CN115594689B - Synthesis method of Rayleigh Lu Geli intermediate and Rayleigh Lu Geli - Google Patents

Synthesis method of Rayleigh Lu Geli intermediate and Rayleigh Lu Geli Download PDF

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CN115594689B
CN115594689B CN202210831588.XA CN202210831588A CN115594689B CN 115594689 B CN115594689 B CN 115594689B CN 202210831588 A CN202210831588 A CN 202210831588A CN 115594689 B CN115594689 B CN 115594689B
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CN115594689A (en
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朱高翔
杨峰
叶四明
康禄
曹玉婷
刘翊
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JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 present invention provides compounds of formula VI wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Each independently selected from hydrogen, C 1 ‑C 3 Alkyl, C of (2) 1 ‑C 3 Alkoxy, amino or hydroxy, R 8 Selected from hydrogen or C 1 ‑C 3 Is a hydrocarbon group. The invention also provides preferred compounds of formula VI and their use as starting materials in the preparation of Rayleigh Lu Geli. In addition, the invention also provides a novel preparation method of the Rayleigh Lu Geli.

Description

Synthesis method of Rayleigh Lu Geli intermediate and Rayleigh Lu Geli
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a novel intermediate of a Rayleigh Lu Geli and a synthesis method of Rayleigh Lu Geli.
Background
Rayleigh Lu Geli (CAS: 737789-87-6) is the first oral gonadotropin releasing hormone (GnRH) receptor antagonist to bind to and block the GnRH receptor in the anterior pituitary gland, thereby reducing gonadotropin-luteinizing hormone and follicle stimulating hormone release and thereby reducing estrogen and progestin production in the female ovary and testosterone production in the male testis. Rayleigh Lu Geli, developed by the chemical industry Co., ltd., of Wuta-Japan, is currently used clinically for the treatment of uterine fibroids and endometriosis and advanced prostate cancer.
The molecular structure of the Rui Lu Geli is shown in formula I:
chinese patent application publication No. CN104703992a (publication No. 2015, 6, 10) discloses a method for synthesizing rayl Lu Geli:
first, p-nitrophenylacetic acid of formula A and SOCl 2 Preparing acyl chloride of a structural formula B by reaction; condensing, hydrolyzing and decarboxylating the compound with the structural formula B with malonate to obtain a compound with the structural formula C; thirdly, condensing and cyclizing the compound with the structural formula C, a sulfur simple substance and ethyl cyanoacetate to prepare a compound with the structural formula D, wherein the total yield of the three steps is 79.8%; fourthly, reacting the compound of the structural formula D with ethyl chloroformate to obtain a compound of the structural formula F, wherein the yield is 96.1%; fifthly, carrying out substitution reaction on the compound of the structural formula E and 2, 3-difluorobenzyl bromide in the presence of alkali to prepare a compound of the structural formula F, wherein the yield is 95.5%; in the sixth step, 2 '-azobis (2, 4-dimethyl valeronitrile is used as a free radical initiator, a compound of a structural formula F and NBS are subjected to free radical reaction and bromine-adding to obtain a compound of a structural formula G, the yield is 92.1%, the purity is 93%, in the seventh step, the compound of the structural formula G and dimethylamine salt are subjected to substitution reaction to obtain a compound of a structural formula H, the yield is 89.6%, in the eighth step, the compound of the structural formula F is subjected to hydrolysis to obtain a compound of a structural formula J, the yield is 89.9%, in the ninth step, the compound of the structural formula J and 3-amino-6-methoxypyridazine are subjected to amide condensation reaction in the presence of propylphosphonic anhydride and alkali to obtain a compound of a structural formula K, the yield is 97%, in the tenth step, the compound of the structural formula K is subjected to ring closure under alkaline conditions to obtain a compound of a structural formula L, the yield is 98%, in the eleventh step, the compound of the structural formula L is subjected to reduction reaction to obtain a compound of a structural formula M, the yield is 84.1%, in the twelfth step, the compound of the structural formula M is subjected to hydrolysis reaction to obtain a crystalline compound of a structural formula J, 3-amino-6-methoxypyridyl (I) under the condition of which is subjected to crystallization reaction with tetrahydrofuran in the presence of tetrahydrofuran, and the crystalline structure of 3-1' -dicarboxyl is 57I, namely, the crystalline compound of Lu Geli%.
