CN115073491A - Rugosril intermediate, preparation method and application thereof - Google Patents
Rugosril intermediate, preparation method and application thereof Download PDFInfo
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a Ruogeli intermediate, a preparation method and application thereof. The invention provides a preparation method of a compound shown as A6, which comprises the following steps: in ethyl acetate, the compound shown as the formula A5 and a chlorinating agent are subjected to chlorination reaction shown as the following formula to obtain the compound shown as the formula A6. The Rugoside prepared by using the intermediate can be prepared at a high yield, the generation of impurities which are difficult to separate is avoided, and the purity of the Rugoside is improved.
Description
Technical Field
The invention relates to a Ruugeli intermediate, a preparation method and application thereof.
Background
On day 18/12/2020, Ruogeli Orgovyx (relugolix) was approved by the U.S. Food and Drug Administration (FDA) for treatment of adult patients with advanced prostate cancer. Ruogeli is an oral non-peptide gonadotropin releasing hormone GnRH receptor blocker, co-developed by Wutian, ASKA and Myovant, and has been approved in Japan for the treatment of hysteromyoma in 2018. Besides the approved uterine fibroids and prostate cancer, a compound preparation of Ruogeli and norgestrel is developed and used for treating pain (phase 3), dysmenorrheal (phase 2) and the like caused by endometriosis.
The currently disclosed synthetic method of Ruugeli mainly has the following route.
(1) Med chem.2011,54, 4998-:
the final yield of the route is only 44%, and the total yield is relatively low.
(2) Patent CN104703992A discloses the following synthetic route:
this route is generally high in yield, but has the drawback-the last step of the urea-forming reaction, produces approximately 2.0% of the condensed urea by-product, an impurity which is difficult to remove. The impurities have an increasing trend along with the enlargement of the feeding scale, and the removal difficulty is further increased. Furthermore, the preparation of Int-6 from Int-5 in this routeImpurities with 6.1 percent and 2.5 percent of LC-MS detection content and [ M + H with 6.1 percent of impurities which are difficult to remove are generated in the process] + 537.1, [ M + H ] with a 2.5% impurity content] + ＝508.1。
(3) Chinese patent CN111333633A discloses the following synthetic route:
this route has a high overall yield, but has the disadvantage that, during the preparation of Int-3 from Int-2, the hydrogenation process produces a molecular weight of [ M + H ]] + 503.1 of impurities. It is difficult to remove the resin during post-treatment. Along with the scale enlargement of the fed materials, the impurities tend to increase, and the removal difficulty is further increased.
Disclosure of Invention
The invention aims to solve the technical problem that impurities which are difficult to separate are easy to generate in the existing Ruugeli preparation method, and therefore the invention provides a Ruugeli intermediate, a preparation method and application thereof. The intermediate disclosed by the invention can be used for efficiently preparing Ruugeli, and avoids the generation of impurities which are difficult to separate. The preparation method has high total yield.
The invention provides a preparation method of a compound shown as A6, which comprises the following steps: in ethyl acetate, carrying out chlorination reaction on a compound shown as a formula A5 and a chlorination reagent shown as a formula to obtain a compound shown as a formula A6;
in the chlorination reaction, the chlorination reaction is carried out in the presence of an initiator, which is conventional in the art for such reactions. Preferably, the initiator may be AIBN. More preferably, the molar ratio of the initiator to the compound shown in formula A5 can be 1: 5.
In the chlorination reaction, the reaction temperature of the chlorination reaction is the conventional reaction temperature of the reaction in the field, and preferably, the reaction temperature of the chlorination reaction can be 60 ℃.
In the chlorination reaction, the molar ratio of the chlorinating reagent to the compound shown as the formula A5 can be 1.1: 1.
In the chlorination reaction, the chlorination reagent is N-chlorosuccinimide (NCS).
In the chlorination reaction, the mass-to-volume ratio of the compound shown as the formula A5 to the ethyl acetate can be 58 g/L.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: scheme 1 or scheme 2;
the scheme 1 comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction on a compound shown as a formula A4 to obtain the compound shown as a formula A5; r is C 1 -C 4 Alkyl groups of (a);
the scheme 2 comprises the following steps: in a solvent, carrying out amidation reaction on a compound shown as a formula B4, N' -Carbonyldiimidazole (CDI) and methoxyamine in the presence of alkali to obtain a compound shown as a formula A5;
in the cyclization reaction of scheme 1, the compound C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl.
In the cyclization reaction of scheme 1, the solvent is a solvent conventional in such reactions in the art, and preferably, the solvent may be a mixed solvent of an alcohol solvent and an ether solvent; the alcohol solvent is preferably methanol; the ether solvent is preferably tetrahydrofuran; more preferably, the volume ratio of the methanol to the tetrahydrofuran is 10: 1.
In the cyclization reaction of scheme 1, the base is a base conventional in such reactions in the art; preferably, the base is an alkoxide; the alkoxide is preferably sodium methoxide; for example 30% sodium methoxide in methanol.
In the cyclization reaction of scheme 1, the molar ratio of the base to the compound represented by formula a4 may be 1: 2.
The reaction temperature of the cyclization reaction of scheme 1 is a conventional reaction temperature in such reactions in the art, and preferably, the reaction temperature of the cyclization reaction may be 60 ℃.
In the amidation reaction in scheme 2, the solvent is a solvent conventional in such reactions in the art, preferably, the solvent is a nitrile solvent; preferably, the nitrile solvent may be acetonitrile.
In the amidation reaction in scheme 2, the base is a base conventional in such reactions in the art; preferably, the base may be triethylamine.
The reaction temperature of the amidation reaction in scheme 2 is a conventional reaction temperature in this type of reaction in the art, and preferably, the reaction temperature of the amide reaction may be 60 ℃.
In the amide reaction in scheme 2, the molar ratio of the base to the compound represented by formula B4 is 1: 1.
In the amidation reaction in scheme 2, the molar ratio of the N, N' -carbonyldiimidazole to the compound represented by formula B4 is 2: 1.
In the amidation reaction in scheme 2, the methoxyamine is added as a methoxyamine salt, for example, methoxyamine hydrochloride.
In the amidation reaction in scheme 2, the molar ratio of the methoxyamine to the compound represented by the formula B4 is 2: 1.
In the amidation reaction in scheme 2, the N, N' -carbonyldiimidazole and the methoxyamine are mixed first and then the compound shown in formula B4 is added.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Q shown as the following formula on a compound shown as a formula A3 and 3-amino-6-methoxypyridazine to obtain a compound shown as a formula A4;
in the amidation reaction Q, the base is a base conventional in such reactions in the art; preferably, the base may be N, N-diisopropylethylamine.
