CN111253402B - Intermediate compound of TRK kinase inhibitor compound and preparation method thereof - Google Patents
Intermediate compound of TRK kinase inhibitor compound and preparation method thereof Download PDFInfo
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- CN111253402B CN111253402B CN201811457027.8A CN201811457027A CN111253402B CN 111253402 B CN111253402 B CN 111253402B CN 201811457027 A CN201811457027 A CN 201811457027A CN 111253402 B CN111253402 B CN 111253402B
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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Abstract
The invention provides a preparation method of a compound of formula (I) or a salt thereof, which comprises the step of carrying out coupling reaction on a compound of formula (II) and a compound of formula (III) or a compound of formula (II) and a compound of formula (IV), and the method has high yield of the obtained product and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an intermediate compound of a TRK kinase inhibitor compound and a preparation method thereof.
Background
NTRK/TRK (neurotrophin receptor kinase) is a neurotrophic factor tyrosine kinase receptor, belonging to the receptor tyrosine kinase family. The Trk family mainly comprises 3 members, NTRK1/TrkA, NTRK2/TrkB and NTRK 3/TrkC. Trk kinases play important physiological roles in the development of nerves, including the growth and functional maintenance of neuronal axons, the development of memory, and the protection of neurons from injury, among others. Meanwhile, a great deal of research shows that the activation of the Trk signal transduction pathway is strongly related to the occurrence and development of tumors, and activated Trk signal proteins are found in neurocytoma, prostatic cancer, breast cancer and the like. In recent years, the discovery of various Trk fusion proteins shows that the Trk fusion proteins can promote the biological function of tumorigenesis.
However, after receiving the treatment with the TRK inhibitor, some mutations may be generated in the TRK gene of the cancer patient (e.g., mutations at the sites NTRK 1G 595R, NTRK3G623R, etc.), resulting in the generation of drug resistance. The existing drugs do not solve this problem, and LOXO-195 produces better therapeutic effects in treating such mutations. LOXO-195 compounds and methods for their preparation are disclosed in WO2017075107 and WO2018081417, respectively. Among them, WO2018081417 discloses a method of preparing LOXO-195 involving a method comprising ten steps.
This process not only has a large number of steps, but also the addition step uses Pd/C hydrogenation, which is a step that is dangerous for explosion, and the remaining Pd/C needs to be disposed of in the post-treatment process, which is undesirable for large-scale production.
Since LOXO-195 has significant effects in treating cancer patients with drug resistance due to mutation of TRK gene, there is a need to provide a more optimized method for preparing LOXO-195. Therefore, there is a need to develop an industrial synthesis method which is scalable, safer, convenient to operate, and suitable in overall yield.
Disclosure of Invention
The present invention addresses the above problems by providing a novel process for preparing LOXO-195 and salts thereof and suitable for small scale or large scale manufacturing, novel intermediates useful for preparing LOXO-195 and methods for preparing the intermediates.
Compared with the method reported in WO2018081417, the method for preparing LOXO-195 provided by the invention has at least the following advantages:
(1) the raw materials used in the invention are cheap and easily available, thereby reducing the cost of the reagent.
(2) The method provided by the invention can obtain LOXO-195 with fewer steps and high yield, thereby reducing the cost of the reagent and saving the labor cost.
(3) The method provided by the invention avoids the use of Pd/C hydrogenation and is easy to operate.
The invention relates to an intermediate compound of a TRK kinase inhibitor compound, which is shown as a formula (VIII):
wherein R is3Is H, C1-C6An alkyl group, a carboxyl group,
R2is an amino protecting group.
Further, R2Is benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methyloxycarbonyl (or ethyloxycarbonyl), o-phenylethoxy, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, benzoyl, triphenylmethyl, p-methoxybenzyl, benzyl, 2, 4-dimethoxybenzyl.
