CN115417876B - Intermediate compound of barytinib - Google Patents

Intermediate compound of barytinib Download PDF

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CN115417876B
CN115417876B CN202211140636.7A CN202211140636A CN115417876B CN 115417876 B CN115417876 B CN 115417876B CN 202211140636 A CN202211140636 A CN 202211140636A CN 115417876 B CN115417876 B CN 115417876B
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baratinib
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CN115417876A (en
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梁淑红
翟立海
王少林
徐杰
李廷武
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Shandong New Time Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a barytinib intermediate compound. The invention takes 1, 3-tetraethoxy propane as raw material, and (4-chloro-7H-pyrrolo [2,3-D ] pyrimidine-7-yl) methyl pivalate is subjected to nucleophilic substitution reaction and then hydrolyzed to obtain a baratinib new intermediate; and the new compound and 2- (1- (ethylsulfonyl) -3-hydrazino azetidin-3-yl) acetonitrile are subjected to Knorr reaction and then subjected to deprotection to finally obtain the baratinib, and the obtained final product is high in purity, stable in process and suitable for mass industrialized production.

Description

Intermediate compound of barytinib
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a barytinib intermediate compound.
Background
Baratinib (Baricitinib) is a selective oral JAK1/JAK2 inhibitor developed by the American Gift pharmaceutical company and the Incyte pharmaceutical company and can inhibit intracellular signaling of various inflammatory cytokines such as IL-6, IL-23 and the like. In month 2 2017, baroretinib was approved by the european union as a single or combination with methotrexate for the treatment of adult patients with moderate to severe active rheumatoid arthritis who are under-relieved or intolerant of one or more disease modifying antirheumatic drugs (DMARDs). This is also the first JAK inhibitor approved by the european union for the treatment of rheumatoid arthritis; in month 6 2018, the us FDA approved barbitinib for the market for the treatment of moderate to severe rheumatoid arthritis and in month 6 2022 as an oral drug for the treatment of severe alopecia areata. The chemical name of barytinib is: 1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2, 3-D)]Pyrimidin-4-yl) -1H-pyrazol-1-yl]-3-azetidinylacetonitrile, CAS number 1187594-09-7, molecular formula C 16 H 17 N 7 O 2 S, the molecular weight is 371.4, and the medicine molecule contains pyrrolopyrimidine, pyrazole and azetidine core structural fragments and has a quaternary carbon center, and the structural formula is as follows:
Figure BDA0003853401260000011
at present, the method for synthesizing the baratinib mainly comprises the following routes:
route 1: patent WO2009114512 and WO2010039939 report that a compound 2 and pyrazole borate with a protecting group (namely a compound 3) are subjected to Suzuki coupling reaction to obtain an intermediate 4, and then the pyrazole N atom protecting group is removed by the action of hydrochloric acid to obtain a key intermediate 2; critical intermediate 1 and critical intermediate 2 in 1, 8-diazabicyclo [5,4,0]And (3) carrying out Michael addition reaction on undec-7-ene (DBU) and then deprotecting to obtain the final product baratinib.When R is Pivaloyloxymethyl (POM), the baratinib is obtained by one-step deprotection in LiOH solution; when R is 2- (trimethylsilyl) ethoxymethyl (SEM), it is desired to use LiBF 4 And NH 4 The OH is removed in two steps, and the synthetic route is as follows:
Figure BDA0003853401260000021
the use of the metal palladium catalyst in the route not only increases the total cost but also has the risk of exceeding the heavy metal content of the bulk drug; in addition, multiple deprotection reactions are involved, reducing atomic economy.
Figure BDA0003853401260000022
Route 2: document Journal of Chemical Research,2016,40,205-208 reports that 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile (i.e. compound 15) is used as an initial raw material, and a Michael addition reaction is carried out with 4-pyrazole boronic acid pinacol ester (i.e. compound 13) under the catalysis of DBU to obtain a compound 19; the compound 19 and 4-chloropyrrolo [2,3-d ] pyrimidine (namely the compound 9) are subjected to Suzuki coupling reaction in the presence of a heavy metal palladium catalyst to obtain the barytanib (1).
Although the route has only two steps of reactions, the intermediate and the final product are separated and purified by adopting a silica gel column chromatography mode; in addition, the Suzuki coupling reaction needs to be carried out at high temperature for 48 hours, so that the energy consumption is high and the working hours are long. These factors severely restrict the practical application of the reaction route in industrial production.
Figure BDA0003853401260000031
Route 3: patent CN105294699 reports that 4-pyrazole boronic acid pinacol ester (i.e. compound 7) and 3- (cyanomethylene) azetidine-1-carboxylic acid tert-butyl ester (i.e. compound 8) are used as starting materials, intermediate 9 is prepared by michael addition reaction under DBU catalysis, and intermediate 11 is prepared by palladium catalysis Suzuki coupling reaction with compound 10; simultaneously removing two molecules of tert-butyloxycarbonyl (Boc) from the intermediate 11 under acidic conditions to obtain an intermediate 12; finally, intermediate 12 is subject to a sulfonamide reaction with ethylsulfonyl chloride to give baratinib (i.e., compound 1).