The reaction temperature in the amidation reaction Q is a conventional reaction temperature in this type of reaction in the art, and preferably, the reaction temperature in the amidation reaction may be 80 ℃.
In the amidation reaction Q, the molar ratio of the base to the compound represented by formula a3 may be 1.5: 1.
In the amidation reaction Q, the molar ratio of HATU { (2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate) } to the compound represented by formula a3 may be 1.1: 1.
In the amidation reaction Q, the molar ratio of the 3-amino-6-methoxypyridazine to the compound represented by the formula A3 can be 1.2: 1.
In the amidation reaction Q, the solvent is a solvent conventional in such reactions in the art, preferably, the solvent is an amide solvent; more preferably, the amide solvent may be N, N-dimethylacetamide.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: hydrolyzing the compound shown as the formula A2 to obtain the compound shown as the formula A3; r -1 Is C 1 -C 4 Alkyl groups of (a);
in the hydrolysis reaction, the C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example ethyl.
In the hydrolysis reaction, the solvent is ethanol.
In the hydrolysis reaction, the alkali is the alkali which is conventional in the reaction in the field; preferably, the base may be 2.0M aqueous potassium hydroxide.
In the hydrolysis reaction, the molar ratio of the alkali to the compound shown as formula a2 can be 2.5: 1.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, carrying out amidation reaction M shown as the following formula on a compound shown as a formula A1, N' -Carbonyl Diimidazole (CDI) and methoxyamine in the presence of alkali to obtain the compound shown as the formula A2;
in the amidation reaction M, the solvent is a solvent conventional in such reactions in the art, preferably, the solvent is a nitrile solvent; preferably, the nitrile solvent may be acetonitrile.
In the amidation reaction M, the base is a base conventional in such reactions in the art; preferably, the base may be triethylamine.
In the amidation reaction M, the reaction temperature is a reaction temperature conventionally used in such reactions in the art, and preferably, the reaction temperature of the amination reaction may be 60 ℃.
In the amidation reaction M, the molar ratio of the base to the compound represented by formula a1 may be 1: 1.
In the amidation reaction M, the molar ratio of the N, N' -carbonyldiimidazole to the compound shown as formula a1 may be 2: 1.
In the amidation reaction M, the methoxyamine is added as methoxyamine salt, for example, methoxyamine hydrochloride.
In the amidation reaction M, the molar ratio of the methoxylamine to the compound shown as the formula A1 can be 2: 1.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in SnCl 2 2H 2 In the presence of O, carrying out a reduction reaction shown as the following formula on the compound shown as the formula SM-1 to obtain the compound shown as the formula A1;
in the reduction reaction, the solvent may be ethanol.
In the reduction reaction, the reaction temperature of the reduction reaction is the conventional reaction temperature in the reaction in the field, and preferably, the reaction temperature of the reduction reaction can be 60 ℃.
In the reduction reaction, the SnCl 2 2H 2 The molar ratio of O to the compound of formula SM-1 can be 5: 1.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in the presence of a catalyst, carrying out a reduction reaction shown as the following formula on a compound shown as a formula B3 to obtain a compound shown as a formula B4;
in the reduction reaction, the solvent can be a mixed solvent of methanol and dichloromethane; preferably, the volume ratio of methanol to dichloromethane is 1: 3.
In the reduction reaction, in the preparation method of the compound shown as B4, the catalyst is a palladium catalyst, such as Pd/C, and further such as 10% Pd/C (55% of water in 10% Pd/C).
In the reduction reaction, the reaction temperature of the reduction reaction is a conventional reaction temperature in the field of such reactions, and preferably, the reaction temperature is 25 ℃.
In the reduction reaction, the mass ratio of the catalyst to the compound shown as the formula B3 is 1: 10.
In the reduction reaction, the reducing agent for the reduction reaction is hydrogen gas, for example, atmospheric hydrogen gas.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction on a compound shown as a formula B2 to obtain a compound shown as a formula B3;
in the cyclization reaction, the solvent is a solvent which is conventional in the reaction in the field, and preferably, the solvent is a mixed solvent of an alcohol solvent and an ether solvent; the alcohol solvent is preferably methanol; the ether solvent is preferably tetrahydrofuran.
In the cyclization reaction, the base is a base which is conventional in the reaction in the field; preferably, the base is an alkoxide; the alkoxide is preferably sodium methoxide.
In the cyclization reaction, the molar ratio of the alkali to the compound shown as the formula B2 is 1: 2.
In the cyclization reaction, the reaction temperature of the cyclization reaction is the conventional reaction temperature in the reaction in the field, and preferably, the reaction temperature of the cyclization reaction is 60 ℃.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Y shown as the following formula on a compound shown as a formula B1 and 3-amino-6-methoxypyridazine to obtain a compound shown as a formula B2;
in the amidation reaction Y, the base is a base conventional in such reactions in the art; preferably, the base may be N, N-diisopropylethylamine.
In the amidation reaction Y, the reaction temperature of the amidation reaction is a conventional reaction temperature in this kind of reaction in the art, and preferably, the reaction temperature of the amidation reaction may be 80 ℃.
In the amidation reaction Y, the molar ratio of the base to the compound represented by formula B1 may be 1.5: 1.
In the amidation reaction Y, the molar ratio of HATU (2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate) to the compound shown in the formula B1 can be 1.1: 1.
In the amidation reaction Y, the molar ratio of the 3-amino-6-methoxypyridazine to the compound shown as the formula B1 can be 1.2: 1.
In the amidation reaction Y, the solvent is a solvent conventional in such reactions in the art, preferably, the solvent is an amide solvent; preferably, the amide solvent is N, N-dimethylacetamide.
In some embodiments of the present invention, the method for preparing the compound represented by a6 further comprises the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the compound shown as the formula SM-1 to obtain a compound shown as a formula B1;
in the hydrolysis reaction, the solvent may be ethanol.
In the hydrolysis reaction, the alkali is the alkali which is conventional in the reaction in the field; preferably, the base may be 2.0M aqueous potassium hydroxide.
In the hydrolysis reaction, the molar ratio of the alkali to the compound shown as the formula SM-1 can be 2.5: 1.
The invention also provides a preparation method of the compound A1, which comprises the following steps: in a solvent, in SnCl 2 2H 2 In the presence of O, carrying out a reduction reaction shown as the following formula on the compound shown as the formula SM-1 to obtain a compound shown as the formula A1; r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A1, the reaction conditions of the reduction reaction are as described above.
