CN112430208A - Preparation method of PF-06651600 intermediate - Google Patents
Preparation method of PF-06651600 intermediate Download PDFInfo
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- CN112430208A CN112430208A CN201910790622.1A CN201910790622A CN112430208A CN 112430208 A CN112430208 A CN 112430208A CN 201910790622 A CN201910790622 A CN 201910790622A CN 112430208 A CN112430208 A CN 112430208A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of a PF-06651600 intermediate, belonging to the field of pharmaceutical chemistry. The method comprises the steps of taking D-Boc-pyroglutamic acid ethyl ester subjected to ring opening in a format as a raw material, and obtaining a target compound through reduction, hydroxyl sulfonylation and cyclization, wherein the target compound can be subjected to further deprotection and salification. The intermediate compound used in the method has the advantages of novel structure, mild condition, easily obtained reagent, high product purity, high yield and safe operation, and can be used for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a PF-06651600 intermediate.
Background
Alopecia areata is an autoimmune disease, which is mainly characterized by gross hair loss of the head, face and body. The symptoms are caused by the attack of the patient's immune cells on the autologous hair follicles, which are initially round alopecia areata. Alopecia areata has an average age between 25 and 35 years of age, but can also affect children and adolescents, and can occur in both men and women and in all races.
PF-06651600 is a potent, selective inhibitor of JAK3, previously approved by FDA breakthrough therapy for the treatment of alopecia areata. Currently, it is subjected to a phase 3 clinical trial for the treatment of moderate to severe alopecia areata, while continuing the trial for the treatment of Rheumatoid Arthritis (RA), Crohn's Disease (CD) and Ulcerative Colitis (UC); the structure of PF-06651600 is shown by the following formula:
in the prior art, 5-methyl-3-aminopyridine is used as a raw material, for example, WO2010048012 discloses that a metal rhodium catalyst is used to reduce a pyridine ring into a piperidine ring; WO2016112298 discloses the use of PtO2As a catalyst to reduce the pyridine ring. However, the metal catalyst is expensive, generally uses hydrogen for reduction, and is heated and hydrogenated under high pressure for a long time, and the reaction conditions are harsh. E.g. using PtO2The generated platinum black is flammable and dangerous to produce. In the prior art, the multi-step reaction needs column chromatography purification and is difficult to be produced in an enlarged way. In the prior art, (R) -N-3, 5-dinitrobenzoyl phenylglycine is used as a resolving agent, which is expensive and is a document (Organic Process Research)&Development (2019), Ahead of Print) records that the resolving agent has a violent exothermic phenomenon when used, and has potential safety hazard when the resolving agent is not well controlled during production.
Therefore, a new intermediate is urgently needed to be found, or a new method for preparing the intermediate of PF-06651600 is researched to obtain a method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost and environment-friendly, so that the compound PF-06651600 can be better prepared.
Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate, which is characterized in that D-Boc-pyroglutamic acid ethyl ester subjected to ring opening in a format is used as a raw material, a target compound is obtained through reduction, hydroxyl sulfonylation and cyclization, and the target compound can be further subjected to deprotection and salification.
In a first aspect, the present invention provides a process for the preparation of intermediate compound 04. A process for preparing compound 04 includes reaction between compound 03 and phenylmethylamine in reaction solvent, post-treating to obtain compound 04,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 04 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the reaction solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, ethylene glycol dimethyl ether. The method has the advantages of mild reaction conditions, safe operation, easily obtained reagents and low production cost.
In some embodiments, the molar ratio of compound 03 to benzylamine is from 1:1 to 1: 20; or the molar ratio is 1:5-1: 15; or a molar ratio of 1: 10.
In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 80 ℃.
In some embodiments, the reaction time of the reaction is from 4 hours to 48 hours. In some embodiments, the reaction time of the reaction is from 12 hours to 40 hours. In some embodiments, the reaction time of the reaction is from 24 hours to 30 hours.