Further, the intermediate compound of formula (viii) is:
the present invention provides a process for preparing a compound of formula (V): reacting a compound of a formula (II) with a compound of a formula (III) or reacting the compound of the formula (II) with a compound of a formula (IV) under the action of a metal catalyst to obtain a compound of a formula (V);
the structural formula of the formula (II) is as follows:
the structural formula of formula (III) is:
the structural formula of the formula (IV) is
The structural formula of the compound of formula (V) is
Wherein R is1F, Cl, Br, I, OTf, OMs, OTs;
x is F, Cl, Br, I;
R2is an amino protecting group;
m is alkali metal, iron, magnesium, calcium and copper;
n is the number of charges carried by M metal ions and is a positive integer;
r is H, C1-C10Alkyl or C1-C10Substituted alkyl, wherein said C1-C10The substituents of the alkyl groups being selected from C1-C10Substituted by a substituent of alkoxy; the 2 ORs may be configured as four-ten membered rings.
Further, the reaction is carried out under the action of a base.
Further, the base is selected from the group consisting of a metal carbonate, an alkali metal phosphate, an alkali metal hydride, an alkali metal alkoxide, and an alkali metal hydroxide.
Further, the base is potassium carbonate.
Further, the alkali metal M is selected from lithium, sodium and potassium.
Further, n is 1,2,3, 4.
Further, the compound of formula (IV) is
Further, the metal catalyst is selected from palladium catalyst, nickel catalyst, copper catalyst.
Still further, the palladium catalyst is 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II).
Further, the reaction is carried out in a mixed solvent of water and an organic solvent.
Further, the organic solvent is selected from ether, tetrahydrofuran, and alcohol.
Further, the ether is dimethyl ether.
Further, wherein water: the volume ratio of the dimethyl ether is 1: 4.
Further, said R2Selected from benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, trimethylsiloxycarbonyl, methyloxycarbonyl (or ethyloxycarbonyl), o-phenylethoxy, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, benzoyl, triphenylmethyl, p-methoxybenzyl, benzyl, 2, 4-dimethoxybenzyl.
Further, said R2Is tert-butoxycarbonyl.
The present invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, characterized in that: the method comprises the following steps:
a. preparing a compound of formula (vi) by ester hydrolysis according to the method described above;
b. deprotection of the compound of formula (VI)2To obtain a compound of formula (VII);
c. cyclizing the compound of the formula (VII) to obtain the compound of the formula (I).
Further, the reaction of step a is carried out in a strong base.
Further, the strong base is selected from the group consisting of hydroxides and alkoxides.
Still further, the strong base is sodium hydroxide.
Further, the reaction of step a is carried out in tetrahydrofuran, alcohol, water or a mixed solvent thereof.
Further, the alcohol is methanol.
Still further, the solvent is tetrahydrofuran: methanol: the water volume ratio is 2:1: 1.
Further, in the step b, the amino protecting group R is removed2Under acidic conditions.
Still further, the acid is hydrochloric acid.
Further, the cyclization in the step c reaction is carried out in the presence of a condensing agent.
Further, the condensing agent is selected from dicyclohexylcarbon, Ν, Ν ' -diisopropyl, N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N ' -carbonyldiimidazole, 2- (7-azabenzotriazol-1-yl) -N, N ' -tetramethylurea hexafluorophosphate, 1- (benzotriazol-1-yl) -N, N ' -tetramethylurea hexafluorophosphate.
Further, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 1- (benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate.
The invention provides a method for preparing a TRK kinase inhibitor compound LOXO-195 and a salt thereof, which has the advantages of safety, convenient operation and high product yield and is suitable for small-scale or large-scale industrial production.
The words "comprises," "comprising," or any other variation thereof, when used in this specification, are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.
The term "C" as used in the present invention1-C10Alkyl "refers to a straight or branched chain of 1 to 10 carbon atoms. For example, methyl, ethyl, isopropyl, tert-butyl and hexyl.
The term "C" as used herein1-C10Alkoxy "refers to a straight or branched chain monovalent alkoxy group of 1 to 10 carbon atoms, wherein the radical is on an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy and butoxy.