The preparation method has the following problems:
firstly, the price of the initial raw material, p-nitrophenylacetic acid, is relatively high, which is not beneficial to reducing the cost; second, the preparation of the compounds of formula B requires the use of large amounts of SOCl 2 The odor is big and toxic, which is unfavorable for the ringEnsuring and safely producing; thirdly, adding a large amount of acid when preparing the compound of the structural formula C, and washing with saline water to generate a larger amount of waste liquid; fourth, in the sixth step, the synthesis of the compound of formula G from the compound of formula F is achieved by free radical reaction, which is difficult to control, resulting in a compound of formula G having a low purity (93%); finally, the whole route is 12 steps, which is more complicated.
Therefore, developing a new method for preparing the Rui Lu Geli, which has the advantages of short steps, simple control, low cost and environmental friendliness, is necessary for ensuring safe production and reducing the cost of administration to people.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a revascularization Lu Geli intermediate with a structural formula VI, a preparation method thereof and a method for preparing the revascularization Lu Geli by the intermediate. The novel method for preparing the Rayleigh Lu Geli provided by the invention has a short route; compared with 12 steps disclosed in the prior art CN104703992A, the preparation method of the Rayleigh Lu Geli provided by the invention only needs 7 steps. In addition, the preparation method has low price of the initial raw materials; free radical reaction is not adopted, and the control is easy; in addition, the use of the thionyl chloride which has large odor and is toxic and a large amount of acid are avoided, so that the production is safer and more environment-friendly.
In order to achieve the technical effects, the invention adopts the following technical scheme:
a compound of the formula VI,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R7 are each independently selected from hydrogen, C 1 -C 3 Alkyl, C of (2) 1 -C 3 Alkoxy, amino or hydroxy, R 8 Selected from hydrogen or C 1 -C 3 Is a hydrocarbon group.
As a preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Are all hydrogen, R 8 Methyl, the compound is a compound of the structural formula VI-1,
the invention also provides a preparation method of the compound with the structural formula VI, which comprises the following steps:
step A: the method comprises the steps of (1) carrying out condensation reaction on a compound with a structural formula IX serving as a starting material and N, N-dimethylformamide dimethyl acetal to obtain a compound with a structural formula VIII;
and (B) step (B): reacting a compound of a structural formula VIII with a sulfur simple substance and a compound of a structural formula VII in the presence of alkali to obtain a compound of a structural formula VI;
wherein R is 1 -R 8 As defined previously.
As a preferred embodiment, the present invention provides a process for the preparation of a compound of formula VI-1 comprising the steps of:
step A-1: the p-nitrotoluene of the structural formula IX-1 is used as a starting material to carry out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound of the structural formula VIII-1;
step B-1: the compound of the structural formula VIII-1 reacts with a sulfur simple substance and the compound of the structural formula VII-1 in the presence of alkali to obtain the compound of the structural formula VI-1.
Preferably, in the step A-1, the molar ratio of the paranitrotoluene of the structural formula IX-1 to the N, N-dimethylformamide dimethyl acetal is 1:1 to 1:10; more preferably 1:1 to 1:3.
Also preferably, in the step A-1, N, N-dimethylformamide dimethyl acetal is added in 2 to 3 times.
Preferably, the reaction solvent of step A-1 is selected from DMF, DMAc (N, N-dimethylacetamide), N-methylpyrrolidone, DMSO or toluene; more preferably DMF.
Preferably, the reaction temperature of step A-1 is 50-200deg.C, more preferably 80-160deg.C.
Preferably, in step B-1, the molar ratio of the compound of formula VIII-1 to elemental sulfur is from 1:1 to 1:2, more preferably from 1:1 to 1:1.2.
Preferably, in step B-1, the molar ratio of the compound of formula VIII-1 to the compound of formula VII-1 is from 1:1 to 1:2, more preferably from 1:1 to 1:1.2.
Preferably, in the step B-1, the base is selected from morpholine, piperidine or tetrahydropyrrole; more preferably morpholine.
Preferably, in the step B-1, the molar ratio of the compound of the formula VIII-1 to the base is 1:0.5 to 1:5; more preferably 1:0.5 to 1:3.
Preferably, the reaction solvent of step B-1 is selected from methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, acetone or tetrahydrofuran; more preferably methanol, ethanol or isopropanol.
Preferably, the reaction temperature of step B-1 is from 30 to 100deg.C, more preferably from 50 to 80deg.C.
