CN107188888A - A kind of methanesulfonic acid for preparing steps the auspicious method for Buddhist nun - Google Patents
A kind of methanesulfonic acid for preparing steps the auspicious method for Buddhist nun Download PDFInfo
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- CN107188888A CN107188888A CN201610144859.9A CN201610144859A CN107188888A CN 107188888 A CN107188888 A CN 107188888A CN 201610144859 A CN201610144859 A CN 201610144859A CN 107188888 A CN107188888 A CN 107188888A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The auspicious method for Buddhist nun is stepped the invention discloses a kind of methanesulfonic acid for preparing.Methods described includes：3 (pyrimidine radicals of 2 chlorine 4) 1 methyl 1H indoles and the nitroaniline of 4 fluorine, 2 methoxyl group 5 occur after substitution reaction, again and N, N, substitution reaction occurs for N' trimethyls ethylenediamine, by catalytic hydrogenating reduction nitro, occurs coupling reaction with 3 chlorpromazine chlorides again, obtain stepping auspicious for Buddhist nun after eliminating through sodium hydroxide, Mai Rui obtains methanesulfonic acid into salt with methanesulfonic acid in acetone and water for Buddhist nun and steps auspicious for Buddhist nun, and the catalyst of the catalytic hydrogenating reduction nitro is Raney's nickel, palladium carbon or hydroxide palladium carbon.The method of the invention cost is low, and high income, environmental pollution is small, and simple production process is easy to operate, is adapted to industrialized production.
Description
Technical field
The auspicious preparation method for Buddhist nun is stepped the present invention relates to medicinal chemistry arts, more particularly to methanesulfonic acid.
Background technology
Methanesulfonic acid step it is auspicious for Buddhist nun be Astrazeneca AB's research and development the third generation is oral, irreversible selective EGFR mutation suppression
Preparation, available for activation and resistant mutation EGFR.For patients with advanced NSCLC, 50% anti-EGFR treatments are obtained
Property resistance is that caused by T790M mutation, methanesulfonic acid, which is stepped, auspicious to be had to the T790M non-small cell lung cancers being mutated and preferably control for Buddhist nun
Therapeutic effect.
It is existing prepare methanesulfonic acid step the auspicious method for Buddhist nun for 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles and 4- it is fluoro-
2- methoxyl group -5- nitroanilines occur substitution reaction, then and N, N, N'- trimethyl ethylenediamine occur substitution reaction, reduce nitro,
Coupling is eliminated, then into salt.The method of the reduction nitro is iron ammonium reducing process, in last handling process, first has to use ion exchange
Resin is pre-processed, and cost is high, is not suitable for industry chemical conversion production；And iron powder adsorption is big, cause yield low, the waste residue and liquid of generation also compared with
It is many, it is unfavorable for environmental protection.
The content of the invention
The auspicious method for Buddhist nun is stepped it is an object of the invention to provide a kind of methanesulfonic acid for preparing, methods described cost is low, yield
Height, environmental pollution is small, and simple production process is easy to operate, is adapted to industrialized production.
The compound methanesulfonic acid prepared the invention provides one kind as shown in formula (I) steps the auspicious method for Buddhist nun
Including：
(1) 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles are under acid catalysis, with the fluoro- 2- methoxyl groups -5- nitros of 4-
Aniline reaction prepares the compound as shown in formula (II)
(2) in the solvent that alkali is present, the compound and N, N, N'- trimethyl ethylenediamine as shown in formula (II) occurs
Substitution reaction prepares the compound as shown in formula (III)
(3) compound as shown in formula (III) is under catalyst action, and hydrogenating reduction is prepared as shown in formula (IV)
Compound
(4) compound as shown in formula (IV) is coupled with 3- chlorpromazine chlorides, under conditions of sodium hydroxide presence, hair
Raw elimination reaction generates the compound as shown in formula (V)
(5) compound as shown in formula (V) obtains described with methanesulfonic acid in the in the mixed solvent of acetone and water into salt
Compound methanesulfonic acid steps auspicious for Buddhist nun；
Characterized in that, catalyst described in step (3) is Raney's nickel, palladium carbon or hydroxide palladium carbon.
