CN113880773A - Preparation method of oxalagogri intermediate - Google Patents
Preparation method of oxalagogri intermediate Download PDFInfo
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- CN113880773A CN113880773A CN202010632650.3A CN202010632650A CN113880773A CN 113880773 A CN113880773 A CN 113880773A CN 202010632650 A CN202010632650 A CN 202010632650A CN 113880773 A CN113880773 A CN 113880773A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Abstract
The invention relates to a preparation method of an oxalagril intermediate 5-bromo-1- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -6-methyl-2, 4(1H, 3H) pyrimidinedione (a compound shown in a formula I), in particular to a method for preparing N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } urea (a compound shown in a formula III) by using 2-fluoro-6- (trifluoromethyl) benzylamine or hydrochloride thereof (a compound shown in a formula II) as a raw material and reacting with urea; reacting the compound shown in the formula III with acetyl meldrum's acid (the compound shown in the formula IV), and then performing ring closure under the action of organic acid to generate a compound shown in the formula V; the compound of formula V is finally reacted with liquid bromine to form 5-bromo-1- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -6-methyl-2, 4(1H, 3H) pyrimidinedione (compound of formula I). The method has the advantages of simple and safe operation, good yield, good economic effect and suitability for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a preparation method of an oxagoril intermediate.
Background
Endometriosis refers to a benign invasive gynecological disease commonly seen in women during childbearing period, which is formed by the implantation of activated endometrial cells in a location other than the endometrium. The disease incidence rate reaches 10.0%, and the disease is in a clear rising trend, and is mainly characterized by dysmenorrheal, pelvic cavity pain and infertility.
Elagolix is an oral GnRH antagonist that has received approval from the U.S. Food and Drug Administration (FDA) for the treatment of pain due to endometriosis. One intermediate used in the synthesis process is a polysubstituted pyrimidine derivative shown as a formula I:
the Journal of Medicinal Chemistry,51(23), 7478-; 2008, the following synthesis method is disclosed:
1、aq.HCl/reflux，6h，73％；2、diketene/TMSCl/NaI/CAN/0℃to rt,20h，79％；3、Br2/HOAC/rt，2h。
in the synthetic route, the used raw material diketene is expensive, has high toxicity and is explosive, so that the production process has certain danger and is not suitable for industrial production.
The synthetic route for the compounds of formula V reported in international patent publication WO200906287a1 is as follows:
according to the method, the acetoacetic acid tert-butyl ester is used for replacing diketene in the previous route to carry out the ring-closing reaction, but the reaction time is long, the ring-closing reaction is not completely carried out, the yield is only 50-60%, the repeatability is poor, and the method is not suitable for industrial production.
Therefore, the development of a novel preparation method of the oxalagogrel intermediate is of great significance.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects of toxic and explosive reagents, low yield, troublesome post-treatment and the like in the process for preparing the intermediate compound V of the Oxagolide in the prior art, and provides an improved method for preparing 5-bromo-1- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -6-methyl-2, 4(1H, 3H) pyrimidinedione (the compound shown in the formula I), wherein the method has the advantages of easily available raw materials, simplicity and convenience in operation, high product purity of more than 99 percent, 60-65 percent of total yield of three-step reaction and suitability for industrial production.
In one aspect, the present invention provides a process for the preparation of compound V, comprising: carrying out ammonolysis reaction on a compound shown in a formula III and a compound shown in a formula IV in an organic solvent, and then closing a ring under the action of acid to prepare a compound shown in a formula V, wherein the acid is organic acid,
preferably, the molar ratio of the compound of formula III to the compound of formula IV is 1: 0.9-3.
Preferably, the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid.
Preferably, the molar ratio of the compound of formula III to the organic acid is in the range of 1: 0.5-2.0.
Preferably, the organic solvent is selected from one or more of toluene, chlorobenzene, xylene, N-dimethylformamide, dimethyl sulfoxide, anisole or acetonitrile.
Preferably, the organic solvent is toluene.
Preferably, the temperature range of the ammonolysis reaction is 60-reflux; after the ammonolysis reaction, the ring closing reaction temperature range under the action of organic acid is 95-105 ℃.