The term "substituted" as used herein means that a hydrogen atom in a molecule is replaced with another, different atom or molecule.
The term "amino protecting group" as used herein refers to benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methyl (or ethyl) oxycarbonyl, o-phenylethoxy, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, benzoyl, triphenylmethyl, p-methoxybenzyl, benzyl, 2, 4-dimethoxybenzyl.
As used herein, "strong base" refers to a basic compound capable of deprotonating a weak acid in an acid-base reaction. Strong bases are also capable of hydrolyzing ester compounds in a hydrolysis reaction to produce the corresponding carboxylic acid compound. Examples of strong bases include, but are not limited to, hydroxides, alkoxides, and ammonia. Common examples of strong bases are alkali metal hydroxides and alkaline earth metals, such as NaOH. Some strong bases are even capable of deprotonating the very weakly acidic C — H groups in the absence of water. Strong bases include, but are not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, lithium hydroxide, and rubidium hydroxide. In this embodiment, NaOH is used as the strong base.
As used herein, "condensing agent" refers to a reagent that forms an amide or ester bond, for example, by coupling an acid and an amine or alcohol, respectively. The condensing agent is commercially available. Condensing agents include, but are not limited to, Dicyclohexylcarbon (DCC), Ν, Ν 'Diisopropyl (DIC), N- (3-dimethylaminopropyl) -N' -Ethylcarbodiimide (EDCI), gold Carbonyl Diimidazole (CDI), 2- (7-azabenzotriazol-1-yl) -N, N '-tetramethyluronium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium Hexafluorophosphate (HBTU). In some embodiments, one or more condensing agents may be used simultaneously. The condensing agent may be used in combination with a catalyst.
The term "room temperature" as used herein is understood in the art and is generally related to a temperature (e.g., reaction temperature) that is about the temperature of the environment in which the reaction is conducted, e.g., at a temperature of about 20 ℃ to about 30 ℃.
The reagents and abbreviations involved in the present invention are as follows:
boc tert-butoxycarbonyl
DIBAL diisobutyl aluminum hydride
DME dimethyl ether
DMF N, N-dimethylformamide
EA Ethyl acetate
H2O water
OTf triflate
OTs p-toluenesulfonyl
OMs methylsulfonyl radical
PE Petroleum Ether
The present invention will be described in further detail with reference to the following examples. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict the present application (including but not limited to defined terms, usage of terms, described techniques, etc.), the present application controls.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products. 1. Preparation of tert-butyl N- [ (1R) -3-hydroxy-1-methyl-propyl ] carbamate
(R) -3-aminobutanol (50g,561mmol) was dissolved in methanol (500mL), and di-tert-butyl dicarbonate (128g,589mmol) was added dropwise under ice bath. Stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure to give tert-butyl N- [ (1R) -3-hydroxy-1-methyl-propyl ] carbamate (100g,528mmol, 94.2% yield) which was used directly in the next reaction.
MS(ESI)m/z＝190(M+1)+。
2. Preparation of tert-butyl (4R) -4-methyl-1, 2, 3-oxathiolane-3-carboxylic acid 2-oxo
Imidazole (143.7g,2.11mol) was dissolved in dry dichloromethane (1000mL), triethylamine (160g,1.59mol, 221mL) was added, cooling to-40 ℃ was performed, thionyl chloride (75g,634mmol,46mL) was added dropwise, after completion of the addition (30min), tert-butyl N- [ (1R) -3-hydroxy-1-methyl-propyl ] carbamate (100g,528mmol) was dissolved in dry dichloromethane (300 mL). After the completion of the dropwise addition (1 hour), the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 4 hours. Extraction with dichloromethane and water, extraction of the aqueous phase once more with dichloromethane, combination of the organic phases, drying over anhydrous sodium sulfate and evaporation under reduced pressure to remove the solvent. To obtain tert-butyl (4R) -4-methyl-1, 2, 3-oxathiolane-3-carboxylic acid 2-oxyl (104g,442mmol, 84% yield) which is directly used in the next reaction.