Optionally, the acid described in step (1) is anhydrous p-methyl benzenesulfonic acid, trifluoroacetic acid, acetic acid.
Optionally, the acid described in step (1) is anhydrous p-methyl benzenesulfonic acid.
Optionally, the consumption of anhydrous p-methyl benzenesulfonic acid for 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles 0.1~
1.0 equivalent.
Optionally, the alkali described in step (2) is at least one of alkali carbonate.
Optionally, the alkali carbonate is potassium carbonate.
Optionally, catalyst described in step (3) is Raney's nickel.
Optionally, step (4) further comprises stepping the compound as shown in formula (V) of preparation and auspicious existed for Buddhist nun's dissolving crude product
In polar solvent, then with after activated carbon decolorizing the step of crystallization.
Optionally, the polar solvent is methanol, ethanol or isopropanol.
Optionally, the polar solvent is isopropanol.
Optionally, the temperature of salt-forming reaction described in step (5) is 20-50 DEG C.
Optionally, described in step (5) as shown in formula (V) compound and the mol ratio of methanesulfonic acid is 0.5：1~1：1.
The method of the invention compared with prior art, has the following advantages that：
Catalytic hydrogenation of the present invention uses Raney's nickel, palladium carbon or hydroxide palladium carbon for catalyst, it is to avoid rear place
The step of ion exchange resin is pre-processed is needed during reason, cost is reduced, it is simple to operate, it is adapted to industry chemical conversion production；And not
There is iron powder adsorption big, cause the problem of yield is low；The waste residue and liquid of generation is also less, is conducive to environmental protection.
Further, reduced using raney ni catalysis, room temperature can be carried out, it is not necessary to be heated, energy consumption is low.Post processing side
Just, it is easy to filter, it is not necessary to pre-process, small, high income is adsorbed.
Further, catalysis acid is anhydrous p-methyl benzenesulfonic acid, it is to avoid 3- (the chloro- 4- pyrimidine radicals of 2-) -1- methyl -
Chlorine on 1H- indoles is hydrolyzed into hydroxyl.
Further, the consumption of p-methyl benzenesulfonic acid is reduced, the risk that genotoxicity impurity is introduced in product is reduced.
Further, make alkali from potassium carbonate, greatly reduce cost.Reaction time is short, and post processing is quick and easy, adds water
Crystallization, the solid of precipitation is loose, easily filtering.
Further, the step of step (4) includes activated carbon decolorizing, purity is obtained higher as shown in formula (V)
Compound, purity can reach pharmaceutical grade.
It is as follows that the present invention provides following technical scheme：
A kind of compound methanesulfonic acid of preparation structure formula as shown in formula (I) steps the auspicious method for Buddhist nun
Including：
(1) 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles are under acid catalysis, with the fluoro- 2- methoxyl groups -5- nitros of 4-
Aniline reaction prepares the compound as shown in formula (II)
Because the chlorine reactivities of 2 in pyrimidine ring are not high, cause reaction speed slow and can not react completely.It is to urge with acid
Agent activates pyrimidine ring, so that the nucleophilic substitution of aniline can quickly be carried out and reacted completely.Some implementations of the present invention
Acid described in example is p-methyl benzenesulfonic acid, anhydrous p-methyl benzenesulfonic acid, trifluoroacetic acid, acetic acid.Further, in order to avoid 3-, (2- is chloro-
4- pyrimidine radicals) chlorine on -1- Methyl-1H-indoles be hydrolyzed into it is preferably anhydrous to toluene sulphur in hydroxyl, some embodiments of the invention
Acid is acid catalyst.Further, in order to reduce the risk of introducing genotoxicity impurity in product, present invention reduces to toluene
In the consumption of sulfonic acid, some embodiments, the consumption of p-methyl benzenesulfonic acid is 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles
0.1-1.0 equivalents, preferably 0.1-0.5 equivalents.