In another aspect, the present invention provides a process for the preparation of compound I, comprising:
carrying out ammonolysis reaction on the compound of the formula III and the compound of the formula IV, and then closing a ring under the action of organic acid to prepare a compound of the formula V; reacting the compound shown in the formula V with liquid bromine under the action of alkali to generate a compound I;
preferably, the alkali is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide;
preferably, in the step of preparing the compound of formula I from the compound of formula V, the molar ratio of the compound of formula V to liquid bromine is 1: 1-1.5, and more preferably 1: 1.02-1.1.
The inventors have found that in the step of preparing the compound of formula V, in accordance with the Journal of Medicinal Chemistry,51(23), 7478-7485; the method of 2008, under the acidic (acetic acid) condition, reacts with liquid bromine, and generates a large amount of by-product I-imp, which is generated by the radical bromination reaction of methyl on the pyrimidine ring, and the specific structural formula is as follows:
if more I-imp is generated in the reaction system, the purity of the product is difficult to reach more than 99 percent; and because the byproduct I-imp is a genotoxic impurity, the quality of the product needs to strictly control the content of the I-imp.
In another aspect, the present invention provides a process for the preparation of compound I, comprising:
reacting a compound 2-fluoro-6- (trifluoromethyl) benzylamine shown in the formula II or hydrochloride of the compound shown in the formula II with urea under the catalysis of concentrated hydrochloric acid to generate a compound shown in the formula III; carrying out ammonolysis reaction on the compound of the formula III and the compound of the formula IV, and then closing a ring under the action of acid to prepare a compound of the formula V; reacting the compound shown in the formula V with liquid bromine under an alkaline condition to generate a compound I; preferably, the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid; preferably, the alkali is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide; the molar ratio of the compound shown in the formula V to the bromine is 1: 1-1.5.
Advantageous effects
According to the preparation method of 5-bromo-1- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -6-methyl-2, 4(1H, 3H) pyrimidinedione (compound of formula I), 2-fluoro-6- (trifluoromethyl) benzylamine or hydrochloride thereof (compound of formula II) is used as a raw material, so that the product quality is easier to control, and the transportation and feeding operation are facilitated; the compound of formula III is used for preparing the compound of formula V, acetyl meldrum's acid (compound of formula IV) is used for replacing diketene or tert-butyl acetoacetate in the prior art, so that the post-reaction treatment is more convenient, the production period is greatly shortened, the purity of the obtained product can reach more than 99 percent, and the yield is more than 85 percent. The compound of formula V is used for preparing the compound of formula I, which is different from the prior art, and reacts with liquid bromine under an alkaline condition, so that the generation of a large amount of dibromo-substituted by-products I-imp is effectively avoided, the purity of the obtained product is up to more than 99%, the post-treatment is more convenient, and the yield is more than 85%. In conclusion, the technical scheme provided by the invention is suitable for industrial production and has higher economic benefit.
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of the compound of formula III:
adding water (700g) into a 3L four-neck flask, sequentially adding concentrated hydrochloric acid (198g, 1.95mol, 1.4eq.) and a compound (270g, 1.398mol, 1.0eq.) of a formula II and urea (251.8g, 4.194mol, 3.0eq.) under ice-bath stirring, heating to 90-100 ℃, and carrying out heat preservation stirring reaction for 16 hours; and (3) cooling the reaction liquid to room temperature, carrying out suction filtration, leaching a filter cake with water, adding ethanol, heating to reflux and stirring for 4 hours, cooling, carrying out suction filtration, drying, and weighing to obtain 285.6g of the compound shown in the formula III as an off-white solid, wherein the yield is 86.5% and the purity is 99.5%.1HNMR(400MHz，DMSO-d6)δ(ppm)：7.6002-7.6015(m，3H)，6.1821-6.1602(m，3H)，5.4923(s，2H)，4.3802-4.3656(m，2H)；(ESI-TOF)m/z：[M+H]+calcd for C9H8N2OF4：236；found：237。