In the preparation method of the compound shown as A1, C is 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl.
The invention also provides a preparation method of the compound A2, which comprises the following steps: in a solvent, in the presence of alkali, carrying out amidation reaction M shown as the following formula on a compound shown as a formula A1, N' -carbonyldiimidazole and methoxylamine to obtain a compound shown as a formula A2; r -1 Is C 1 -C 4 Alkyl groups of (a); r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A2, the reaction conditions of the amidation reaction M are as described above.
In the preparation method of the compound shown as A2, C is 1 -C 4 The alkyl is methyl, ethyl, n-propyl, isopropyl or n-butylAn alkyl, isobutyl or tert-butyl group, such as n-butyl or ethyl; preferably, R is n-butyl; r -1 Is ethyl.
The preparation method of the compound shown as A2 further comprises the following steps: the compound shown as the formula A1 is prepared according to the preparation method of the compound shown as the formula A1.
The invention also provides a preparation method of the compound A3, which comprises the following steps: the compound shown as the formula A2 is subjected to hydrolysis reaction to obtain a compound shown as the formula A3; r -1 Is C 1 -C 4 Alkyl groups of (a); r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A3, the reaction conditions of the hydrolysis reaction are as described above.
In the preparation method of the compound shown as A3, C is 1 -C 4 Alkyl of (b) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl or ethyl; preferably, R is n-butyl; r -1 Is ethyl.
The preparation method of the compound shown as A3 further comprises the following steps: the compound shown as A2 is prepared according to the preparation method of the compound shown as the formula A2.
The invention also provides a preparation method of the compound shown as A4, in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Q shown as the following formula on the compound shown as the formula A3 and 3-amino-6-methoxypyridazine to obtain a compound shown as the formula A4; r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A4, the conditions of the amidation reaction Q are as described above.
In the preparation method of the compound shown as A4, C is 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl.
The preparation method of the compound shown as A4 further comprises the following steps: the compound shown as A3 is prepared according to the preparation method of the compound shown as the formula A3.
The present invention also provides a process for the preparation of a compound represented by a5, which is scheme 1 or scheme 2;
the scheme 1 comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction shown as the following formula on a compound shown as a formula A4 to obtain a compound shown as a formula A5; r is C 1 -C 4 Alkyl groups of (a);
the scheme 2 comprises the following steps: in a solvent, carrying out amidation reaction on a compound shown as a formula B4, N' -Carbonyldiimidazole (CDI) and methoxyamine in the presence of alkali to obtain a compound shown as a formula A5;
in the preparation method of the compound shown as A5, C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl.
In the process for preparing the compound represented by a5, the reaction conditions for the cyclization reaction in scheme 1 are as described above.
In the preparation method of the compound represented by A5, the reaction conditions of the amidation reaction in the scheme 2 are as described above.
The preparation method of the compound shown as A5 further comprises the following steps: the compound shown as A4 is prepared according to the preparation method of the compound shown as the formula A4.
The preparation method of the compound shown as A5 further comprises the following steps: the compound shown as B4 is prepared according to the preparation method of the compound shown as the formula B4.
The invention also provides a preparation method of the compound shown as B1, which comprises the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on a compound shown as a formula SM-1 to obtain a compound shown as a formula B1; r is n-butyl; r -1 Is ethyl;
preferably, in the preparation method of the compound shown as B1, the reaction conditions of the hydrolysis reaction are as described above.
The invention also provides a preparation method of the compound shown as B2, which comprises the following steps: in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Y shown as the following formula on a compound shown as a formula B1 and 3-amino-6-methoxypyridazine to obtain a compound shown as a formula B2;
preferably, in the preparation method of the compound shown as B2, the reaction conditions of the amidation reaction Y are as described above.
The preparation method of the compound shown as B2 further comprises the following steps: the compound shown as B1 is prepared according to the preparation method of the compound shown as the formula B1.
The invention also provides a preparation method of the compound shown as B3, which comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction shown as the following formula on a compound shown as a formula B2 to obtain a compound shown as a formula B3;
preferably, in the preparation method of the compound shown as B3, the reaction conditions of the cyclization reaction are as described above.
The preparation method of the compound shown as B3 further comprises the following steps: the compound shown as B2 is prepared according to the preparation method of the compound shown as the formula B2.
The invention also provides a preparation method of the compound shown as B4, which comprises the following steps: in a solvent, in the presence of a catalyst, carrying out a reduction reaction shown as the following formula on a compound shown as a formula B3 to obtain a compound shown as a formula B4;
preferably, in the preparation method of the compound shown as B4, the reaction conditions of the reduction reaction are as described above.
The preparation method of the compound shown as B4 further comprises the following steps: the compound shown as B3 is prepared according to the preparation method of the compound shown as the formula B3.
The invention also provides a compound as shown in A1, A2, A3, A4, A5, B1, B2 or B4:
preferably, A4 is
A1 is
The invention also provides application of the compounds A1, A2, A3, A4, A5, B1, B2 or B4 in preparation of Ruogeli.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The brand new Ruogeli intermediates are shown as formulas A1, A2, A3, A4, A5, B1, B2, B3 and B4, and Ruogeli can be prepared by the intermediates in seven steps, wherein the total molar yield of the seven steps is over 70%.
Drawings
Fig. 1 is a liquid chromatogram of relugeli prepared in comparative example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
When the synthesis process of Chinese patent CN104703992A is repeated, impurity (RS-1) which is difficult to remove is generated in the process of nitro reduction, the content is 6.1% by LC-MS detection, and [ M +H] + 537.1, the structure of which is RS-1 by separation and identification
And the impurity can participate in the next reaction to generate an impurity RS-2
The structure of the impurity RS-2 is very similar to relogeli, and therefore, cannot be removed cleanly, and thus high-purity relogeli cannot be prepared. In addition, impurities (RS-3) which are difficult to remove are generated in the nitro reduction process, the content is 2.5 percent by LC-MS detection, and the content is M + H] + The structure of the compound is RS-3 through separation and identification
And the impurity can participate in the next reaction to generate an impurity RS-4
The structure of the impurity RS-4 is very similar to relogeli, and thus cannot be removed cleanly, so that high-purity relogeli cannot be prepared. The impurities cannot be removed by adjusting the reaction conditions of the reduction.