The invention also provides application of the compound with the structural formula VI-1 in preparation of the Rayleigh Lu Geli.
Therefore, the invention also provides a preparation method of the Rayleigh Lu Geli, which takes the compound with the structural formula VI-1 as the starting material and comprises the following steps:
step 1, reacting a compound of a structural formula VI-1 with triphosgene to generate a compound of a structural formula V;
step 2, carrying out substitution reaction on a compound with a structural formula V and 2, 6-difluorobenzyl chloride in the presence of alkali to generate a compound with a structural formula IV;
step 3, reducing the compound with the structural formula IV by a catalyst to obtain a compound with the structural formula III;
step 4, reacting a compound of a structural formula III and 1,1' -Carbonyl Diimidazole (CDI) with methoxyamine hydrochloride in the presence of alkali to prepare a compound of a structural formula II;
and 5, in the presence of acid, performing a Mannich reaction on the compound of the structural formula II, dimethylamine and formaldehyde to generate the compound of the structural formula I.
Preferably, in the step 1, the molar ratio of the compound of the structural formula VI-1 to triphosgene is used in an amount of 1:0.35 to 1:3; more preferably 1:0.35 to 1:1.
Preferably, the reaction solvent of step 1 is selected from tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, DMF or DMSO; more preferably tetrahydrofuran.
Preferably, the reaction temperature of step 1 is 0 to 100 ℃, more preferably 30 to 80 ℃.
Preferably, in the step 2, the molar ratio of the compound of the structural formula V to the 2, 6-difluorobenzyl chloride is 1:1 to 1.5:1; more preferably 1:1 to 1.2:1.
Preferably, in the step 2, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide; more preferably potassium carbonate or sodium carbonate.
Preferably, in said step 2, the molar ratio of the compound of formula V to said base is from 1:0.5 to 1:2; more preferably 1:0.8 to 1:1.5.
Preferably, the reaction solvent of step 2 is selected from DMF, N-dimethylacetamide, N-methylpyrrolidone, DMSO, acetonitrile or tetrahydrofuran; more preferably DMF.
Preferably, the reaction temperature of step 2 is 30-120 ℃, more preferably 50-100 ℃.
Preferably, the catalyst of step 3 is selected from palladium on carbon, platinum on carbon or Raney nickel; more preferably palladium on carbon.
Preferably, in step 3, the mass ratio of catalyst to compound of formula IV is from 0.05:1 to 0.5:1, more preferably from 0.1:1 to 0.3:1.
Preferably, the reducing agent in the step 3 is ammonium formate, formic acid or hydrogen; more preferably ammonium formate.
Preferably, the reaction solvent of the step 3 is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, DMF and DMSO.
Preferably, the reaction temperature of step 3 is 10-60 ℃, more preferably 20-50 ℃.
Preferably, in said step 4, the molar ratio of 1,1' -carbonyldiimidazole to the compound of formula III is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1.
Preferably, in said step 4, the molar ratio of methoxyamine hydrochloride to the compound of formula III is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1.
Preferably, in the step 4, the base is selected from triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine or triethylenediamine; more preferably triethylamine.
Preferably, in step 4, the molar ratio of base to compound of formula III is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1.
Preferably, the reaction solvent of step 4 is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile or toluene; more preferably dichloromethane.
Preferably, the reaction temperature of step 4 is 10-80 ℃, more preferably 30-60 ℃.
Preferably, in said step 5, the molar ratio of the compound of formula II to formaldehyde is from 1:1 to 1:100, more preferably from 1:2 to 1:30.
Preferably, in said step 5, the molar ratio of the compound of formula II to dimethylamine is from 1:1 to 1:100, more preferably from 1:2 to 1:30.
Preferably, in the step 5, the condition that the acid exists means that the pH of the reaction system is 3-4; the acid is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid, more preferably acetic acid.
Preferably, the reaction temperature of step 5 is 20-80 ℃, more preferably 30-60 ℃.
Drawings
The invention is further described below with reference to the accompanying drawings.
FIG. 1 shows an HPLC chromatogram of the compound of formula VI-1 prepared in example 1, with the peak labeled "1-31.345" being the chromatographic peak of the compound of formula VI-1.
FIG. 2 shows an HPLC chromatogram of the prepared Rayleigh Lu Geli of example 6, with the peak labeled "31.708-RIGL" being the chromatographic peak of Rayleigh Lu Geli.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified.