The route still needs to realize the coupling of the pyrrolopyrimidine ring and the pyrazole ring through a heavy metal catalyst; the product 12 of the compound 11 after Boc protection contains two active amino sites, and long-time low-temperature operation is needed when the sulfonamide reaction is carried out, otherwise, the double sulfonamide byproducts are obviously increased to influence the yield and the purity; in addition, the use of ethylsulfonyl chloride also increases the potential risk of residual genotoxic impurities in the drug substance.
Figure BDA0003853401260000032
Route 4: patent CN108586465 reports the use of di-tert-butyl dicarbonate (Boc) starting from 4-chloropyrrolopyrimidine (i.e. Compound 2) 2 O) protecting amino to obtain a compound 3, and carrying out one-pot substitution and intramolecular cyclization on the compound 3, acrolein and hydrazine hydrate under the oxygen condition to obtain a compound 4 containing a pyrazole ring without purification; the compound 4 and the compound 7 undergo Michael addition under the action of tetrabutylammonium bromide (TBAB) in acetonitrile, and then deamination of the protecting group is carried out in hydrochloric acid solution to obtain the barytanib (namely the compound 1).
This route requires a reflux reaction in an oxygen atmosphere at the time of synthesizing compound 4, and is not only highly dangerous but also prone to the generation of oxidized impurities. When the route is repeated, the byproducts of the reaction of the compound 3 and the hydrazine hydrate are found in the reaction process, and meanwhile, more 1, 4-addition byproducts (1, 2-addition is a target product) exist in the reaction process of the compound 3 and the acrolein, so that more byproducts with similar structures not only increase the purification difficulty, but also reduce the total yield.
Therefore, aiming at the defects in the prior art, a baratinib synthesis method which is simple in process, suitable for industrial production, high in yield and low in cost is urgently needed to meet the market demand.
Disclosure of Invention
Aiming at the defects, the invention aims to provide a synthetic route and a method suitable for industrial production of baratinib. The method successfully avoids the use of heavy metal catalysts, has the advantages of simple synthetic route, mild reaction conditions, high safety and simple and convenient operation, is suitable for industrial amplification, and has obvious technical advantages.
The invention is realized by the following technical scheme:
the first aspect of the invention provides a novel intermediate compound of baratinib, which has a structure shown in a formula II:
Figure BDA0003853401260000041
the invention provides a preparation method of a barytinib intermediate compound II, which specifically comprises the following steps: adding the compound SM-1, the compound SM-2, the alkali A and the potassium iodide into the organic solvent A, heating and refluxing until the reaction is finished, and obtaining the compound II after the reaction is finished:
Figure BDA0003853401260000042
preferably, the base A is selected from one of potassium carbonate, sodium bicarbonate and sodium hydrogen phosphate, wherein potassium carbonate is particularly preferred.
Preferably, the feeding mole ratio of the compound SM-1, the compound SM-2, the alkali A and the potassium iodide is as follows: 1.0:1.0 to 1.5:1.0 to 2.0:0.05 to 0.1, of which particular preference is given to: 1.0:1.02:1.2:0.08.
Preferably, the organic solvent a is selected from one or a combination of tetrahydrofuran, acetonitrile, 1, 2-dichloroethane, ethanol, of which tetrahydrofuran is particularly preferred.
In a preferred reaction, after completion of the reaction, a post-treatment is required, specifically: cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, filtering, washing with cold water, and drying in vacuum to obtain the compound II.
The third aspect of the invention provides an application of a novel intermediate compound II of baratinib in preparing baratinib, which comprises the following steps:
step 1: adding the compound II and the compound III into an organic solvent B, heating and refluxing until the reaction is finished, and performing post-treatment on the reaction to obtain a compound IV;
step 2: dissolving the compound IV in tetrahydrofuran and methanol, stirring, adding 1.0mol/L sodium hydroxide aqueous solution, stirring at 20-30 ℃ for reaction, and performing post-treatment on the reaction to obtain baratinib;
the synthetic route is as follows:
Figure BDA0003853401260000051
preferably, the molar ratio of the compound II to the compound III in the step 1 is as follows: 1.0:1.0 to 2.0, with 1.0:1.1 being particularly preferred.
Preferably, the organic solvent B in step 1 is selected from one of ethanol, methanol, tetrahydrofuran, acetonitrile, and ethanol is particularly preferred.