In a second aspect, the present invention provides a process for preparing compound 03 comprising reacting compound 02 with R-Cl in the presence of a base to obtain compound 03,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 03 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of preparing compound 03, the base is at least one of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate.
In some embodiments, the molar ratio of compound 02 to base is from 1:2 to 1: 3. The method is favorable for better enabling the compound 02 to react completely and obtaining the target compound with high yield.
In some embodiments, in the method of making compound 03, the reaction temperature of the reaction is between-10 ℃ and 10 ℃. In some embodiments, in the method of making compound 03, the reaction temperature of the reaction is between 0 ℃ and 10 ℃.
In a third aspect, the present invention provides a process for preparing compound 02, which comprises reacting compound 01 with a reducing agent in a solvent to obtain compound 02,
wherein the reducing agent is at least one of sodium borohydride, potassium borohydride, red aluminum and lithium aluminum hydride. The method is beneficial to obtaining the intermediate compound 02 with a novel structure, ensures the raw material of the compound 03 to be obtained, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the molar ratio of compound 01 to reducing agent is from 1:3 to 1: 8. In some embodiments, the molar ratio of compound 01 to reducing agent is from 1:4 to 1: 5.
In some embodiments, in the method of making compound 02, the solvent is at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran.
In some embodiments, in the method of making compound 02, the reaction temperature of the reaction is between-10 ℃ and 10 ℃.
In a fourth aspect, the present invention provides a process for preparing compound 05, which comprises reacting compound 04 with an acid to prepare compound 05 or a salt thereof,
wherein the acid is hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or sulfuric acid. The method is beneficial to further preparing the compound 04 to obtain the compound 05 with a novel structure, so that PF-06651600 is easier to obtain, and the method has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the compound 04 to acid molar ratio is from 1:1 to 1: 6. In some embodiments, the compound 04 to acid molar ratio is from 1:2 to 1: 5.
In a fifth aspect, the present invention provides a compound selected from the group consisting of compounds represented by the following formulas,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The compound has a novel structure, is favorable for better preparing a target compound and is favorable for preparing PF-06651600.
In some embodiments, a method for preparing a PF-06651600 intermediate is provided by the following reaction scheme:
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The reaction route takes D-Boc-pyroglutamic acid ethyl ester as a raw material, and a target compound is obtained through ring opening, reduction, hydroxyl sulfonylation, cyclization, deprotection and/or salification. The preparation method uses D-Boc-pyroglutamic acid ethyl ester as a starting material, the raw material is obtained by fermentation, the price is low, the cost is reduced, a chiral center is introduced into the raw material, and the pressure for resolving a subsequent compound is reduced. The preparation method has the advantages of mild reaction conditions, easily obtained reagents, high product purity, high yield and safe operation, and can be used for industrial production.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the terms "some embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound 01" and "compound represented by formula (01)" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, ml means ml, M means mol/L, THF means tetrahydrofuran, 2Me-THF means 2-methyltetrahydrofuran, MeOH means methanol, EtOH means ethanol, CH3CN represents acetonitrile, DCM represents dichloromethane, EA represents ethyl acetate, Boc2O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, NaBH4Represents sodium borohydride, NaOH represents sodium hydroxide, Ms represents methylsulfonyl, Ts or Tos represents p-toluenesulfonyl, L-DBTA represents L- (-) -dibenzoyltartaric acid monohydrate, L-DTTA represents di-p-methylbenzyltartaric acid, NaBH4Denotes sodium borohydride, NH4Cl represents ammonium chloride, NaHCO3Denotes sodium bicarbonate, Na2CO3Representing sodium carbonate, DME glycol dimethyl ether, palladium hydroxide/C palladium hydroxide/carbon and TEA triethylamine.