The present invention does not have particular/special requirement to the solvent system of above-mentioned reaction, as long as can realize, preferably alcohols.This
Invent in some embodiments, reaction temperature is 80~120 DEG C, the reaction time is 0.5~10h.
(2) in the solvent that alkali is present, the compound and N, N, N'- trimethyl ethylenediamine as shown in formula (II) occurs
Substitution reaction prepares the compound as shown in formula (III)
In some embodiments of the invention, alkali described in step (2) is DIPEA, sodium carbonate, potassium carbonate, carbon
Sour caesium etc., preferably potassium carbonate.Make alkali from potassium carbonate, greatly reduce cost.Reaction time is short, and post processing is quick and easy,
Add water crystallization, and the solid of precipitation is loose, easily filtering.The preferable amount of potassium carbonate is for the compound as shown in formula (II)
1~5 equivalent.
Currently preferred dicyandiamide solution is non-protonic solvent, preferably DMA.Reaction temperature is excellent
Elect 60~120 DEG C as, the reaction time is 0.5~8h.
(3) compound as shown in formula (III) is under catalyst action, and hydrogenating reduction is prepared as shown in formula (IV)
Compound
The catalyst is Raney's nickel, palladium carbon or hydroxide palladium carbon.
The catalyst of catalytic hydrogenation is Raney's nickel, palladium carbon or hydroxide palladium carbon in the present invention, need not in last handling process
The step of ion exchange resin is pre-processed, reduces cost, simple to operate, is adapted to industry chemical conversion production；And in the absence of iron powder adsorption
Greatly, the problem of yield is low is caused；The waste residue and liquid of generation is also less, is conducive to environmental protection.In some embodiments of the invention, urge
The catalyst for changing hydrogenation is Raney's nickel.Reduced using raney ni catalysis, room temperature can be carried out, it is not necessary to be heated, energy consumption is low.After locate
Reason is convenient, it is easy to filter, it is not necessary to pre-process, and adsorbs small, high income.
The dicyandiamide solution of the present invention is preferably alcoholic solution, especially methanol.The compound and thunder as shown in formula (III)
The ratio of weight and number 1 of Buddhist nun's nickel：1~5：1, the pressure of hydro-reduction is 1~10 atmospheric pressure, 25-60 DEG C of reaction temperature, reaction time
1~10 hour.
(4) compound as shown in formula (IV) is coupled with 3- chlorpromazine chlorides, under conditions of sodium hydroxide presence, hair
Raw elimination reaction generates the compound as shown in formula (V)
The temperature of the coupling reaction is preferably -15~50 DEG C, and the reaction time is preferably 0.5-6h.The elimination reaction
Temperature is preferably 30~70 DEG C, and the reaction time is preferably 3~16h.
In some embodiments, step (4) further comprises the crude compound as shown in formula (V) being dissolved in polar solvent
In, then use activated carbon decolorizing.The polar solvent is methanol, ethanol or isopropanol etc., preferably isopropanol.It is de- by activated carbon
Crystallization after color, can prepare the compound as shown in formula (V) of pharmaceutical grade.
(5) compound as shown in formula (V) obtains described with methanesulfonic acid in the in the mixed solvent of acetone and water into salt
Compound methanesulfonic acid steps auspicious for Buddhist nun.
The temperature of salt-forming reaction is preferably 20~50 DEG C described in step (5).Reaction time is preferably 1~6h.It is described such as
The mol ratio of compound and methanesulfonic acid shown in formula (V) is 0.5：1~1：1, the consumption of methanesulfonic acid is reduced, it is possible to prevente effectively from raw
Cheng Mairui replaces the bimolecular mesylate of Buddhist nun.