When the synthesis process of the Chinese patent CN111333633A is repeated, the following impurity RS-5 is generated in the hydrogenation reaction process. Molecular weight is [ M + H] + When the molecular weight is 503.1, the analytical structure is shown in the following formula
Intermediate 3 due to structure and reaction thereof
The structures of (a) are very similar and difficult to remove during post-processing. Along with the scale enlargement of the fed materials, the impurities tend to increase, and the removal difficulty is further increased. The inventors have analyzed and searched for the cause of the above impurities and have found that the hydrogenation step tends to produce a large amount of impurities and is not easy to remove. Therefore, in order to avoid the generation of the above impurities, the present invention develops a total recovery by changing the synthesis order of the backbone segmentsA high rate Ruugeli process route.
In the embodiment of the application, R is n-butyl, R -1 For the ethyl group as an example, a method for preparing relogelide, and methods for preparing intermediates a1, a2, A3, a4, a5, B1, B2, B3, and B4 are described.
EXAMPLE 1 preparation of intermediate A1
SM-1(106.4g,0.20mol,1.0eq.) and SnCl were added at room temperature 2 2H 2 O (225.6g,1.0mol,5.0eq.) was added to ethanol (1.2L) in this order, and the reaction was stirred for 2 hours after the temperature was raised to 60 ℃. After the completion of the reaction by LC-MS monitoring, the solvent ethanol of the reaction solution was removed under reduced pressure, methylene chloride (2.0L) and 1.0M sodium hydroxide solution (2.0L) were sequentially added, stirred for 15 minutes, filtered, the cake was washed with methylene chloride (1.0L), the organic phase was collected, the aqueous phase was further extracted with methylene chloride (2.0L), the organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and dried to give intermediate A1 (pale yellow oil; 98.5 g; yield: 98%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):7.43-7.38(m,1H),7.06(t,J＝7.8Hz,2H),6.98(d,J＝8.4Hz,2H),6.59(d,J＝8.4Hz,2H),5.37(s,2H),4.86(s,2H),4.14(q,J＝6.6Hz,2H),4.03(t,J＝7.2Hz,2H),2.23(s,3H),1.50-1.40(m,2H),1.23-1.16(m,5H),0.88-0.79(m,3H).ESI(m/z):[M+H] + :503.1.
EXAMPLE 2 preparation of intermediate A2
CDI (58.4g,0.36mol,2.0eq.) and triethylamine (18.2g,0.18mol,1.0eq.) were added sequentially to acetonitrile (0.5L), the reaction was stirred at 25 ℃ for 15 minutes, methoxyamine hydrochloride (30.0g,0.36mol,2.0eq.) was added in portions, after the addition was complete, stirring was carried out at this temperature for 1 hour, intermediate a1(90.4g,0.18mol,1.0eq.) was added, and the reaction was heated to 60 ℃ and stirred for 2 hours. LC-MS monitoring the reactionAfter completion, after removing acetonitrile which is a solvent of the reaction solution under reduced pressure, ethyl acetate (1.2L) and water (1.2L) were added, extraction was carried out, the layers were separated, the organic phase was collected and concentrated to about 0.3L, n-heptane (0.6L) was added, and the mixture was stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate A2 (pale yellow solid; 101.6 g; yield: 98%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):9.60(s,1H),9.05(s,1H),7.68(d,J＝8.4Hz,2H),7.42-7.40(m,1H),7.25(d,J＝6.6Hz,2H),7.06(t,J＝7.8Hz,2H),4.88(s,2H),4.15(q,J＝6.6Hz,2H),4.03(t,J＝7.2Hz,2H),3.63(s,3H),2.27(s,3H),1.55-1.43(m,2H),1.23-1.16(m,5H),0.88-0.79(m,3H).ESI(m/z):[M+H] + :576.1.
EXAMPLE 3 preparation of intermediate A3
Intermediate a2(97.8g,0.17mol,1.0eq.) and 2.0M aqueous potassium hydroxide solution (0.21L,0.425mol,2.5eq.) were added in sequence to ethanol (0.8L), and the reaction solution was stirred for 8 hours after being heated to 60 ℃. After completion of the reaction, the solvent ethanol in the reaction mixture was removed under reduced pressure by LC-MS monitoring, and then water (0.5L) and 12N hydrochloric acid (80mL) were added to adjust the pH of the reaction mixture to about 2. Ethyl acetate (1.0L) was added, extracted, the layers separated, the organic phase collected and, when concentrated to about 0.3L, n-heptane (0.7L) was added and the mixture was stirred at 10 ℃ for 2 hours to afford intermediate A3 (light yellow solid; 89.3 g; yield: 96%) after filtration and drying. 1 H-NMR(600MHz,DMSO-d 6 ,δppm):12.93(s,1H),9.59(s,1H),9.04(s,1H),7.66(d,J＝9.0Hz,2H),7.42-7.38(m,1H),7.22(d,J＝7.8Hz,2H),7.06(t,J＝7.8Hz,2H),4.88(s,2H),4.03(t,J＝7.2Hz,2H),3.62(s,3H),2.29(s,3H),1.55-1.44(m,2H),1.23-1.16(m,2H),0.86-0.80(m,3H).ESI(m/z):[M+H] + :548.1.
EXAMPLE 4 preparation of intermediate A4
The intermediate is reacted with a catalystA3(87.6g,0.16mol,1.0eq.), 3-amino-6-methoxypyridazine (24.0g,0.192mol,1.2eq.), N, N-diisopropylethylamine (31.0g,0.24mol,1.5eq.) and HATU (66.8g,0.176mol,1.1eq.) were added in this order to N, N-dimethylacetamide (0.8L), and the reaction mixture was stirred for 5 hours after the temperature was raised to 80 ℃. After the completion of the reaction, the reaction solution was naturally cooled to room temperature by LC-MS, water (0.8L) and ethyl acetate (0.8L) were added, extraction was carried out, the layers were separated, the organic phase was collected and concentrated to about 0.3L, n-heptane (0.6L) was added, and the mixture was stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate A4 (white solid; 99.5 g; yield: 95%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):10.60(s,1H),9.60(s,1H),9.06(s,1H),8.20(d,J＝9.0Hz,1H),7.70(d,J＝9.0Hz,2H),7.42-7.37(m,1H),7.31-7.29(m,3H),7.04(t,J＝8.4Hz,2H),4.97(s,2H),4.06(t,J＝6.6Hz,2H),4.00(s,3H),3.63(s,3H),2.24(s,3H),1.50-1.45(m,2H),1.18(q,J＝7.2Hz,2H),0.75(t,J＝7.2Hz,3H).ESI(m/z):[M+H] + :655.2.