EXAMPLE 1 preparation of Compounds of formula VI-1
Step A, preparation of Compounds of formula VIII-1
60.0g (0.438 mol) of paranitrotoluene of the formula IX-1, 57.4g (0.482 mol) of N, N-dimethylformamide dimethyl acetal and 200ml of DMF are added into a reaction flask, and the temperature is raised to 140 ℃ for reaction for 7 hours; 14.4g (0.12 mol) of N, N-dimethylformamide dimethyl acetal are added and the reaction is continued for 3 hours at 140 ℃; then 14.4g (0.12 mol) of N, N-dimethylformamide dimethyl acetal is added again, and the reaction is carried out for 3 hours at 140 ℃; cooling to room temperature, pouring the reaction solution into 1200ml of ice water, washing a reaction bottle with 50ml of DMF, and pouring the washing solution into the ice water; stirring for 30min, and filtering; the filter cake was washed sequentially with 400ml of water and 400ml of n-hexane and dried to give 78.2g of a brick-red solid of formula VIII-1 in 93% yield and 98% HPLC purity.
1 H-NMR(400M，DMSO-d 6 )∶8.11(2H，d)，7.50(1H，d)，7.27(2H，d)， 5.19(1H，d)，2.92(6H，s)。
Step 2, preparation of Compounds of formula VI-1
Method 1: 14.3g (74.4 mmol) of the compound of formula VIII-1, 14.4g (75 mmol) of the compound of formula VII-1, 2.4g (75 mmol) of elemental sulfur, 150ml of methanol and 15.0ml (173 mmol) of morpholine are added into a reaction flask, and the temperature is raised to 70 ℃ for reaction for 6 hours; distillation, adding 100ml ice water until the reaction liquid is about 50ml, stirring at 0-10deg.C for 1 hr, filtering, and oven drying the filter cake to obtain 23.5g red solid of formula VI-1 with yield of 85% and HPLC purity of 99.8% (HPLC chart shown in figure 1).
Method 2: 14.3g (74.4 mmol) of the compound of formula VIII-1, 15.4g (80 mmol) of the compound of formula VII-1, 2.6g (80 mmol) of elemental sulfur, 150ml of ethanol and 17.3g (200 mmol) of piperidine are added into a reaction flask, and the temperature is raised to 60 ℃ for reaction for 10 hours; distillation, adding 100ml ice water until the reaction liquid is about 50ml, stirring at 0-10deg.C for 1h, filtering, and oven drying the filter cake to obtain 24.3g red solid of formula VI-1 with 88% yield and 98% HPLC purity (HPLC chart is omitted).
Method 3: 14.3g (74.4 mmol) of the compound of formula VIII-1, 14.4g (75 mmol) of the compound of formula VII-1, 2.4g (75 mmol) of elemental sulfur, 150ml of isopropanol and 17.4g (200 mmol) of morpholine are added into a reaction flask, and the mixture is heated to 70 ℃ for reaction for 8 hours; distillation, adding 100ml ice water until the reaction liquid is about 50ml, stirring at 0-10deg.C for 1h, filtering, and oven drying the filter cake to obtain 23.8g red solid of formula VI-1, 86% yield and 99% HPLC purity (HPLC chart is omitted).
MS(m/z)：[M+1] + 372.1。
1 H-NMR(400M，CDCl 3 )：12.32(1H，br)，8.15(2H，d)，7.57-7.51 (4H，m)，7.43(1H，s)，6.25(2H，s)，4.18(3H，s)。
EXAMPLE 2 preparation of Compounds of formula V
Example 2a
15.0g (40.4 mmol) of the compound of formula VI-1, 4.81g (16.2 mmol) of triphosgene and 200ml of tetrahydrofuran are introduced into a reaction flask, and the mixture is heated to 60℃for reaction for 3 hours; distilling to remove all solvents, adding 100ml ice water, adjusting pH to 10 with potassium carbonate, and stirring at 0-10deg.C for 1 hr; filtration, washing of the filter cake with 20ml of water and drying gave 15.2g of a yellow solid of formula V in 95% yield and 99% purity by HPLC.