In a preferred reaction, after completion of the reaction, a post-treatment is required, step 1 being specifically performed as follows: cooling the reaction liquid, adding water into the reaction liquid, stirring for crystallization, filtering, washing with water, and vacuum drying to obtain a compound IV; the post-treatment of step 2 specifically operates as: cooling to 0-10 ℃, regulating the pH to be neutral by using 1.0mol/L hydrochloric acid aqueous solution, continuously stirring for 1 hour, performing suction filtration, washing a filter cake by using ethanol, adding the wet filter cake into ethanol/water mixed solution, heating and refluxing, cooling to 0-10 ℃, performing suction filtration, washing by using cold ethanol, and performing vacuum drying to obtain the compound I.
Compared with the prior art, the invention has the technical effects that: (modified)
1. The synthetic method has few reaction steps and high atom utilization rate;
2. heavy metal catalysts are not used, so that the heavy metal residue risk of the bulk drug is reduced;
3. the method has the advantages of mild reaction conditions, simple and easy operation of post-treatment and purification, small energy consumption, short working hours, less waste emission and environmental friendliness, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
characterization of Compound III Structure
Figure BDA0003853401260000061
ESI-MS(m/z)：219.1[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 ):δ＝4.46(s,4H),3.26(br,3H),3.81(s,2H),3.15(q,2H),1.29(t,3H)ppm。
Characterization of Compound II Structure
Figure BDA0003853401260000071
ESI-MS(m/z)：304.2[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 ):δ＝15.53(s,1H),9.46(s,2H),8.77(s,1H),7.59(d,1H),7.43(d,1H),5.83(s,2H),1.07(s,9H)。
Characterization of Compound IV Structure
Figure BDA0003853401260000072
ESI-MS(m/z)：486.5[M+H] + ； 1 H NMR(400MHz，CDCl 3 )δ＝8.81(s,1H),8.40(s,1H),8.32(s,1H),7.49(d,1H),6.72(d,1H),6.20(s,2H),4.65(d,2H),4.24(d,2H),3.43(s,2H),3.10(q,2H),1.44(t,3H),1.12(s,9H)ppm。
Characterization of Compound I Structure
Figure BDA0003853401260000073
ESI-MS(m/z)372.5[M+H] + ； 1 H NMR(400MHz，DMSO-d 6 )δ＝12.15(s,1H),8.94(s,1H),8.72(s,1H),8.49(s,1H),7.63(d,1H),7.09(d,1H),4.62(d,2H),4.25(d,2H),3.71(s,2H),3.24(q,2H),1.26(t,3H)ppm。
Preparation of Compound III
Example 1
2- [1- (ethylsulfonyl) -3-azetidinylidene ] acetonitrile (37.24 g,200 mmol), 80% hydrazine hydrate (12.50 g,200 mmol) were added sequentially to acetonitrile (100 mL), stirred and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.50 g,10 mmol) was added, and stirred at 20-30℃for 6 hours; the reaction solution was poured into a mixture of dichloromethane (200 mL) and water (100 mL) and stirred, the mixture was left to stand for separation, the aqueous phase was extracted with dichloromethane (50 ml×2), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, the filtrate was collected, and concentrated under reduced pressure to give compound II, which was used in the next reaction without further purification.
Preparation of Compound II
Example 2
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (16.58 g,120 mmol), potassium iodide (1.33 g,8 mmol) were added to THF (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 98.5%, and the HPLC purity is 99.72%.
Example 3
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.03 g,100 mmol), sodium carbonate (12.71 g,120 mmol), potassium iodide (1.33 g,8 mmol) were added to THF (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 94.3%, and the HPLC purity is 99.66%.
Example 4
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (44.06 g,200 mmol), sodium bicarbonate (10.08 g,120 mmol), potassium iodide (1.33 g,8 mmol) were added to THF (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 95.5%, and the HPLC purity is 99.52%.
Example 5
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (13.82 g,100 mmol), potassium iodide (1.33 g,8 mmol) were added to acetonitrile (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 93.8%, and the HPLC purity is 99.69%.
Example 6
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (27.64 g,200 mmol), potassium iodide (1.33 g,8 mmol) were added to ethanol (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 94.5%, and the HPLC purity is 99.52%.
Example 7
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (16.58 g,120 mmol), potassium iodide (0.83 g,5 mmol) were added to 1, 2-dichloroethane (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 94.8%, and the HPLC purity is 99.60%.
Example 8
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (16.58 g,120 mmol), potassium iodide (1.66 g,10 mmol) were added to 1, 2-dichloroethane (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, then carrying out suction filtration, washing with cold water, and vacuum drying to obtain the compound II, wherein the yield is 95.6%, and the HPLC purity is 99.48%
Example 9
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), potassium carbonate (16.58 g,120 mmol), potassium iodide (0.66 g,4 mmol) were added to THF (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 87.7%, and the HPLC purity is 98.92%.