EXAMPLE 5 preparation of intermediate A5
Intermediate a4(98.1g,0.15mol,1.0eq.) and 30% sodium methoxide methanol solution (13.5g,0.075mol,0.5eq.) were added in this order to a mixed solution of tetrahydrofuran (0.15L) and methanol (1.5L), and the reaction solution was stirred for 1 hour after being heated to 60 ℃. After the completion of the reaction was monitored by LC-MS, the reaction mixture was naturally cooled to room temperature, 12N hydrochloric acid (6.25mL) was added thereto to adjust the pH of the reaction mixture to neutral, and the mixture was concentrated under reduced pressure to about 1.0L, stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate A5 (white solid; 85.3 g; yield: 98%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):9.70(s,1H),9.25(s,1H),7.75(d,J＝9.0Hz,1H),7.70(d,J＝8.4Hz,2H),7.46(d,J＝9.0Hz,2H),7.35(d,J＝8.4Hz,2H),7.13(t,J＝8.4Hz,2H),5.38(d,J＝13.8Hz,1H),5.17(d,J＝13.8Hz,1H),4.09(s,3H),3.63(s,3H),2.40(s,3H).ESI(m/z):[M+H] + :581.1.
Example 6 preparation of intermediate a6
Intermediate a5(87.0g,0.15mol,1.0eq.), N-chlorosuccinimide (22.0g,0.165mol,1.1eq.) and AIBN (4.92g,0.03mol,0.2eq.) were added in sequence to ethyl acetate (1.5L), and the reaction solution was stirred for 30 minutes after being warmed to 60 ℃. After the completion of the reaction, the reaction solution was naturally cooled to a room temperature by LC-MS, water (1.5L) was added thereto, extraction and layer separation were carried out, the organic phase was collected and concentrated to about 0.5L, and the mixture was stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate A6 (white solid; 85.0 g; yield: 92%). 1 H-NMR(400MHz,DMSO-d 6 ,δppm):9.70(s,1H),9.16(s,1H),7.81-7.76(m,3H),7.49-7.46(m,4H),7.15(t,J＝8.0Hz,2H),5.36(s,1H),5.23(s,1H),4.86(s,2H),4.10(s,3H),3.64(s,3H).ESI(m/z):[M+H] + :615.1&617.1.
EXAMPLE 7 preparation of intermediate B1
Intermediate SM-1(106.4g,0.20mol,1.0eq.) and 2.0M aqueous potassium hydroxide (0.25L,0.50mol,2.5eq.) were added to ethanol (0.8L), and the reaction was stirred for 2 hours after warming to 60 ℃. After the completion of the reaction was monitored by LC-MS, the solvent ethanol of the reaction solution was removed under reduced pressure, water (0.3L) and 12N hydrochloric acid (60mL) were added to adjust the pH of the reaction solution to about 2, ethyl acetate (0.8L) was added, extraction was carried out, the layers were separated, the organic phase was collected and concentrated to about 0.3L, N-heptane (0.6L) was added, the mixture was stirred at 10 ℃ for 2 hours, and after filtration and drying, intermediate B1 (off-white solid; 98.8 g; yield: 98%) was obtained. 1 H-NMR(400MHz,DMSO-d 6 ,δppm):13.05(s,1H),8.27(d,J＝8.8Hz,2H),7.63(d,J＝8.0Hz,2H),7.45-7.37(m,1H),7.07(t,J＝8.0Hz,2H),4.90(s,2H),4.03(t,J＝7.2Hz,2H),2.36(s,3H),1.55-1.45(m,2H),1.23-1.15(m,2H),0.86-0.80(m,3H).ESI(m/z):[M+H] + :505.1.
EXAMPLE 8 preparation of intermediate B2
Intermediate B1(95.8g,0.19mol,1.0eq.), 3-amino-6-methoxypyridazine (28.5g,0.228mol,1.2eq.), N, N-diisopropylethylamine (36.8g,0.285mol,1.5eq.) and HATU (79.4g,0.209mol,1.1eq.) were added in this order to N, N-dimethylacetamide (1.0L), and the reaction was stirred for 5 hours after warming to 80 ℃. After the completion of the reaction, the reaction solution was naturally cooled to room temperature by LC-MS, water (1.0L) and ethyl acetate (1.0L) were added, extraction was carried out, the layers were separated, the organic phase was collected and concentrated to about 0.35L, n-heptane (0.7L) was added, and the mixture was stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate B2 (white solid; 108.0 g; yield: 93%). 1 H-NMR(400MHz,DMSO-d 6 ,δppm):10.79(s,1H),8.31(d,J＝8.8Hz,2H),8.21(d,J＝9.6Hz,1H),7.69(d,J＝8.8Hz,2H),7.45-7.37(m,1H),7.31(d,J＝9.6Hz,1H),7.06(t,J＝8.0Hz,2H),4.99(s,2H),4.05(t,J＝6.8Hz,2H),4.00(s,3H),2.32(s,3H),1.50-1.43(m,2H),1.17(q,J＝7.6Hz,2H),0.74(t,J＝7.6Hz,3H).ESI(m/z):[M+H] + :612.1.
EXAMPLE 9 preparation of intermediate B3
Intermediate B2(103.9g,0.17mol,1.0eq.) and 30% sodium methoxide methanol solution (15.3g,0.085mol,0.5eq.) were sequentially added to the mixed solution of tetrahydrofuran (0.15L) and methanol (1.5L), and the reaction solution was stirred for 1 hour after being warmed to 60 ℃. After the completion of the reaction was monitored by LC-MS, the reaction solution was naturally cooled to room temperature, 12N hydrochloric acid (7.0mL) was added thereto to adjust the pH of the reaction solution to neutral, and the mixture was concentrated under reduced pressure to about 1.0L, stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate B3 (pale yellow solid; 89.5 g; yield: 98%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):8.32(d,J＝9.0Hz,2H),7.77-7.74(m,3H),7.47(d,J＝9.0Hz,2H),7.14(t,J＝8.4Hz,2H),5.39(s,1H),5.22(s,1H),4.09(s,3H),2.50(s,3H).ESI(m/z):[M+H] + :538.0.