Example 2b
15.0g (40.4 mmol) of the compound of formula VI-1, 5.94g (20.0 mmol) of triphosgene and 200ml of acetonitrile are introduced into a reaction flask, and the mixture is heated to 50 ℃ for reaction for 6 hours; distilling to remove all solvents, adding 100ml ice water, adjusting pH to 10 with potassium carbonate, and stirring at 0-10deg.C for 1 hr; filtration, washing of the filter cake with 20ml of water and drying gave 14.8g of a yellow solid of formula V in 92% yield and 99% HPLC purity.
1 H-NMR(400M，CDCl 3 )：11.85(1H，br)，8.22(2H，d)，7.63-7.56 (5H，m)，4.21(3H，s)。
EXAMPLE 3 preparation of Compounds of formula IV
Example 3a
Into the reaction flask were charged 10.0g (25.2 mmol) of the compound of formula V, 3.8g (27.7 mmol) of potassium carbonate powder, 50ml of DMF and 4.5g (27.7 mmol) of 2, 4-difluorobenzyl chloride, and the mixture was heated to 70℃for 2 hours; pouring the reaction solution into 150ml ice water, extracting with ethyl acetate three times, 70ml each time, combining organic phases, and distilling until the volume of the solution is about 30ml; cooling to 0-10deg.C, slowly adding 120ml heptane, and stirring for 60min; filtration and filter cake drying gave 12.6g of compound IV as a yellow solid in 96% yield and 99% HPLC purity.
Example 3b
Into the reaction flask were charged 10.0g (25.2 mmol) of the compound of formula V, 4.14g (30.0 mmol) of potassium carbonate powder, 50ml of DMSO and 4.87g (30.0 mmol) of 2, 4-difluorobenzyl chloride, and the mixture was heated to 60℃to react for 5 hours; pouring the reaction solution into 150ml ice water, extracting with ethyl acetate three times, 70ml each time, combining organic phases, and distilling until the volume of the solution is about 30ml; cooling to 0-10deg.C, slowly adding 120ml heptane, and stirring for 60min; filtration and filter cake drying gave 12.1g of compound IV as yellow solid in 92% yield and 99% HPLC purity.
1 H-NMR(400M，CDCl 3 )：8.25(2H，d)，7.67-7.57(5H，m)，7.25(2H， t)，6.88(1H，d)，5.31(2H，s)，4.23(3H，s)。
EXAMPLE 4 preparation of Compounds of formula III
Example 4a
To the reaction flask were added 10.0g (19.1 mmol) of the compound of formula IV, 50ml of methylene chloride, 50ml of methanol, 1.3g of palladium on carbon (10% content, 50% water), and the mixture was heated to 30℃and 4.8g (76.4 mmol) of ammonium formate was added in portions, and after the addition was completed, the mixture was allowed to react at 30℃for 5 hours; cooling to 0-10deg.C, adding 50ml dichloromethane, stirring for 30min, filtering, distilling the filtrate, and removing all solvent to obtain 9.14g white solid compound of formula III with 97% yield and 98% HPLC purity.
Example 4b
10.0g (19.1 mmol) of the compound of formula IV, 50ml of dichloromethane, 50ml of ethanol, 1.8g of palladium on carbon (10% content, 50% water) are added to the reaction flask, the temperature is raised to 45℃and 4.6g (100 mmol) of formic acid are added in portions, and after the addition, the reaction is carried out for 6 hours at 45 ℃. Adding 100ml of water, and adjusting the pH to 9 by using potassium carbonate; filtering, distilling the filtrate, removing the solvent, cooling to 0-10 ℃, stirring for 30min, filtering, and drying the filter cake to obtain 8.6g of white solid compound with structural formula III, yield 91% and HPLC purity 97%.
1 H-NMR(400M，CDCl 3 )：7.58-7.56(2H，m)，7.30-7.24(4H，m)，6.86 (2H，d)，6.63(2H，d)，5.24(2H，s)，4.15(3H，s)，3.62(2H，br)。
EXAMPLE 5 preparation of Compounds of formula II
Example 5a
100ml of dichloromethane, 7.0g (43.26 mmol) of 1,1' -Carbonyldiimidazole (CDI) and 2.63g (26.0 mmol) of triethylamine are added into a reaction bottle, the temperature is reduced to 10 ℃, 4.0g (47.6 mmol) of methoxyamine hydrochloride is added in portions, the temperature is raised to 30 ℃ after the addition, the reaction is carried out for 30min, 10.7g (21.63 mmool) of a compound of the structural formula III is added, and the reaction is carried out for 6h after the addition, and the temperature is kept at 40 ℃; adding 100ml of water, maintaining at 20-30deg.C under stirring for 30min, separating, and extracting the water phase with 50ml of dichloromethane; mixing the organic phases, distilling until the solution is about 30ml, cooling to 0-10deg.C, dropwise adding 80ml heptane, and stirring for 2 hr; filtration and drying of the filter cake gave 11.67g of the compound of formula II as a white solid in 95% yield and 99% purity by HPLC.