EXAMPLE 1 preparation of (R) -2- (N-Boc-amino) -5-carbonyl-hexanoic acid ethyl ester (Compound 01)
Under the protection of nitrogen, 60g (1.0eq, 233.2mmol) of Boc-D-pyroglutamic acid ethyl ester and THF500ml are sequentially added into a 1000ml three-neck flask, stirred at room temperature, dissolved and cleared, cooled to-40 ℃, 110ml (1.4eq, 330mmol) of MeMgBr format reagent is slowly added dropwise, after dropping, the temperature is slowly increased to-20 ℃, and TLC is controlled. After the reaction of the raw materials is finished, 300ml of saturated NH is added dropwise4The Cl solution is quenched, the layers are separated, the aqueous phase is extracted with 300ml of ethyl acetate, the combined organic phases are washed with 500ml of waterThen, the mixture was spin-dried under reduced pressure, 300ml of N-heptane was added, and the mixture was cooled, crystallized, stirred, filtered and dried to obtain 63.7g of an off-white solid of ethyl (2R) -2- (N-Boc-amino) -5-carbonyl-hexanoate in a yield of 93%. GC-MS: M/z:274.1(M +),1H NMR(400MHz,CDCl3)δ5.16(d,J＝6.5Hz,1H),4.15(q,J＝7.1Hz,3H),2.61–2.41(m,2H),2.16–2.02(m,4H),1.84(td,J＝14.4,8.0Hz,1H),1.40(s,9H),1.24(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ207.32,172.27,155.42,79.76,61.33,52.92,39.29,29.85,28.22,26.46,14.07。
EXAMPLE 2 preparation of (R) -2- (N-Boc-amino) -1, 5-hexanediol (Compound 02)
Adding 0160 g (1.0eq, 219.5mmol) of compound and 240ml of absolute ethyl alcohol and 240ml of THF (tetrahydrofuran) into a 1000ml four-mouth bottle at room temperature, stirring for dissolving, cooling to-5 ℃, and adding NaBH in batches433.2g (4.0eq, 878mmol), stirring for 2h under heat preservation, slowly heating to room temperature for reaction, controlling in TLC until the raw materials react completely, cooling to-10 ℃, slowly dropwise adding 300ml of saturated ammonium chloride solution to quench the reaction, separating out a large amount of solid, filtering, extracting the filtrate with 300ml of EA, spin-drying, adding 200ml of DCM for dissolution, adding 200ml of DCM for extraction twice, spin-drying under reduced pressure, adding N-heptane for crystallization at low temperature, performing suction filtration, and performing vacuum pumping on the solid to obtain 46.1g of (2R) -2- (N-Boc-amino) -1, 5-hexanediol white solid with the yield of 90%. GC content is 100%. LC-MS, M/z (ESI), 256.3(M + Na)+)+。1H NMR(400MHz,CDCl3)δ5.07(s,1H),3.81(dd,J＝11.1,5.0Hz,1H),3.70(dd,J＝13.9,7.0Hz,1H),3.59(s,2H),3.18(d,J＝27.1Hz,1H),2.70(s,1H),1.77–1.46(m,4H),1.44(s,9H),1.19(d,J＝6.1Hz,3H)。
EXAMPLE 3 preparation of (R) -1, 5-dimethylsulfonic acid-2- (N-Boc-amino) hexane (Compound 03-Ms)
Under the protection of nitrogen, 0245 g (1.0eq, 192.9mmol) of the compound and DCM250ml are added into a 1000ml four-opening bottle, the mixture is stirred and dissolved at room temperature, the temperature is reduced to 0 ℃, 48.8g (2.5eq, 482.2mmol) of TEA is added, the mixture is stirred for 0.5h, the reaction temperature is controlled to be lower than 0 ℃, 48.6g (2.2eq, 424.4mmol) of MsCl solution in DCM is added dropwise, after the dropwise addition, the heat preservation reaction is carried out, TLC monitors until the raw material reaction is completed, 250ml of water is added for quenching, liquid separation is carried out, the DCM layer is completely quenched by 250ml of saturated NaHCO3The mixture was washed once with the aqueous solution and then rotary-evaporated to dryness under reduced pressure at room temperature to give 72.8g of (R) -1, 5-dimethylsulfonato-2- (N-Boc-amino) hexane as a yellow oily substance in a yield of 97%. LC-MS, M/z (ESI), 412.0(M + Na)+)+。1H NMR(400MHz,CDCl3)δ4.82(d,J＝8.8Hz,2H),4.20(dd,J＝14.4,10.6Hz,2H),3.86(d,J＝28.2Hz,1H),3.02(d,J＝10.6Hz,6H),1.70(dd,J＝23.5,14.0Hz,4H),1.50–1.36(m,12H).