EXAMPLE 10 preparation of intermediate B4
Intermediate B3(85.9g,0.16mol,1.0eq.) and 10% Pd/C (8.59g, 55% water) were added to a mixed solution of dichloromethane (1.2L) and methanol (0.4L), and the reaction system was replaced with H 2 After the atmosphere, the mixture was stirred at 25 ℃ for 24 hours. After the completion of the reaction was monitored by LC-MS, the catalyst was filtered off and washed with dichloromethane (0.3L), the filtrate was concentrated to about 0.35L under pressure, methanol (0.3L) was added, stirred at 10 ℃ for 2 hours, filtered and dried to obtain intermediate B4 (white solid; 78.0 g; yield: 96%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):7.75(d,J＝9.0Hz,1H),7.46(d,J＝9.0Hz,2H),7.14(t,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),6.64(d,J＝8.4Hz,2H),5.43(s,2H),5.38(d,J＝15.0Hz,1H),5.17(d,J＝15.0Hz,1H),4.10(s,3H),2.36(s,3H).ESI(m/z):[M+H] + :508.1.
EXAMPLE 11 preparation of intermediate A5
CDI (48.6g,0.30mol,2.0eq.) and triethylamine (15.2g,0.15mol,1.0eq.) were added in this order to acetonitrile (0.5L), the reaction was stirred at 25 ℃ for 15 minutes, methoxylamine hydrochloride (25.0g,0.30mol,2.0eq.) was added thereto in portions, after completion of the addition, after stirring at this temperature for 1 hour, intermediate B4(76.0g,0.15mol,1.0eq.) was added, and the reaction was heated to 60 ℃ and stirred for 2 hours. After the reaction was monitored by LC-MS, the reaction was concentrated to about 0.15L under hydraulic pressure, methanol (0.8L) was added, stirred at 10 ℃ for 2 hours, filtered and dried to give intermediate A5 (white solid; 82.8 g; yield: 95%). 1 H-NMR(600MHz,DMSO-d 6 ,δppm):9.70(s,1H),9.25(s,1H),7.75(d,J＝9.0Hz,1H),7.70(d,J＝8.4Hz,2H),7.46(d,J＝9.0Hz,2H),7.35(d,J＝8.4Hz,2H),7.13(t,J＝8.4Hz,2H),5.38(d,J＝13.8Hz,1H),5.17(d,J＝13.8Hz,1H),4.09(s,3H),3.63(s,3H),2.40(s,3H).ESI(m/z):[M+H] + :581.1.
Example 12 preparation of Ruogeli
Intermediate a6(80.0g,0.13mol,1.0eq.) prepared in example 6, a 2.0M dimethylamine tetrahydrofuran solution (0.071L,0.143mol,1.1eq.) and triethylamine (15.7g,0.156mol,1.2eq.) were added in this order to acetonitrile (0.8L), and the reaction mixture was stirred at 25 ℃ for 2 hours. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated under reduced pressure, water (0.8L) and dichloromethane (0.8L) were added, extracted, and the layers were separated, the organic phase was collected and concentrated to about 0.35L, ethyl acetate (0.3L) was added, and slurried at room temperature for 24 hours, filtered and dried to obtain Ruugeli (white solid; 79.3 g; purity: 99.82%; yield: 98%). 1 H-NMR(400MHz,DMSO-d 6 ,δppm):9.63(s,1H),9.07(s,1H),7.76-7.71(m,3H),7.53-7.44(m,4H),7.14(t,J＝8.0Hz,2H),5.38(s,1H),5.22(s,1H),4.09(s,3H),3.64-3.53(m,5H),2.04(s,6H).ESI(m/z):[M+H] + :624.1
The chemical purity of the Ruugeli obtained by the patent is as follows: 99.82%, the above-mentioned related impurities RS-2 and RS-4 were not detected. HPLC conditions are shown in table 1:
TABLE 1
Comparative example 1
Ruogeli was prepared according to Chinese patent CN 104703992A.
Acetonitrile (30mL) and 1, 1-carbonyldiimidazole (CDI, 5.01g, 30.9mmol, 1.7eq) were added to the reactor and the mixture was stirred. Triethylamine (1.56g,15.4mmol,0.85eq) was added with stirring and cooled to an internal temperature of 10 ± 5 ℃. Methoxyamine hydrochloride (2.90g, 34.7mmol, 1.91eq) was added thereto portionwise with stirring at an internal temperature of 30 ℃ or lower, and the container used for the reagent was washed with acetonitrile (5 mL). After stirring the mixture at an internal temperature of 25 ± 5 ℃ and confirming that the mixture is dissolved, the solution is stirred for another 10 minutes or more. Then, 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2, 3-d ] pyrimidine-2, 4(1H, 3H) -dione (10.0g,18.1mmol) was added thereto with stirring, and the container used for the reagent was washed with acetonitrile (5 mL). The reaction mixture was warmed to an internal temperature of 50. + -. 5 ℃ and stirred at the same temperature for 2 hours to give a reaction mixture referred to as a reaction mixture. Triethylamine (2.35g,23.2mmol,1.28eq) was added thereto at an internal temperature of 50. + -. 5 ℃ with stirring. Tap water (40mL) was added dropwise thereto at an internal temperature of 40-55 ℃, the mixture was stirred for 1 hour, and tap water (100mL) was again added dropwise thereto at an internal temperature of 40-55 ℃. The mixture is aged at an internal temperature of 25 + -5 deg.C for 1 hour or more with stirring. The crystals were collected by filtration, washed with a mixed solvent of tap water (16mL) and acetonitrile (4mL) to give wet crystals, and dried to obtain Ruugeli. The HPLC chromatogram is shown in FIG. 1, and the detection conditions are shown in Table 1 above. Time to peak of rilogeli: 12.13min (99.22% content), time to peak of impurity RS-4: 18.15min (content 0.78%).
Claims (15)
1. A method for preparing a compound shown as A6, which is characterized by comprising the following steps: in ethyl acetate, carrying out chlorination reaction on a compound shown as a formula A5 and a chlorination reagent shown as a formula to obtain a compound shown as a formula A6;
2. the process according to claim 1 for the preparation of the compound represented by a6, wherein in the chlorination reaction, the chlorination reaction is carried out in the presence of an initiator; preferably, the initiator is AIBN; more preferably, the molar ratio of the initiator to the compound shown as the formula A5 is 1: 5;
and/or in the chlorination reaction, the reaction temperature of the chlorination reaction is 60 ℃;
and/or in the chlorination reaction, the molar ratio of the chlorination reagent to the compound shown as the formula A5 is 1.1: 1;
and/or in the chlorination reaction, the chlorination reagent is N-chlorosuccinimide;
and/or in the chlorination reaction, the mass-to-volume ratio of the compound shown as the formula A5 to the ethyl acetate is 58 g/L.