Example 5b
100ml of ethyl acetate, 6.47g (40.0 mmol) of 1,1' -Carbonyldiimidazole (CDI) and 3.03g (30.0 mmol) of triethylamine are added into a reaction bottle, the temperature is reduced to 10 ℃, 3.36g (40.0 mmol) of methoxyamine hydrochloride is added in batches, the temperature is raised to 40 ℃ after the addition, the reaction is carried out for 30min, 10.7g (21.63 mmol) of a compound of the structural formula III is added, and the reaction is carried out for 5h after the addition and the reaction is maintained at 50 ℃; adding 100ml of water, maintaining at 20-30deg.C, stirring for 30min, separating, and extracting the water phase with 100ml of ethyl acetate; mixing the organic phases, distilling until the solution is about 50ml, cooling to 0-10deg.C, dropwise adding 100ml heptane, and stirring for 2 hr; filtration and filter cake drying gave 11.42g of the compound of formula II as a white solid in 93% yield and 99% purity by HPLC.
1 H-NMR(400M，CDCl 3 )：7.73(1H，s)，7.65(1H，s)，7.59-7.57(2H， m)，7.44-7.36(5H，m)，7.29(1H，t)，6.89(2H，d)，5.28(2H，s)，4.17 (3H，s)，3.82(3H，s)。
EXAMPLE 6 preparation of Compound of formula I (Rate Lu Geli)
Example 6a
9.22g (16.28 mmol) of the compound of formula II, 100ml of glacial acetic acid, 6.6g of aqueous formaldehyde solution (81.4 mmol,37% (w/w)), 7.3g of aqueous dimethylamine solution (81.4 mmol, 50% (w/w)) were introduced into the reaction flask, and the mixture was heated to 50℃to react for 4 hours; pouring the reaction solution into 150ml of water, extracting with dichloromethane three times, 100ml each time, and combining organic phases; washing the organic phase with water twice, 50ml each time, then distilling the organic phase until 30ml remains, cooling to 10-15 ℃, and dripping 60ml of heptane; after the addition, stirring for 2 hours; filtration and drying of the filter cake gave 9.24g of the compound of formula I as a white solid in 91% yield and 99% HPLC purity (HPLC profile see FIG. 2).
Example 6b
9.22g (16.28 mmol) of the compound of formula II, 100ml of formic acid, 13.2g of aqueous formaldehyde solution (162.8 mmol,37% (w/w)), 14.6g of aqueous dimethylamine solution (162.8 mmol, 50% (w/w)) and the temperature were added to the flask, and the mixture was reacted at 70℃for 2 hours; pouring the reaction solution into 150ml of water, extracting with dichloromethane three times, 100ml each time, and combining organic phases; the organic phase is washed twice with 50ml each time, then distilled to about the remaining 30ml, cooled to 10-15 ℃ and 60ml heptane is added dropwise; stirring for 2h after the addition is completed; filtration and drying of the filter cake gave 9.04g of the compound of formula I as a white solid in 89% yield and 98% HPLC purity (HPLC profile).
1 H-NMR(400M，CDCl 3 )：7.64-7.12(8H，m)，6.91(2H，t)，6.80(1H， br)，5.33(2H，br)，4.17(3H，s)，3.81(3H，s)，3.69(2H，s)，2.13(6H， s)。
In summary, the present invention provides a novel process for the preparation of Rayleigh Lu Geli. Compared with the prior art, the preparation method has the advantages of short and concise route, low raw material price, easy control of reaction, avoidance of using the thionyl chloride which has large odor and is toxic, great reduction of the dosage of the acid solvent, and safer and more environment-friendly production.

Claims (68)

1. A compound of formula VI-1,
2. a process for the preparation of a compound of structural formula VI-1 comprising the steps of:
step A-1: the p-nitrotoluene of the structural formula IX-1 is used as a starting material to carry out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound of the structural formula VIII-1;
step B-1: the compound of the structural formula VIII-1 reacts with a sulfur simple substance and the compound of the structural formula VII-1 in the presence of alkali to obtain the compound of the structural formula VI-1.