3. Preparation of tert-butyl (4R) -4-methyl-1, 2, 3-oxathiazepine-3-carboxylic acid 2, 2-dioxy
Tert-butyl (4R) -4-methyl-1, 2, 3-oxathiolane-3-carboxylic acid 2-oxo (100g,340 mmol) was dissolved in acetonitrile (1000mL) under ice-bath, ruthenium chloride (282mg,1.36mmol), sodium periodate (116g,544 mmol) and water (800mL) were added in this order, stirred for 2 hours while cooling on ice, acetonitrile was distilled off under reduced pressure, cooled to room temperature, filtered, and the solid was washed twice with water (500 mL). To obtain tert-butyl (4R) -4-methyl-1, 2, 3-oxathiolane-3-carboxylic acid 2, 2-dioxy (71g, 282mmol, 83% yield) which is directly used in the next reaction.
Preparation of (R) -tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborol-2-yl) butan-2-yl) carbamate
Tert-butyl (4R) -4-methyl-1, 2, 3-oxathiolane-3-carboxylic acid 2, 2-dioxo (69g,274mmol) was dissolved in DMF (500mL) and pinacol diboron (83.7g,329mmol), cuprous iodide (5.23g,27.5 mmol), triphenylphosphine (9.36g,35.7mmol), tetrabutylammonium iodide (152g,412mmol), lithium tert-butoxide (43.9 g,549mmol) were added in that order. Under nitrogen, the mixture was stirred at room temperature for 3 hours, ethyl acetate (1000mL) and water (1500mL) were added to extract, the organic phase was washed twice with saturated brine, the solvent was distilled off under reduced pressure, and column chromatography purification (PE/EA ═ 8/1) was carried out to obtain (R) -tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborocan-2-yl) butan-2-yl) carbamate (76g,253mmol, 93% yield) which was directly used in the next reaction.
MS(ESI)m/z＝300(M+1)+，244(M+1-56)+。
5. Preparation of potassium (R) - (3- ((tert-butoxycarbonyl) amino) butyl) trifluoroborate
(R) -tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) butan-2-yl) carbamate (75g, 251mmol) was dissolved in tetrahydrofuran (500mL), and potassium hydrogen fluoride (78.2g,1.00mol) and water (150mL) were added in that order. The mixture was stirred at room temperature for 10 hours, the solvent was evaporated under reduced pressure, the solid was washed with hot acetone, the filtrate was dried by spinning, slurried and washed with PE/EA (10/1), and filtered to give potassium (R) - (3- ((tert-butoxycarbonyl) amino) butyl) trifluoroborate (51g,182mmol, yield 73%) as a solid which was used directly in the next reaction.
Example 1:
step 1: preparation of (R) -N- ((2-chloro-5-fluoropyridin-3-yl) methylene) -2-methylpropane-2-sulfinamide
2-chloro-3-formyl-5-fluoropyridine (7.00g,43.9mmol) was dissolved in DCM (70mL), followed by addition of (R) - (+) -tert-butylsulfenamide (5.58g,46.1mmol), cesium carbonate (10.01g,30.7mmol), stirring overnight at room temperature, post-treatment with 65mL of 15% citric acid monohydrate (9.67g,46.1mmol), extraction with dichloromethane, extraction of the aqueous phase with dichloromethane twice, combination of the organic phases washed once with saturated brine, drying of the organic phase over anhydrous sodium sulfate, and removal of the solvent under reduced pressure. To give (R) -N- ((2-chloro-5-fluoropyridin-3-yl) methylene) -2-methylpropane-2-sulfinamide (11.2g,42.7 mmol, 96% yield).