3. The method of claim 2, wherein the method further comprises the steps of scheme 1 or scheme 2;
the scheme 1 comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction on a compound shown as a formula A4 to obtain the compound shown as a formula A5; r is C 1 -C 4 Alkyl groups of (a);
the scheme 2 comprises the following steps: in a solvent, in the presence of alkali, carrying out amidation reaction on a compound shown as a formula B4, N' -carbonyldiimidazole and methoxylamine to obtain a compound shown as a formula A5;
preferably, in the cyclization reaction of scheme 1, C is 1 -C 4 Alkyl of (b) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl;
and/or, in the cyclization reaction of the scheme 1, the solvent is a mixed solvent of an alcohol solvent and an ether solvent; the alcohol solvent is preferably methanol; the ether solvent is preferably tetrahydrofuran; more preferably the volume ratio of said methanol to said tetrahydrofuran is 10: 1;
and/or, in the cyclization reaction of scheme 1, the base is alkoxide; the alkoxide is preferably sodium methoxide; for example 30% sodium methoxide methanol solution;
and/or, in the cyclization reaction of scheme 1, the molar ratio of the base to the compound shown as formula a4 is 1: 2;
and/or, the reaction temperature of the cyclization reaction of the scheme 1 is 60 ℃;
and/or, in the amidation reaction in the scheme 2, the solvent is a nitrile solvent; more preferably, the nitrile solvent is acetonitrile;
and/or, in the amidation reaction in scheme 2, the base is triethylamine;
and/or, the reaction temperature of amidation reaction in scheme 2 is 60 ℃;
and/or, in the amide reaction in scheme 2, the molar ratio of the base to the compound shown as formula B4 is 1: 1;
and/or, in the amidation reaction in the scheme 2, the molar ratio of the N, N' -carbonyldiimidazole to the compound shown in the formula B4 is 2: 1;
and/or, in the amidation reaction in the scheme 2, the methoxylamine is added in the form of methoxylamine salt, such as methoxylamine hydrochloride;
and/or, in the amidation reaction in the scheme 2, the molar ratio of the methoxyamine to the compound shown in the formula B4 is 2: 1;
and/or in the amidation reaction in the scheme 2, the N, N' -carbonyldiimidazole and the methoxyamine are mixed firstly, and then the compound shown as the formula B4 is added.
4. The method for preparing the compound represented by A6 according to claim 3, wherein the method for preparing the compound represented by A6 further comprises the steps of: in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Q shown as the following formula on a compound shown as a formula A3 and 3-amino-6-methoxypyridazine to obtain a compound shown as a formula A4;
and/or, the preparation method of the compound shown as A6 further comprises the following steps: in a solvent, in the presence of a catalyst, carrying out a reduction reaction shown as the following formula on a compound shown as a formula B3 to obtain the compound shown as the formula B4;
preferably, in the amidation reaction Q, the base is N, N-diisopropylethylamine;
and/or in the amidation reaction Q, the reaction temperature of the amidation reaction is 80 ℃;
and/or in the amidation reaction Q, the molar ratio of the alkali to the compound shown as the formula A3 is 1.5: 1;
and/or in the amidation reaction Q, the molar ratio of the HATU to the compound shown in the formula A3 is 1.1: 1;
and/or in the amidation reaction Q, the molar ratio of the 3-amino-6-methoxypyridazine to the compound shown in the formula A3 is 1.2: 1;
and/or in the amidation reaction Q, the solvent is an amide solvent; more preferably, the amide solvent is N, N-dimethylacetamide;
and/or in the reduction reaction, the solvent is a mixed solvent of methanol and dichloromethane; more preferably, the volume ratio of the methanol to the dichloromethane is 1: 3;
and/or, in the reduction reaction, the catalyst is a palladium catalyst, such as Pd/C, for example, 10% Pd/C;
and/or in the reduction reaction, the reaction temperature of the reduction reaction is 25 ℃;
and/or in the reduction reaction, the mass ratio of the catalyst to the compound shown as the formula B3 is 1: 10;
and/or, in the reduction reaction, the reducing agent of the reduction reaction is hydrogen, such as normal pressure hydrogen.
5. The method for preparing the compound represented by A6 according to claim 4, wherein the method for preparing the compound represented by A6 further comprises the following steps: hydrolyzing the compound shown as the formula A2 to obtain the compound shown as the formula A3; r is -1 Is C 1 -C 4 Alkyl groups of (a);
and/or the preparation method of the compound shown as A6 further comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction on a compound shown as a formula B2 to obtain a compound shown as a formula B3;
preferably, in the hydrolysis reaction, C is 1 -C 4 The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl or isopropylButyl or tert-butyl, such as ethyl;
and/or, in the hydrolysis reaction, the solvent is ethanol;
and/or, the alkali in the hydrolysis reaction is 2.0M potassium hydroxide aqueous solution;
and/or, in the hydrolysis reaction, the molar ratio of the alkali to the compound shown as the formula A2 is 2.5: 1;
and/or, in the cyclization reaction, the mixed solvent of the solvent alcohol solvent and the ether solvent; the alcohol solvent is preferably methanol; the ether solvent is preferably tetrahydrofuran;
and/or, in the cyclization reaction, the alkali is alkoxide; the alkoxide is preferably sodium methoxide;
and/or in the cyclization reaction, the molar ratio of the alkali to the compound shown as the formula B2 is 1: 2;
and/or in the cyclization reaction, the reaction temperature of the cyclization reaction is 60 ℃.
6. The method of claim 5, wherein the method further comprises the steps of: in a solvent, in the presence of alkali, carrying out amidation reaction M shown as the following formula on a compound shown as a formula A1, N' -carbonyldiimidazole and methoxyamine to obtain a compound shown as a formula A2;
and/or the preparation method of the compound shown as A6 further comprises the following steps: in a solvent, in the presence of alkali and HATU, carrying out amidation reaction Y shown as the following formula on a compound shown as a formula B1 and 3-amino-6-methoxypyridazine to obtain a compound shown as a formula B2;
and/or in the amidation reaction M, the solvent is a nitrile solvent; preferably, the nitrile solvent is acetonitrile;
and/or in the amidation reaction M, the base is triethylamine;
and/or, in the amidation reaction M, the reaction temperature of the amination reaction is 60 ℃;
and/or in the amidation reaction M, the molar ratio of the alkali to the compound shown as the formula A1 is 1: 1;
and/or in the amidation reaction M, the molar ratio of the N, N' -carbonyldiimidazole to the compound shown as the formula A1 is 2: 1;
and/or, in the amidation reaction M, the methoxylamine is added to the reaction in the form of methoxyamine salt, such as methoxyamine hydrochloride;
and/or in the amidation reaction M, the molar ratio of the methoxylamine to the compound shown as the formula A1 is 2: 1;
and/or in the amidation reaction Y, the base is N, N-diisopropylethylamine;
and/or in the amidation reaction Y, the reaction temperature of the amidation reaction is 80 ℃;
and/or in the amidation reaction Y, the molar ratio of the base to the compound shown as the formula B1 is 1.5: 1;
and/or in the amidation reaction Y, the molar ratio of the HATU to the compound shown in the formula B1 is 1.1: 1;
and/or in the amidation reaction Y, the molar ratio of the 3-amino-6-methoxypyridazine to the compound shown in the formula B1 is 1.2: 1;
and/or the solvent is an amide solvent; more preferably, the amide solvent is N, N-dimethylacetamide.