Embodiment：
With reference to embodiment, the present invention is described in more detail, it is understood, however, that these embodiments are only
Only used for specifically describing in more detail, and be not to be construed as limiting the present invention in any form.
The method of reagent and use used in the embodiment of the present invention is the conventional reagent and conventional method of this area.
It will be apparent to those skilled in the art that hereinafter, if not otherwise specified, temperature represents that operation temperature exists with degree Celsius (DEG C)
Carried out under room temperature environment, shown room temperature refers to 10 DEG C~30 DEG C, and preferably 20 DEG C~25 DEG C, described yield is mass percent.
Embodiment 1
(1) compound shown in formula (II) is prepared
At room temperature, 1000 milliliters of 2- amylalcohols are added in 2L reaction bulbs, add 50 grams of 3- (the chloro- 4- pyrimidine radicals of 2-) -1-
Methyl-1H-indole, the fluoro- 2- methoxyl groups -5- nitroanilines of 42 grams of 4-, 3.54 grams of p-methyl benzenesulfonic acid heat the mixture to 80
DEG C, react 6 hours.Mixture is cooled to 25 DEG C~28 DEG C, and suction filtration, filter cake is washed with 50 milliliters of 2- amylalcohols.After filter cake is drained, enter
Vacuum drying chamber drying obtains 80.1 grams of yellow solid, yield：99.0%.1HNMR(400MHz,DMSO)δ3.92(3H,s),
4.00 (3H, s), 7.14 (1H, dd), 7.30-7.33 (1H, m), 7.44-7.52 (2H, m), 7.60 (1H, d), 8.22 (1H,
M), 8.35 (1H, d), 8.68 (1H, s), 8.79 (1H, d), 9.76 (1H, s).m/z(M+H)+=394.20.
Embodiment 2
Prepare compound shown in formula (III)
At room temperature, 801 milliliters of DMAs are added in 2L reaction bulbs, add 80.1 grams of formula (II) institutes
Show compound, 20.6 grams of N, N, N'- trimethyl ethylenediamines, 28.1 grams of potassium carbonate.Mixture is heated 110 DEG C, reacted 7 hours.
Slow cooling is slowly added into 801 milliliters of water, stirring and crystallizing 1 hour to 25 DEG C~28 DEG C.Suction filtration, filter cake is washed with 160 milliliters
Wash.Filter cake enters vacuum drying chamber drying, obtains 92.8 grams of orange red solid, yield：95.9%.1HNMR(400MHz,DMSO)δ
2.16 (6H, s), 2.48 (2H, t), 2.86 (3H, s), 3.27 (2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.84 (1H, s),
7.12 (1H, t), 7.22 (1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.11 (1H, s), 8.31 (1H, d), 8.32 (1H, s),
8.36(1H,d),8.64(1H,s)。m/z(M+H)+=476.20.
Embodiment 3
Prepare compound shown in formula (IV)
Under nitrogen protection, 928 ml methanols are added in 2L four-hole boiling flasks, then add 92.8 grams of formula (III) institutes
Show compound, under stirring, add 18.6g Raney's nickels (aqueous wet product), hydro-reduction under 8 atmospheric pressures, 25 DEG C of reaction temperature,
Reaction 6 hours.Filtering is spin-dried for producing 82.6 grams of gray solids, yield：95.0%.1HNMR(400MHz,DMSO)δ2.18(6H,
S), 2.37 (2H, t), 2.63 (3H, s), 2.89 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.62 (2H, s), 6.76 (1H,
Brs), 7.14-7.19 (2H, m), 7.23-7.26 (1H, m), 7.48 (1H, s), 7.52 (1H, d), 7.81 (1H, s), 8.27
(1H, d), 8.31 (1H, s), 8.43 (1H, d).m/z(M+H)+=446.30.