Example 10
Compound SM-1 (26.77 g,100 mmol), compound SM-2 (22.47 g,102 mmol), sodium hydrogen phosphate (31.23 g,220 mmol), potassium iodide (1.99 g,12 mmol) were added to THF (150 mL), and heated under reflux for 6 hours; cooling to 0-10 ℃, adding dilute hydrochloric acid (1.0 mol/L) into the reaction solution to adjust the pH to 3-4, stirring for 2 hours at 20-30 ℃, carrying out suction filtration, washing with cold water, and carrying out vacuum drying to obtain the compound II, wherein the yield is 85.3%, and the HPLC purity is 98.55%.
Preparation of Compound IV
Example 11
Compound II (15.15 g,50 mmol) and compound III (11.99 g,55 mmol) were added to ethanol (150 mL), heated and stirred overnight, cooled, water (600 mL) was added to the reaction solution, stirred and crystallized, suction filtered, water washed, and dried under vacuum to give compound IV in 98.0% yield and 99.88% HPLC purity.
Example 12
Compound II (15.15 g,50 mmol) and compound III (10.90 g,50 mmol) were heated in methanol (150 mL), stirred overnight, cooled, water (600 mL) was added to the reaction mixture, stirred for crystallization, filtered off with suction, washed with water, and dried under vacuum to give compound IV in 94.5% yield and with HPLC purity of 99.72%.
Example 13
Compound II (15.15 g,50 mmol) and compound III (21.80 g,100 mmol) were added to tetrahydrofuran (150 mL), heated and stirred overnight, cooled, water (600 mL) was added to the reaction mixture, stirred and crystallized, filtered off with suction, washed with water, and dried in vacuo to give compound IV in 95.1% yield and 99.60% HPLC purity.
Example 14
Compound II (15.15 g,50 mmol) and compound III (26.17 g,120 mmol) were heated in acetonitrile (150 mL), stirred overnight, cooled, water (600 mL) was added to the reaction solution, stirred for crystallization, suction filtered, water washed and dried under vacuum to give compound IV in a yield of 87.6% and an HPLC purity of 98.55%.
Preparation of barytinib
Example 15
Compound IV (9.71 g,20 mmol) was dissolved in a tetrahydrofuran (40 mL)/methanol (10 mL) mixture, stirred and 1.0mol/L aqueous sodium hydroxide solution (24 mL) was added, and stirred at 20-30℃for 2 hours; cooling to 0-10 ℃, regulating the pH to be neutral by using 1.0mol/L hydrochloric acid aqueous solution, continuously stirring for 1 hour, filtering, and washing a filter cake by ethanol. The wet cake was added to a mixture of ethanol (40 mL)/water (20 mL), heated under reflux for half an hour, cooled to 0-10 ℃, filtered off with suction, washed with cold ethanol, and dried under vacuum to give compound 1 (6.01 g,16.18 mmol) in 98.9% yield and 99.95% HPLC purity.

Claims (6)

1. The intermediate compound of baratinib is characterized in that the structure of the intermediate compound is shown as a formula II:
Figure QLYQS_1
。
2. a process for the preparation of the baratinib intermediate compound II of claim 1, characterized in that the process comprises the steps of: adding the compound SM-1, the compound SM-2, the alkali A and the potassium iodide into the organic solvent A, heating and refluxing until the reaction is finished, and obtaining the compound II after the reaction is subjected to post-treatment, wherein the route is as follows:
Figure QLYQS_2
the base isA is selected from one of potassium carbonate, sodium bicarbonate and sodium hydrogen phosphate;
the organic solvent A is selected from one or a combination of tetrahydrofuran, acetonitrile, 1, 2-dichloroethane and ethanol.
3. The preparation method according to claim 2, wherein the compound SM-1, compound SM-2, base a and potassium iodide are fed in a molar ratio of: 1.0: 1.0-1.5:1.0-2.0:0.05-0.1.
4. Use of compound II according to claim 1 for the preparation of baratinib.
5. Use of a baratinib intermediate compound II according to claim 1 for the preparation of baratinib, characterized in that the preparation method comprises the steps of:
step (1): adding the compound II and the compound III into an organic solvent B, heating and refluxing until the reaction is finished, and performing post-treatment on the reaction to obtain a compound IV;
step (2): dissolving a compound IV in tetrahydrofuran and methanol, stirring, adding a 1.0mol/L sodium hydroxide aqueous solution, stirring at 20-30 ℃ for reaction, and performing post-treatment on the reaction to obtain barytanib;
the synthetic route is as follows:
Figure QLYQS_3
the organic solvent B in the step (1) is selected from one of ethanol, methanol, tetrahydrofuran and acetonitrile.
6. The use according to claim 5, wherein the molar ratio of compound II to compound III in step (1) is: 1.0:1.0 to 2.0.
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