7. The compound of claim 6, as represented by A6The preparation method of the compound shown as A6 is characterized by further comprising the following steps: in a solvent, in SnCl 2 2H 2 In the presence of O, carrying out a reduction reaction shown as the following formula on the compound shown as the formula SM-1 to obtain a compound shown as the formula A1;
and/or, the preparation method of the compound shown as A6 further comprises the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the compound shown as the formula SM-1 to obtain a compound shown as a formula B1;
preferably, in the reduction reaction, the solvent is ethanol;
and/or in the reduction reaction, the reaction temperature of the reduction reaction is 60 ℃;
and/or, in the reduction reaction, the SnCl 2 2H 2 The molar ratio of O to the compound shown as the formula SM-1 is 5: 1;
and/or, in the hydrolysis reaction, the solvent is ethanol;
and/or, in the hydrolysis reaction, the alkali is 2.0M potassium hydroxide aqueous solution;
and/or in the hydrolysis reaction, the molar ratio of the alkali to the compound shown as the formula SM-1 is 2.5: 1.
8. A method for preparing a compound represented by a1, comprising the steps of: in a solvent, in SnCl 2 2H 2 In the presence of O, carrying out a reduction reaction shown as the following formula on the compound shown as the formula SM-1 to obtain a compound shown as the formula A1; r is C 1 -C 4 Alkyl groups of (a);
preferably, in the method for preparing the compound shown as A1, the reaction conditions of the reduction reaction are as defined in claim 7;
and/or, in the preparation method of the compound shown as A1, the C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl.
9. A preparation method of a compound shown as A2 comprises the following steps: in a solvent, in the presence of alkali, carrying out amidation reaction M shown as the following formula on a compound shown as a formula A1, N' -carbonyldiimidazole and methoxylamine to obtain a compound shown as a formula A2; r -1 Is C 1 -C 4 Alkyl groups of (a); r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A2, the reaction conditions of the amidation reaction M are as set forth in claim 6;
and/or, in the preparation method of the compound shown as A2, the C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl or ethyl; preferably, R is n-butyl; r -1 Is ethyl;
and/or, the preparation method of the compound shown as A2 further comprises the following steps: the compound shown as the formula A1 is obtained by the preparation method of the compound shown as the formula A1 according to claim 8.
10. A method for preparing a compound represented by a3, comprising the steps of:the compound shown as the formula A2 is subjected to hydrolysis reaction to obtain a compound shown as the formula A3; r -1 Is C 1 -C 4 Alkyl groups of (a); r is C 1 -C 4 Alkyl groups of (a);
preferably, in the method for preparing the compound shown as A3, the reaction conditions of the hydrolysis reaction are as defined in claim 6;
and/or, in the preparation method of the compound shown as A3, the C 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl or ethyl; preferably, R is n-butyl; r -1 Is ethyl;
and/or, the preparation method of the compound shown as A3 further comprises the following steps: the compound of formula a2 is prepared according to the method of claim 9 for the preparation of the compound of formula a 2.
11. A preparation method of a compound shown as A4 comprises the following steps of carrying out amidation reaction Q shown as the following formula on a compound shown as a formula A3 and 3-amino-6-methoxypyridazine in a solvent in the presence of alkali and HATU to obtain a compound shown as a formula A4; r is C 1 -C 4 Alkyl groups of (a);
preferably, in the preparation method of the compound shown as A4, the condition of the amidation reaction Q is as defined in claim 5;
and/or, in the preparation method of the compound shown as A4, the C 1 -C 4 Alkyl of (b) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl;
and/or, the preparation method of the compound shown as A4 further comprises the following steps: the compound of formula A3 prepared according to the method of claim 10, wherein the compound is represented by formula A3.
12. A preparation method of a compound shown as B4 comprises the following steps: in a solvent, in the presence of a catalyst, carrying out a reduction reaction shown as the following formula on a compound shown as a formula B3 to obtain a compound shown as a formula B4;
preferably, in the method for preparing the compound shown as B4, the reaction conditions of the reduction reaction are as defined in claim 5.
13. A process for the preparation of a compound of formula a5, which is scheme 1 or scheme 2;
the scheme 1 comprises the following steps: in a solvent, in the presence of alkali, carrying out cyclization reaction shown as the following formula on a compound shown as a formula A4 to obtain a compound shown as a formula A5; r is C 1 -C 4 Alkyl groups of (a);
the scheme 2 comprises the following steps: in a solvent, in the presence of alkali, carrying out amidation reaction shown as the following formula on a compound shown as a formula B4, N' -carbonyldiimidazole and methoxylamine to obtain a compound shown as a formula A5;
preferably, in the preparation method of the compound shown as A5, C is 1 -C 4 Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example n-butyl;
and/or, in the preparation method of the compound shown as A5, the reaction conditions of the cyclization reaction in the scheme 1 are shown in claim 4;
and/or, in the preparation method of the compound shown as A5, the reaction conditions of the amidation reaction in the scheme 2 are as described in claim 4;
and/or, the preparation method of the compound shown as A5 further comprises the following steps: preparing said compound of formula a4 according to the process of claim 11 for the preparation of a compound of formula a 4;
and/or, the preparation method of the compound shown as A5 further comprises the following steps: the compound of formula B4, prepared according to the process of claim 12, represented by formula B4.
14. A compound as shown in a1, a2, A3, a4, a5, B1, B2, or B4:
preferably, A4 is
A1 is
15. Use of a compound of claim 14 as shown in a1, a2, A3, a4, a5, B1, B2, or B4 for the preparation of rilogeli.
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