MS(ESI)m/z＝263(M+1)+。
Step 2: preparation of (R) -N- ((R) -1- (2-chloro-5-fluoropyridin-3-yl) -3- (1, 3-dioxan-2-yl) propyl) -2-methylpropane-2-sulfinamide
Magnesium (2.04g,83.7mmol) was added to a reaction flask, 90ml of anhydrous tetrahydrofuran was added under nitrogen protection, DIBAL (2M,83.7uL) was added, 2- (2-bromoethyl) -1, 3-dioxane (16.3g,83.7mmol) was dissolved in anhydrous tetrahydrofuran, slowly added dropwise to the reaction system, after completion of the addition, stirred at room temperature for 30 minutes, the Grignard mixture was cooled to-40 ℃ and stirred for 10 minutes, and (R) -N- ((2-chloro-5-fluoropyridin-3-yl) methylene) -2-methylpropane-2-sulfinamide (11g,41.9 mmol) was dissolved in 20ml of anhydrous tetrahydrofuran and added dropwise to the reaction system and stirred at-40 ℃ for 2 hours. And (3) post-treatment: at-10 ℃, the system was poured into a 15% aqueous solution of citric acid, stirred for 15 minutes, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography (PE/EA ═ 1/2) to give (R) -N- ((R) -1- (2-chloro-5-fluoropyridin-3-yl) -3- (1, 3-dioxan-2-yl) propyl) -2-methylpropane-2-sulfinamide (15.1g,39.9mmol, 95% yield).
MS(ESI)m/z＝379(M+1)+。
And step 3: preparation of (R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine
(R) -N- ((R) -1- (2-chloro-5-fluoropyridin-3-yl) -3- (1, 3-dioxan-2-yl) propyl) -2-methylpropane-2-sulfinamide (15g,39.6mmol) was dissolved in trifluoroacetic acid (62mL), water (15mL) was added, stirring was performed at room temperature for 1h, triethylsilane (14.0g,120mmol,19.2mL) was added dropwise to the reaction system, and stirring was performed at room temperature for 3 h. And (3) post-treatment: the solvent of the system was spin-dried, extracted with methyl tert-butyl ether and aqueous solution, the aqueous phase was extracted twice with methyl tert-butyl ether, the combined organic phases were washed with 1M dilute hydrochloric acid, then the aqueous phase was adjusted to pH 12 with 50% sodium hydroxide solution, extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give (R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine (6.6g,33.6mmol, 84% yield) which was used directly in the next reaction.
MS(ESI)m/z＝201(M+1)+。
And 4, step 4: preparation of ethyl (R) -ethyl 5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate
(R) -2-chloro-5-fluoro-3- (pyrrolidin-2-yl) pyridine (6.7g,33.4mmol) was dissolved in N-butanol (35mL), N-diisopropylethylamine (43.1g,334mmol) and ethyl 5-chloropyrazolo [1,5-A ] pyrimidine-3-carboxylate (7.53g,33.4 mmol) were added, and the mixture was stirred at 120 ℃ for 1 hour, and the solvent was distilled off under reduced pressure. Column chromatography purification (PE/EA ═ 1/1) gave ethyl (R) -ethyl 5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (12.6g,32.3mmol, 96% yield)
MS(ESI)m/z＝390(M+1)+。
And 5: preparation of ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazo lo [1,5-a ] pyrimidine-3-carboxylate
Reacting (R) -ethyl 5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (6.89 g,17.7mmol) dissolved in DME/H2O4/1 (100mL), potassium (R) - (3- ((tert-butoxycarbonyl) amino) butyl) trifluoroborate (19.5g,53.0mmol), 1,1 '-bis (diphenylphosphino) ferrocene palladium (II) dichloride (1.29g,1.77mmol) and potassium carbonate (7.32g,53.0mmol) were added, stirred at 100 ℃ for 10 hours under nitrogen protection, and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (1.29g,1.77mmol) and potassium carbonate (7.32g,53.0mmol) were added. The reaction was continued at 100 ℃ for 4h and the solvent was evaporated under reduced pressure. Adding dichloromethane, pulping, washing, filling with diatomite, filtering, spin-drying the filtrate, and purifying by column chromatography (PE/EA is 1/1) to obtain ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidine-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (7.52g,14.3mmol, 81% yield).