3. The process according to claim 2, wherein in step A-1, the molar ratio of paranitrotoluene of formula IX-1 to N, N-dimethylformamide dimethyl acetal is from 1:1 to 1:10.
4. The process according to claim 3, wherein the molar ratio of p-nitrotoluene of formula IX-1 to N, N-dimethylformamide dimethyl acetal is from 1:1 to 1:3.
5. The process according to any one of claims 2 to 4, wherein in step a-1, N-dimethylformamide dimethyl acetal is added in 2 to 3 portions.
6. The preparation method according to claim 2, wherein the reaction solvent of step a-1 is selected from DMF, DMAc, N-methylpyrrolidone, DMSO or toluene.
7. The method according to claim 6, wherein the reaction solvent in the step A-1 is DMF.
8. The method according to claim 2, wherein the reaction temperature of step a-1 is 50 to 200 ℃.
9. The process according to claim 8, wherein the reaction temperature of step a-1 is 80-160 ℃.
10. The method of claim 2, wherein in step B-1, the molar ratio of the compound of formula VIII-1 to elemental sulfur is 1:1 to 1:2.
11. The process of claim 10, wherein the molar ratio of the compound of formula VIII-1 to elemental sulfur is from 1:1 to 1:1.2.
12. The process according to claim 2, wherein in step B-1, the molar ratio of the compound of formula VIII-1 to the compound of formula VII-1 is from 1:1 to 1:2.
13. The process of claim 12, wherein the molar ratio of the compound of formula VIII-1 to the compound of formula VII-1 is from 1:1 to 1:1.2.
14. The process according to claim 2, wherein in step B-1, the base is selected from morpholine, piperidine or tetrahydropyrrole.
15. The method of claim 14, wherein the base is morpholine.
16. The process according to claim 2, wherein in step B-1, the molar ratio of the compound of formula VIII-1 to the base is from 1:0.5 to 1:5.
17. The process of claim 16, wherein the molar ratio of the compound of formula VIII-1 to base is from 1:0.5 to 1:3.
18. The preparation method according to claim 2, wherein the reaction solvent of step B-1 is selected from methanol, ethanol, isopropanol, t-butanol, dichloromethane, ethyl acetate, acetone or tetrahydrofuran.
19. The method according to claim 18, wherein the reaction solvent of step B-1 is methanol, ethanol or isopropanol.
20. The process according to claim 2, wherein the reaction temperature of step B-1 is 30-100 ℃.
21. The process of claim 20, wherein the reaction temperature of step B-1 is 50-80 ℃.
22. The use of a compound of formula VI-1 in the preparation of ray Lu Geli,
23. a preparation method of the Rayleigh Lu Geli takes a compound with a structural formula VI-1 as a starting material, and comprises the following steps:
step 1, reacting a compound of a structural formula VI-1 with triphosgene to generate a compound of a structural formula V;
step 2, carrying out substitution reaction on a compound with a structural formula V and 2, 6-difluorobenzyl chloride in the presence of alkali to generate a compound with a structural formula IV;
step 3, reducing the compound with the structural formula IV by a catalyst to obtain a compound with the structural formula III;
step 4, reacting a compound of a structural formula III and 1,1' -Carbonyl Diimidazole (CDI) with methoxyamine hydrochloride in the presence of alkali to prepare a compound of a structural formula II;
and 5, in the presence of acid, performing a Mannich reaction on the compound of the structural formula II, dimethylamine and formaldehyde to generate the compound of the structural formula I.
24. The process of claim 23, wherein in step 1, the molar ratio of the compound of formula VI-1 to triphosgene is from 1:0.35 to 1:3.
25. The process of claim 24 wherein the molar ratio of the compound of formula VI-1 to triphosgene is from 1:0.35 to 1:1.
26. The method according to claim 23, wherein the reaction solvent of step 1 is selected from tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, DMF or DMSO.
27. The method according to claim 26, wherein the reaction solvent in step 1 is tetrahydrofuran.
28. The process of claim 23, wherein the reaction temperature of step 1 is 0-100 ℃.
29. The process of claim 28, wherein the reaction temperature of step 1 is 30-80 ℃.
30. The process of claim 23, wherein in step 2, the molar ratio of the compound of formula V to 2, 6-difluorobenzyl chloride is from 1:1 to 1.5:1.