Embodiment 4
Prepare compound shown in formula (IV)
Under nitrogen protection, 500 ml methanols are added in 1L three-necked flasks, then added shown in 50 grams of formulas (III)
Compound, under stirring, add 5.0 gram of 10% palladium carbon (hydro-reduction under aqueous 50%), 2 atmospheric pressures, 50 DEG C of reaction temperature,
Reaction 12 hours.Room temperature is cooled to, filtering is spin-dried for producing 39.8 grams of gray solids, yield：85.0%.1HNMR(400MHz,
DMSO)δ2.18(6H,s),2.37(2H,t),2.63(3H,s),2.89(2H,t),3.74(3H,s),3.88(3H,s),4.62
(2H, s), 6.76 (1H, brs), 7.14-7.19 (2H, m), 7.23-7.26 (1H, m), 7.48 (1H, s), 7.52 (1H, d),
7.81 (1H, s), 8.27 (1H, d), 8.31 (1H, s), 8.43 (1H, d).m/z(M+H)+=446.30.
Embodiment 5
Prepare compound shown in formula (V)
At room temperature, by THF-H2O (825 milliliters -82.5 milliliters) is added in 2 liters of four-hole boiling flasks, then adds 82.5
Gram compound shown in formula (IV), 0 DEG C is cooled to by mixture.In at 0 DEG C~5 DEG C, 23.55 grams of 3- chlorpromazine chlorides are added dropwise.It is added dropwise
After end, 25 DEG C~28 DEG C are warming up to, continues to stir 1 hour, disposably adds 22.3 grams of sodium hydroxides.It is heated to reflux 8 hours.
25 DEG C~28 DEG C are cooled to, 825 milliliters of ethyl acetate are added, 410 milliliters of water are stirred 15 minutes.Stand, point liquid.Separate organic
Phase, is washed once with 410 milliliters of saturated sodium-chlorides.Organic phase is separated, with anhydrous sodium sulfate drying 1 hour.Filtering, filter cake acetic acid second
82 milliliters of ester is washed once, and filtrate is spin-dried for obtaining the crude product of compound shown in formula (V).Added into crude product 300 milliliters of isopropanols and
8.26 grams of activated carbons, are heated to reflux 1 hour, filter while hot.Filtrate under agitation, is down to 25 DEG C, separates out solid.Suction filtration,
Filter cake washs (40 milliliters of 2x) with isopropanol, obtains 74 grams of off-white powder, yield：79.6%.1HNMR(400MHz,DMSO)
δ2.21(6H,s),2.30(2H,t),2.72(3H,s),2.89(2H,t),3.86(3H,s),3.92(3H,s), 5.78(1H,
Dd), 6.26 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.23-7.26 (2H, m), 7.52 (1H, d),
7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.69 (1H, s), 9.17 (1H, s), 10.21 (1H, s).m/z(M+H)+
=500.30.HPLC:99.86%.
Embodiment 6
Prepare compound shown in formula (I)
At room temperature, implement compound shown in formula (V) prepared in 5 by 74 grams to be dissolved in 740 milliliters of acetone, add
74 milliliters of water, are stirred five minutes.Mixture is heated to 40 DEG C, 74 milliliters of acetone solns of 13.53 grams of methanesulfonic acids is added dropwise, after dripping off
40 DEG C of insulated and stirreds 30 minutes.Suction filtration.Filter cake is eluted (74 milliliters of 2x) with acetone, and 40 DEG C of filter cake is dried in vacuo 16 hours, is obtained
79 grams of compound, yield shown in pharmaceutical grade formula (I)：89.6%.1HNMR(400MHz,DMSO)δ2.35(3H,s),2.63(3H,
S), 2.82 (6H, s), 3.29 (4H, t), 3.90 (3H, s), 3.91 (3H, s), 5.81 (1H, dd), 6.34 (1H, dd), 6.71
(1H, dd), 7.02 (1H, s), 7.16 (1H, t), 7.23-7.26 (2H, m), 7.53 (1H, d), 7.97 (1H, s), 8.31-8.33
(2H, m), 8.54 (1H, s), 8.79 (1H, s), 9.25 (1H, brs), 10.21 (1H, s).HPLC:99.91%.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, some corrections can be made to it and improved, this will be apparent to those skilled in the art.Cause
This, the modification or improvement made without departing from theon the basis of the spirit of the present invention belong to the scope of protection of present invention.
