a compound C or a compound C in a solvent at a temperature of between 20 ℃ below zero and 100 ℃ in the presence of a base to obtain a mixture of a compound of formula (I) and a compound of formula (III) or a compound of formula (III), wherein the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof; the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water;
(b2) A mixture of a compound of formula (I) and a compound of formula (III) or a compound of formula (III) is reacted in a solvent in the presence of a base at-20 to 100 ℃ to obtain a compound of formula (II) or a 0.5 hydrate thereof, wherein the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof; the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water;
or the preparation method comprises the following steps:
(c1) Reacting a mixture of a compound B and a compound C or a compound C in a solvent at a temperature of between 20 ℃ below zero and 100 ℃ in the presence of a base to obtain a mixture of a compound of formula (I) and a compound of formula (III) or a compound of formula (III), wherein the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof; the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and water;
(c2) A mixture of a compound of formula (I) and a compound of formula (III) or a compound of formula (III) is reacted in a solvent, adding an oxidant and reacting at-20 to 100 ℃ to obtain a compound of formula (IV), wherein the solvent is selected from the group consisting of: one or more mixed solvents selected from dichloromethane, chloroform, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and toluene; the oxidant is selected from the group consisting of: one or more of 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ), tetrachlorobenzoquinone, tetrapropyl ammonium homoruthenate (TPAP), N-methylmorpholine oxide (NMO), and iodosobenzene;
(c3) Adding a reducing agent into a solvent for reaction at the temperature of-20 to 100 ℃ to obtain a compound shown in the formula (IV) or a 0.5 hydrate thereof, wherein the solvent is one or more than two solvents selected from methanol, ethanol, isopropanol, dichloromethane, 1, 2-dichloroethane, ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, isopropyl ether and methyl tertiary butyl ether; the reducing agent is selected from the group consisting of: one or more of hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetyl borohydride, and sodium cyanoborohydride;
in the formulae, R 1 Is hydrogen, benzyl, benzhydryl, trityl or C1-C8 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy;
R 2 selected from the group consisting of:
2. the process according to claim 1, wherein the weight ratio of compound B to compound C is from 1:99 to 99:1.
3. The process according to claim 1, wherein the weight ratio of compound B to compound C is 2-50:98-50.
4. The process according to claim 1, wherein the weight ratio of compound B to compound C is from 5 to 20:95 to 80.
5. The process according to claim 1, wherein the weight ratio of compound B to compound C is from 6 to 15:94 to 85.
6. The process according to claim 1, wherein the weight ratio of the compound of formula (I) to the compound of formula (III) is from 1:99 to 99:1.
7. The process according to claim 1, wherein the weight ratio of the compound of formula (I) to the compound of formula (III) is from 2 to 80:98 to 20.
8. The process according to claim 1, wherein the weight ratio of the compound of formula (I) to the compound of formula (III) is from 5 to 60:95 to 40.
9. The process according to claim 1, wherein the weight ratio of the compound of formula (I) to the compound of formula (III) is from 6 to 50:94 to 50.
10. The method of claim 1, wherein in step a, the base is one or a combination of potassium carbonate and DBU.
11. The process according to claim 1, wherein in step a the reaction is carried out at 50 to 100 ℃.
12. The method of claim 1, wherein in step a, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
13. The method according to claim 1, wherein in the step b1, the alkali is one or a combination of two of potassium carbonate and DBU.
14. The method according to claim 1, wherein in the step c1, the alkali is one or a combination of two of potassium carbonate and DBU.
15. The process according to claim 1, wherein in step b1, the reaction is carried out at 50 to 100 ℃.
16. The method of claim 1, wherein in step b1, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
17. The process according to claim 1, wherein in step c1, the reaction is carried out at 50 to 100 ℃.
18. The method of claim 1, wherein in step c1, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
19. The method according to claim 1, wherein in the step b2, the alkali is one or a combination of two of potassium carbonate and DBU.
20. The process according to claim 1, wherein in step b2, the reaction is carried out at 50 to 100 ℃.
21. The method of claim 1, wherein in step b2, the solvent is selected from the group consisting of: ethanol, ethyl acetate, acetonitrile, DMF and DMA.
22. The method of claim 1, wherein the oxidizing agent is one or a combination of DDQ and tetrachlorobenzoquinone.
23. The process according to claim 1, wherein in step c2, the reaction is carried out at 0 to 40 ℃.
24. The method of claim 1, wherein in step c2, the solvent is selected from the group consisting of: one or more mixed solvents selected from dichloromethane, chloroform, acetonitrile, ethyl acetate and toluene.
25. The method of claim 1, wherein the reducing agent is selected from the group consisting of: hydrogen, sodium borohydride, potassium borohydride, or a combination of two or more thereof.
26. The process according to claim 1, wherein in step c3 the reaction is carried out at 0 to 70 ℃.
27. The method according to claim 1, wherein in step c3, the solvent is one or more selected from the group consisting of methanol, ethanol, methylene chloride, ethyl acetate, DMF, and DMA.