MS(ESI)m/z＝527(M+1)+。
1HNMR(400MHz,CD3OD):δ＝8.13-8.45(m,3H),7.20(dd,J＝2.8,9.6Hz,1H),6.59 (br,0.61H),5.95(br,0.33H),5.48(br,0.61H),5.23(br,0.33H),4.02-4.30(m,3H), 3.66-3.92(m,2H),3.00-3.06(m,2H),2.54(m,1H),1.88-2.24(m,5H),1.41(s,9H),1.25(br, 6H).
Step 6: preparation of 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
Ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (4.6g,8.74mmol) dissolved in THF/MeOH/H2O2/1/1 (40mL), sodium hydroxide (1.05g,26.21mmol) solution was added, stirring was carried out at 65 ℃ for 10 hours, 1N diluted hydrochloric acid was added to adjust PH to about 5, followed by extraction with ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid (4.4g,7.94mmol, 91% yield) was used directly in the next reaction.
MS(ESI)m/z＝499(M+1)+。
And 7: preparation of 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid (4.4g,8.83mmol) was dissolved in 4M ethyl acetate hydrochloride (40mL), stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. 5- ((R) -2- (2- ((R) -3-aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid (4.0g, 8.5mmol, 96% yield) was obtained and used directly in the next reaction.
MS(ESI)m/z＝399(M+1)+。
And 8: preparation of LOXO-195
5- ((R) -2- (2- ((R) -3-Aminobutyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid (4g,8.49mmol) was dissolved in N, N-dimethylformamide (180mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.2g,17.0mmol), 1-hydroxybenzotriazole (2.3g,17.0mmol), triethylamine (4.3g, 42.5mmol) were added successively under ice bath. Stirred at 45 ℃ for 10 hours. Extraction with ethyl acetate, further extraction of the aqueous phase with ethyl acetate twice, merging of the organic phases, drying over anhydrous sodium sulfate and evaporation under reduced pressure to remove the solvent. Column chromatography purification (DCM/MeOH ═ 30/1), evaporation of solvent under reduced pressure gave a solid, addition of isopropyl acetate (1g/5mL) stirred overnight at 65 ℃, filtration and drying of the solid at 50 ℃ (10 h) gave LOXO-195(2.27g,5.95mmol, 70% yield).
MS(ESI)m/z＝381(M+1)+。
1HNMR(400MHz,CDCl3):δ＝8.38(d,J＝8.4Hz,1H),8.31(d,J＝2.8Hz,1H),8.29(d, J＝7.6Hz,1H),8.23(s,1H),7.08(dd,J＝2.8Hz,9.6Hz,1H),6.30(d,J＝7.6Hz,1H), 5.53-5.57(m,1H),4.37-4.43m,1H),3.93-3.99(m,1H),3.78-3.84(m,1H),3.39-3.45(m,1H), 2.81-2.91(m,2H),2.52-2.60(m,1H),2.35-2.45(m,1H),2.14-2.27(m,2H),1.85-1.93(m,1H), 1.33(d,J＝6.4Hz,1H).13CNMR(100MHz,CDCl3):162.3,159.4,156.9,154.1,154.0,138.6, 136.4,136.3,136.2,119.1,119.0,102.6,97.9,58.4,48.8,43.0,34.6,32.9,25.0,24.3,21.5.
Example 2:
steps 1 to 4 were performed according to steps 1 to 4 in example 1.
And 5: preparation of ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazo lo [1,5-a ] pyrimidine-3-carboxylate
Reacting (R) -ethyl 5- (2- (2-chloro-5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (50 mg,129umol) dissolved in DME/H2O4/1 (1mL), added with (R) -tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborocan-2-yl) butan-2-yl) carbamate (96mg,0.32mmol), 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (4.71mg,6.45umol) and potassium carbonate (53.4mg,387umol), protected with nitrogen, stirred at 100 ℃ for 10 hours, evaporated under reduced pressure to remove the solvent, purified by column chromatography (PE/EA 1/1) to give ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butoxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (2mg,3.8umol, 3% yield).