Claims (11)
1. the compound methanesulfonic acid that one kind is prepared as shown in formula (I) steps the auspicious method for Buddhist nun
Including:
(1) 3- (the chloro- 4- pyrimidine radicals of 2-) -1- Methyl-1H-indoles are under acid catalysis, with the fluoro- 2- methoxyl groups -5- nitroanilines of 4-
Reaction prepares the compound as shown in formula (II)
(2) in the solvent that alkali is present, the compound and N, N, N'- trimethyl ethylenediamine as shown in formula (II) replaces
Reaction prepares the compound as shown in formula (III)
(3) compound as shown in formula (III) is under catalyst action, and hydrogenating reduction prepares the chemical combination as shown in formula (IV)
Thing
(4) compound as shown in formula (IV) is coupled with 3- chlorpromazine chlorides, under conditions of sodium hydroxide presence, is disappeared
Except compound of the reaction generation as shown in formula (V)
(5) compound as shown in formula (V) obtains the chemical combination with methanesulfonic acid in the in the mixed solvent of acetone and water into salt
Thing methanesulfonic acid steps auspicious for Buddhist nun；
Characterized in that, catalyst described in step (3) is Raney's nickel, palladium carbon or hydroxide palladium carbon.
2. according to the method described in claim 1, it is characterised in that acid described in step (1) is anhydrous p-methyl benzenesulfonic acid.
3. method according to claim 2, it is characterised in that the consumption of anhydrous p-methyl benzenesulfonic acid is 3- (the chloro- 4- pyrimidines of 2-
Base) -1- Methyl-1H-indoles 0.1~1.0 equivalent.
4. according to the method described in claim 1, it is characterised in that alkali described in step (2) be in alkali carbonate extremely
Few one kind.
5. method according to claim 4, it is characterised in that the alkali carbonate is potassium carbonate.
6. according to the method described in claim 1, it is characterised in that catalyst described in step (3) is Raney's nickel.
7. according to the method described in claim 1, it is characterised in that step (4) further comprises the chemical combination as shown in formula (V)
Thing dissolving crude product is in polar solvent, then with after activated carbon decolorizing the step of crystallization.
8. method according to claim 7, it is characterised in that the polar solvent is methanol, ethanol or isopropanol.
9. method according to claim 8, it is characterised in that the polar solvent is isopropanol.
10. according to the method described in claim 1, it is characterised in that the temperature of salt-forming reaction described in step (5) is 20-50
℃。
11. according to the method described in claim 1, it is characterised in that compound described in step (5) as shown in formula (V) with
The mol ratio of methanesulfonic acid is 0.5：1~1：1.
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| CN113372332A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib |
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| CN113372332B (en) * | 2020-03-10 | 2023-09-12 | 鲁南制药集团股份有限公司 | Novel crystal form of octreotide |
| US20220185794A1 (en) * | 2020-12-16 | 2022-06-16 | Scinopharm Taiwan, Ltd. | Process for preparing osimertinib or a salt thereof |
| US11780824B2 (en) * | 2020-12-16 | 2023-10-10 | Scinopharm Taiwan, Ltd. | Process for preparing osimertinib or a salt thereof |
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Address after: 201203 No. 67 Lane 11, Li Bing Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai Applicant after: Luoxin Pharmaceutical (Shanghai) Co., Ltd. Applicant after: Shandong Luo Xin Pharmaceutical Group Plc Address before: 201203 No. 67 Lane 11, Li Bing Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai Applicant before: Luo Xin Biotechnology (Shanghai) Co., Ltd. Applicant before: Shandong Luo Xin Pharmaceutical Group Plc |
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Application publication date: 20170922 |