28. The process of claim 1, wherein R is 1 Is benzyl, benzhydryl, trityl or C1-C6 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy.
29. The process of claim 1, wherein R is 2 Selected from the group consisting of:
30. a process for the preparation of a compound of formula (I) intermediate to marbalo Sha Wei, comprising the steps of:
(i) Condensing a compound of formula (II) or a 0.5 hydrate thereof with a chiral acid to form a compound a;
(ii) Pulping or recrystallizing the compound A in a solvent, filtering to obtain a filter cake and filtrate,
the filter cake is a compound B, and is hydrolyzed to obtain a key intermediate of the Mabalo Sha Wei, namely a compound of the formula (I);
the filtrate is a mixture of the compound B and the compound C or the compound C,
the preparation method further comprises the steps of preparing the compound of the formula (II) or 0.5 hydrate thereof by taking the filtrate as a raw material according to the method of any one of claims 1-29, repeating the steps I and II, obtaining the key intermediate of the formula (I) of the Mabalo Sha Wei from a filter cake,
in the formulae, R 1 Is hydrogen, benzyl, benzhydryl, trityl or C1-C8 alkyl; the above groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy;
R 2 selected from the group consisting of:
31. the process according to claim 30, wherein in step (i), the compound of formula (II) or 0.5 hydrate thereof is reacted in a solvent with the addition of a condensing agent, a base and a chiral acid to give the compound of formula A,
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from ethyl acetate, DMF, DMA, acetone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether and isopropyl ether;
the condensing agent is selected from the group consisting of: 2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-propylphosphoric anhydride (T) 3 P), 1-Hydroxybenzotriazole (HOBT), benzotriazole-N, N' -tetramethyluronium Hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), diphenyl azide phosphate (DPPA);
the base is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, DIPEA, DBU, pyridine, or a combination of two or more thereof;
the chiral acid is selected from: (R) -tetrahydrofuran-2-carboxylic acid, (S) -tetrahydrofuran-2-carboxylic acid, L-proline, D-proline, (S) -2-methylproproline, (R) -2-methylproproline, N-p-toluenesulfonate-L-proline, N-p-toluenesulfonate-D-proline.
32. The method of claim 31, wherein the solvent is selected from the group consisting of: and one or more than two mixed solvents selected from ethyl acetate, acetonitrile, DMF and DMA.
33. The method according to claim 31, wherein the base is one or a combination of triethylamine and pyridine.
34. The method of claim 31, wherein the condensing agent is selected from the group consisting of: HATU, T 3 P。
35. The method of preparation of claim 31, wherein the chiral acid is selected from the group consisting of: (R) -tetrahydrofuran-2-carboxylic acid, (S) -tetrahydrofuran-2-carboxylic acid.
36. The process of claim 31, wherein the reaction is carried out at 50 to 100 ℃.
37. The process of claim 31, wherein the reaction is carried out at 55 to 65 ℃.
38. The process according to claim 30, wherein in step (ii), compound A is slurried or recrystallized in a solvent, and filtered to obtain compound B, a mixture of compound B and compound C, or compound C,
the solvent is selected from the group consisting of: one or more than two mixed solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, isopropyl ether and methyl tertiary butyl ether.
39. The method of claim 38, wherein the solvent is selected from the group consisting of: one or a combination of two of ethyl acetate and ethanol.
40. A method for preparing marbalo Sha Wei, comprising the steps of:
a compound of formula (I) intermediate to marbaluo Sha Wei obtained from the process of claim 30;
marbalo Sha Wei is prepared from a compound of formula (I) intermediate to Marbalo Sha Wei.
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| WO2019070059A1 (en) * | 2017-10-06 | 2019-04-11 | 塩野義製薬株式会社 | Method for stereoselectively producing substituted polycyclic pyridone derivative |
| CN109956956B (en) * | 2018-05-15 | 2020-07-07 | 广东东阳光药业有限公司 | Preparation method of polycyclic pyridone compound |
| CN109516998B (en) * | 2018-12-25 | 2021-06-25 | 深圳市华先医药科技有限公司 | Synthesis method of Barosavir intermediate |
| CN109912624B (en) * | 2019-04-11 | 2021-05-11 | 杭州科巢生物科技有限公司 | Synthesis method of baroxavir pivoxil key parent nucleus intermediate |
| CN111018803B (en) * | 2019-11-25 | 2022-09-20 | 苏州楚凯药业有限公司 | Preparation method of Barosavir intermediate |
| CN111205304B (en) * | 2020-03-02 | 2022-03-11 | 南京法恩化学有限公司 | Preparation method of Barosavir intermediate |
| CN112079848A (en) * | 2020-09-24 | 2020-12-15 | 广东莱佛士制药技术有限公司 | Synthesis method of baroxavir key intermediate |
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