MS(ESI)m/z＝527(M+1)+。
Step 6 to step 8 steps 6 to 8 in example 1 were followed.
Example 3:
step 1-4: preparation of ethyl (R) -ethyl 5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate
Ethyl (R) -ethyl 5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate was synthesized according to the synthesis method in steps 1 to 4 of example 1, starting from (R) -5-fluoro-2-methoxy-3- (tetrahydropyrrolyl-2-yl) pyridine instead of 2-chloro-3-formyl-5-fluoropyridine in step 1 of example 1.
MS(ESI)m/z＝386(M+1)+。
And 5: preparation of ethyl (R) -ethyl 5- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate
Ethyl (R) -ethyl 5- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (450mg,1.17mmol) was dissolved in acetic acid (2mL) and a 30% solution of hydrobromic acid in acetic acid (2.9g,11.68mmol) was added. After stirring at 90 ℃ for 1 hour, the solvent was distilled off under reduced pressure, and purified by column chromatography (PE/EA ═ 1/1) to give ethyl (R) -ethyl 5- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (421mg,1.13mmol, 96% yield).
MS(ESI)m/z＝372(M+1)+。
Step 6: preparation of ethyl (R) -ethyl 5- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate
Ethyl (R) -ethyl 5- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (420mg,1.13mmol) is dissolved in dichloromethane (10mL) and triethylamine (137mg,1.36mmol) and N-phenylbis (trifluoromethane) sulfonimide (444mg,1.24mmol) are added. The mixture was stirred at room temperature for 10 hours, and the solvent was evaporated under reduced pressure and purified by column chromatography (PE/EA ═ 1/1) to give ethyl (R) -ethyl 5- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) pyrazoxazo [1,5-a ] pyrimidine-3-carboxylate (600mg,1.07mmol, yield 94.8%).
MS(ESI)m/z＝504(M+1)+。
And 7: preparation of phenyl 5-fluoro-2-hydroxyphenyl (methyl) carbamate
(Potassium (R) - (3- ((tert-Butoxycarbonyl) amino) butyl) trifluoroborate (134mg,479umol) was dissolved in DME/H2O4/1 (2mL), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (11.7mg,16.0umol), (R) -ethyl 5- (2- (5-fluoro-2- (((trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a ] was added]Ethyl pyrimidine-3-carboxylate (80.3mg, 159. mu. mol) and potassium carbonate (66mg, 479. mu. mol) were stirred at 100 ℃ for 10 hours under nitrogen protection, and the solvent was evaporated under reduced pressure. Purifying by column chromatography (PE/EA: 1/1) to obtain ethyl 5- ((R) -2- (2- ((R) -3- ((tert-butyloxycarbonyl) amino) butyl) -5-fluoropyridin-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (12mg,23.9umol, yield 5%).
MS(ESI)m/z＝527(M+1)+。
And 8-10: preparation of LOXO-195
Following the synthesis procedures of steps 6 through 8 of example 1, a LOXO-195 compound was obtained.
Example 1 preparation of a Compound of formula (V) by reaction of a Compound of formula (II) with a Compound of formula (III) in example 1 Compound R of formula (II)1The substituent is Cl, and then the compound LOXO-195 is prepared, and the yield of the target product LOXO-195 is 36.4%. The LOXO-195 prepared by the method has high yield.
In conclusion, the present invention provides a process for preparing the TRK kinase inhibitor compound LOXO-195 and salts thereof, which is safe, convenient to operate, high in product yield, and suitable for small-scale or large-scale industrial production.
Claims (25)
1. A process for preparing a compound of formula (V) or a salt thereof: the method is characterized in that: reacting a compound of a formula (II) with a compound of a formula (III) or reacting the compound of the formula (II) with a compound of a formula (IV) under the action of a metal catalyst to obtain a compound of a formula (V);
the structural formula of the formula (II) is as follows:
the structural formula of formula (III) is:
the structural formula of the formula (IV) is
The structural formula of the compound of the formula (V) is
Wherein R is1F, Cl, Br, I;
x is F, Cl, Br, I;
R2is an amino protecting group;
m is alkali metal, iron, magnesium, calcium and copper;
n is the number of charges carried by M metal ions and is a positive integer;
r is H, C1-C10Alkyl or C1-C10Substituted alkyl, wherein said C1-C10The substituents of the alkyl groups being selected from C1-C10An alkoxy group; the 2 ORs may be configured as four-ten membered rings;
the reaction is carried out under the action of a base.