Preparation of a Compound of formula V:
taking a 10L four-mouth bottle, adding 3L of toluene, adding the compound of the formula III (280.1g, 1.186mol, 1.0eq.) and the compound of the formula IV (acetyl Meldrum's acid) (441.6g, 2.372mol, 2.0eq.) respectively under stirring, heating to 65-80 ℃, and carrying out heat preservation stirring reaction for 2 hours. Heating to 95-105 ℃, and continuously stirring for reaction for 2 hours. P-toluenesulfonic acid (408.5g, 2.372mol, 2.0eq.) was added dropwise at 90 ℃ and the reaction was stirred under reflux for 12 h. Cooling the reaction liquid, concentrating under reduced pressure to remove the solvent, evaporating toluene with isopropanol for 1 time to obtain a crude solid, adding 5V isopropanol into the crude solid, heating to reflux and stirring for 4 hours, performing suction filtration, drying a filter cake, and weighing to obtain 288.5g of a white solid of the compound shown in the formula V, wherein the yield is 80.5%.1HNMR(400MHz，DMSO-d6)δ(ppm)：11.2341(s，1H)，7.6586-7.6398(m，1H)，7.5782-7.5176(m，2H)，5.5603(s，1H)，5.2186(s，2H)，2.1889(s，3H)；(ESI-TOF)m/z：[M+H]+calcd for C13H10N2OF4: 302; found: 303. preparation of a Compound of formula I:
adding methanol (2800mL) into a 5000mL four-neck bottle, adding sodium methoxide (125.1g, 2.315mol, 2.5eq.) into the bottle at 10-30 ℃ under stirring, stirring for 10min, and adding a compound (280.00g, 0.926mol, 1.0eq.) shown in the formula V. Cooling, controlling the temperature to be 0 ℃, dropwise adding liquid bromine (406.9g, 2.546mol, 1.1eq.) and keeping the temperature at 0 ℃ for reaction for 1.5h after the dropwise adding is finished. And (2) dropwise adding concentrated hydrochloric acid at the temperature of 0 ℃ to adjust the pH value to 3.5-6.5, adding a sodium sulfite aqueous solution to quench, performing suction filtration, washing with water, performing suction filtration, adding acetonitrile (120mL) into a filter cake, heating to reflux and stirring for 4 hours, cooling, performing suction filtration, leaching the filter cake with acetonitrile, performing suction filtration, drying the filter cake, and weighing to obtain 312.33g of a white solid of the compound shown in the formula I, wherein the yield is 88.5%.
1HNMR(400MHz，DMSO-d6)δ(ppm)：11.8930(s，1H))；7.6694-7.5086(m，3H)；5.3523(s，2H)；2.5078-2.4498(m，3H)；(ESI-TOF)m/z：[M+H]+calcd for C13H9N2O2F4Br：381；found：382。
Example 2
Preparation of the compound of formula III:
adding water (15kg) into a 50L reaction kettle, sequentially adding concentrated hydrochloric acid (515g), a compound (3kg, 13.05mol, 1.0eq.) of a formula II, urea (2.98kg, 49.6mol, 3.8eq.) and the like under stirring, heating to 90-100 ℃, preserving heat, and stirring for reacting for 16 hours. And (3) cooling the reaction liquid to 15-30 ℃, carrying out suction filtration, leaching a filter cake with water, adding ethanol, heating to reflux and stirring for 4 hours, cooling, carrying out suction filtration, drying, and weighing to obtain 2.635kg of the compound of the formula III as a white-like solid, wherein the yield is 85.5% and the purity is 99.5%.
1HNMR(400MHz，DMSO-d6)δ(ppm)：7.6027-7.5967(m，3H)，6.1805-6.1555(t，J＝5Hz，3H)，5.4864(s，2H)，4.3742-4.3617(d，J＝5Hz，2H)；(ESI-TOF)m/z：[M+H]+calcd for C9H8N2OF4：236；found：237。
Preparation of a Compound of formula V:
adding toluene (16.5L) into a 50L reaction kettle, adding a compound of the formula III (1.651kg, 7mol, 1.0eq.) and a compound of the formula IV (acetyl Meldrum's acid) (1.413kg, 7.6mol, 1.09eq.) respectively under stirring, heating to 60-80 ℃, and carrying out heat preservation and stirring reaction for 2 hours. Heating to 95-105 ℃, and continuously stirring for reaction for 2 hours. Trifluoroacetic acid (1.195kg, 10.5mol, 1.5eq.) is added dropwise at 90-100 ℃ and stirred for reaction at 95-105 ℃ for 10 h. Cooling the reaction liquid, concentrating under reduced pressure to remove the solvent, evaporating toluene with isopropanol for 1 time to obtain a crude solid, adding 5V isopropanol into the crude solid, heating to reflux and stirring for 4 hours, performing suction filtration, drying a filter cake, and weighing to obtain 1.805kg of a white solid of the compound shown in the formula V, wherein the yield is 85.6%.1HNMR(400MHz，DMSO-d6)δ(ppm)：11.2281(s，1H)，7.6610-7.6423(m，1H)，7.5802-7.5235(m，2H)，5.5588(s，1H)，5.2221(s，2H)，2.1909(s，3H)；(ESI-TOF)m/z：[M+H]+calcd for C13H10N2OF4：302；found：303。