31. The process of claim 30 wherein the molar ratio of the compound of formula V to 2, 6-difluorobenzyl chloride is from 1:1 to 1.2:1.
32. The method according to claim 23, wherein in the step 2, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide.
33. The method of claim 32, wherein the base is potassium carbonate or sodium carbonate.
34. The process of claim 23, wherein in step 2, the molar ratio of the compound of formula V to the base is from 1:0.5 to 1:2.
35. The process of claim 34, wherein the molar ratio of the compound of formula V to the base is from 1:0.8 to 1:1.5.
36. The method according to claim 23, wherein the reaction solvent of step 2 is selected from DMF, N-dimethylacetamide, N-methylpyrrolidone, DMSO, acetonitrile or tetrahydrofuran.
37. The method of claim 36, wherein the reaction solvent of step 2 is DMF.
38. The process of claim 23, wherein the reaction temperature of step 2 is 30-120 ℃.
39. The process of claim 38, wherein the reaction temperature of step 2 is 50-100 ℃.
40. The method of claim 23, wherein the catalyst of step 3 is selected from palladium on carbon, platinum on carbon, and raney nickel.
41. The process of claim 40 wherein the catalyst of step 3 is palladium on carbon.
42. The process of claim 23, wherein in step 3 the mass ratio of catalyst to compound of formula IV is from 0.05:1 to 0.5:1.
43. The process of claim 42 wherein the mass ratio of catalyst to compound of formula IV is from 0.1:1 to 0.3:1.
44. The method of claim 23, wherein the reducing agent of step 3 is ammonium formate, formic acid or hydrogen.
45. The process of claim 44 wherein the reducing agent of step 3 is ammonium formate.
46. The method according to claim 23, wherein the reaction solvent of step 3 is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, DMF and DMSO.
47. The process of claim 23, wherein the reaction temperature of step 3 is 10-60 ℃.
48. The process of claim 47, wherein the reaction temperature in step 3 is 20-50 ℃.
49. The method of claim 23, wherein in step 4, the molar ratio of 1,1' -carbonyldiimidazole to the compound of formula III is 1:1 to 4:1.
50. The process of claim 49 wherein in step 4 the molar ratio of 1,1' -carbonyldiimidazole to the compound of formula III is 1.1:1 to 2.5:1.
51. The method of claim 23, wherein in step 4, the molar ratio of methoxyamine hydrochloride to the compound of formula III is 1:1 to 4:1.
52. The process of claim 51 wherein the molar ratio of methoxyamine hydrochloride to the compound of formula III is from 1.1:1 to 2.5:1.
53. The process according to claim 23, wherein in step 4, the base is selected from triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine or triethylenediamine.
54. The process of claim 53 wherein the base is triethylamine.
55. The method of claim 23, wherein in step 4, the molar ratio of the base to the compound of formula III is from 1:1 to 4:1.
56. The process of claim 55 wherein the molar ratio of base to compound of formula III is from 1.1:1 to 2.5:1.
57. The method according to claim 23, wherein the reaction solvent of step 4 is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile or toluene.
58. The process of claim 57 wherein the reaction solvent is methylene chloride.
59. The method of claim 23, wherein the reaction temperature in step 4 is 10-80 ℃.
60. The process of claim 59 wherein the reaction temperature of step 4 is 30-60 ℃.
61. The method of claim 23, wherein in step 5, the molar ratio of the compound of formula II to formaldehyde is from 1:1 to 1:100.
62. The process of claim 61 wherein the molar ratio of the compound of formula II to formaldehyde is from 1:2 to 1:30.
63. The method of claim 23, wherein in step 5, the molar ratio of the compound of formula II to dimethylamine is from 1:1 to 1:100.
64. The process of claim 63 wherein the molar ratio of the compound of formula II to dimethylamine is from 1:2 to 1:30.
65. The method according to claim 23, wherein in the step 5, the condition in which the acid is present means that the pH of the reaction system is 3 to 4; the acid is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid.
66. The method of claim 65, wherein the acid is acetic acid.
67. The method of claim 23, wherein the reaction temperature in step 5 is 20-80 ℃.
68. The process of claim 67 wherein the reaction temperature of step 5 is 30-60 ℃.
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