2. The method of claim 1, wherein: the alkali is selected from metal carbonate, alkali metal phosphate, alkali metal hydride, alkali metal alkoxide or alkali metal hydroxide.
3. The method of claim 2, wherein: the alkali is potassium carbonate.
4. The method of claim 1, wherein: the alkali metal M is selected from lithium, sodium and potassium.
5. The method of claim 1, wherein: and n is 1,2 or 3.
6. The method of claim 1, wherein: the compound of the formula (IV) is
7. The method of claim 1, wherein: the metal catalyst is selected from palladium catalyst, nickel catalyst and copper catalyst.
8. The method of claim 7, wherein: the palladium catalyst is 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride.
9. The method according to any one of claims 1 to 8, wherein: the reaction is carried out in a mixed solvent of water and an organic solvent.
10. The method of claim 9, wherein: the organic solvent is selected from ether, tetrahydrofuran and alcohol.
11. The method of claim 10, wherein: the ether is dimethyl ether.
12. The method according to claim 10 or 11, characterized in that: wherein, the water: the volume ratio of the dimethyl ether is 1: 4.
13. According to the claimsThe method of claim 1, comprising: the R is2Selected from benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, trimethylsiloxyethylcarbonyl, methoxycarbonyl, ethoxycarbonyl, o-phenylethoxy, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, benzoyl, triphenylmethyl, p-methoxybenzyl, benzyl, 2, 4-dimethoxybenzyl.
14. The method of claim 13, wherein: the R is2Is tert-butoxycarbonyl.
15. A process for preparing a compound of formula (I) or a salt thereof, characterized in that: it comprises the following steps:
a. preparing a compound of formula (V) by ester hydrolysis according to the process of any one of claims 1 to 14 to obtain a compound of formula (vi);
b. deprotection of a compound of formula (VI) R2To obtain a compound of formula (VII);
c. cyclizing the compound of the formula (VII) to obtain a compound of a formula (I);
and c, performing ester hydrolysis reaction in the step a in a mixed solvent of tetrahydrofuran, alcohol and water.
16. The method of claim 15, wherein: the ester hydrolysis reaction of the step a is carried out in a strong base.
17. The method of claim 16, wherein: the strong base is selected from the group consisting of hydroxides and alkoxides.
18. The method of claim 17, wherein: the strong base is sodium hydroxide.
19. The method of claim 15, wherein: the alcohol is methanol.
20. The method of claim 19, wherein: the solvent is tetrahydrofuran: methanol: the volume ratio of water is 2:1: 1.
21. The method of claim 15, wherein: removing the amino protecting group R in the step b reaction2Under acidic conditions.
22. The method of claim 21, wherein: the acid is hydrochloric acid.
23. The method of claim 15, wherein: the cyclization in the step c is carried out in the presence of a condensing agent.
24. The method of claim 23, wherein: the condensing agent is selected from dicyclohexyl carbon, N, N ' -diisopropyl, N- (3-dimethyl amino propyl) -N ' -ethyl carbodiimide, 1- (3-dimethyl amino propyl) -3-ethyl carbodiimide hydrochloride, N, N ' -carbonyl diimidazole, 2- (7-azabenzotriazole-1-yl) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate and 1- (benzotriazole-1-yl) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate.
25. The method of claim 24, wherein: the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 1- (benzotriazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
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| CN106029660A (en) * | 2013-12-16 | 2016-10-12 | 阿萨纳生物科技有限责任公司 | P2X3 and/or P2X2/3 compounds and methods |
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