Preparation of a Compound of formula I:
taking a 25L reaction kettle, adding 15L of methanol, and adding sodium methoxide under stirring at 10-30 DEG C(402.4g, 7.46mol, 1.5eq.) after stirring for 10min the compound of formula V (1.5kg, 4.95mol, 1.0eq.) was added. Cooling, controlling the temperature to be-40 to-30 ℃, dropwise adding liquid bromine (793.3g, 4.95mol, 1eq.) and keeping the temperature for reaction for 1h after the dropwise adding. And (2) dropwise adding concentrated hydrochloric acid to adjust the pH to 3.5-6.5 at the temperature of-25-10 ℃, adding a sodium sulfite aqueous solution, performing suction filtration after stirring, washing with water, performing suction filtration, adding acetonitrile (120mL) into a filter cake, heating to reflux, stirring for 4 hours, cooling, performing suction filtration, leaching the filter cake with acetonitrile, performing suction filtration, drying the filter cake, and weighing to obtain 1.616kg of a white solid of the compound shown in the formula I, wherein the yield is 85.5%.1HNMR(400MHz，DMSO-d6)δ(ppm)：11.8770(s，1H)；7.6741-7.5121(m，3H)；5.3464(s，2H)；2.5114-2.4579(m，3H)；(ESI-TOF)m/z：[M+H]+calcd for C13H9N2O2F4Br：381；found：382。
Example 3
This example was carried out by reference to example 1 a process for the preparation of compounds of formula V from compounds of formula III and compounds of formula IV, and the results obtained under different reagent conditions are given in table 1 below.
TABLE 1
Claims (11)
1. A process for preparing a compound of formula V, comprising: carrying out ammonolysis reaction on a compound shown in a formula III and a compound shown in a formula IV in an organic solvent, then closing a ring under the action of organic acid to prepare a compound shown in a formula V,
2. the method of claim 1, wherein: the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1: 0.9-3.
3. The production method according to claim 1 or claim 2, characterized in that: the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid.
4. The production method according to claim 3, characterized in that: the molar ratio of the compound shown in the formula III to the organic acid is 1: 0.5-2.0.
5. The production method according to claim 1 or claim 2, characterized in that: the organic solvent is selected from one or more of toluene, chlorobenzene, xylene, N-dimethylformamide, dimethyl sulfoxide, anisole or acetonitrile.
6. The production method according to claim 5, characterized in that: the organic solvent is toluene.
7. The method of claim 1, wherein: the temperature range of the ammonolysis reaction is 60 ℃ to reflux; after the ammonolysis reaction, the ring closing reaction temperature range under the action of organic acid is 95-105 ℃.
8. A process for the preparation of compound I, comprising:
carrying out ammonolysis reaction on the compound of the formula III and the compound of the formula IV, and then closing a ring under the action of organic acid to prepare a compound of the formula V; the compound of formula V reacts with liquid bromine under the action of alkali to produce compound I.
9. The process of claim 8, wherein in the step of reacting the compound of formula V with liquid bromine under basic conditions to form compound I, the base is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, and potassium hydroxide.
10. The process according to claim 8 or 9, wherein the molar ratio of the compound of formula V to liquid bromine is in the range of 1: 1 to 1.5.
11. A process for the preparation of compound I, comprising:
reacting a compound 2-fluoro-6- (trifluoromethyl) benzylamine shown in the formula II or hydrochloride of the compound shown in the formula II with urea under the catalysis of concentrated hydrochloric acid to generate a compound shown in the formula III; carrying out ammonolysis reaction on the compound of the formula III and the compound of the formula IV, and then closing a ring under the action of organic acid to prepare a compound of the formula V; the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid; reacting the compound shown in the formula V with liquid bromine under an alkaline condition to generate a compound I, wherein the alkali is one or more selected from sodium methoxide, sodium ethoxide, sodium hydroxide and potassium hydroxide; the molar ratio of the compound shown in the formula V to the bromine is 1: 1-1.5.
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