EXAMPLE 4 preparation of (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine (Compound 04)
Under the protection of nitrogen, 198mL (10eq,1797mmol) of benzylamine is added into a 1000mL three-necked bottle, the temperature is raised to 45 ℃ under the protection of nitrogen, 70g (1.0eq,179.8mmol) of compound 03-Ms is dissolved in 140mL of 2-MeTHF, the 2-MeTHF is slowly dripped into the system of the benzylamine, the temperature is raised to 60 ℃ after the dripping is finished, the reaction is carried out for 4-48h, the TLC is controlled to be finished, the solvent is removed by reduced pressure distillation, 200mL of DCM is added, the temperature is lowered to 0 ℃, glacial acetic acid is dripped to adjust the system to be neutral, 200mL of water is used for washing three times, and the DCM is dried by reduced pressure rotation to obtain 46.5g of (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine brown yellow oily matter with. The oil was used directly in the next reaction. LC-MS M/z (ESI) 305.3(M + H)+。1H NMR(400MHz,CDCl3)δ7.41–7.30(m,5H),5.48(d,J＝5.7Hz,1H),4.52(s,1H),4.06(d,J＝13.5Hz,1H),3.76(s,1H),3.32(d,J＝13.5Hz,1H),2.71(d,J＝11.2Hz,1H),2.41(dd,J＝12.3,6.1Hz,1H),2.25(d,J＝10.4Hz,1H),1.76(d,J＝11.7Hz,1H),1.60(dd,J＝10.4,6.5Hz,2H),1.44(s,9H),1.24(d,J＝5.8Hz,3H).
EXAMPLE 5 preparation of (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride (Compound 05 hydrochloride)
EA140mL was added to a 500mL single vial containing 0446.5 g (1.0eq, 152.7mmol) of compound at room temperature to dissolve, 3M HCl 230mL (4.5eq,690mmol) EA solution was added dropwise, the solution was stirred at room temperature for Boc-removal, HPLC monitored until the reaction was complete, the reaction solution was transferred to a 1000mL four vial, 370mL water was added and stirred, the solution was separated, the aqueous phase was washed once with 370mL EA, (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride 36.7g, 100% yield. LC-MS M/z (ESI) 205.2(M + H)+。1H NMR(400MHz,MeOD)δ7.35(dt,J＝14.8,7.2Hz,4H),7.25(t,J＝7.0Hz,1H),4.03(d,J＝13.2Hz,1H),3.28(s,1H),2.73(dd,J＝12.4,5.2Hz,1H),2.59(s,1H),2.39(dd,J＝12.4,2.6Hz,1H),1.87–1.69(m,3H),1.62(dt,J＝21.9,8.0Hz,1H),1.34(dd,J＝19.9,7.4Hz,2H),1.24(d,J＝6.3Hz,3H)。
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A process for preparing compound 04 includes reaction between compound 03 and phenylmethylamine in reaction solvent, post-treating to obtain compound 04,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl;
the reaction solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, dichloroethane and ethylene glycol dimethyl ether;
the molar ratio of the compound 03 to the benzylamine is 1:1-1: 20; or the molar ratio is 1:5-1: 15; or a molar ratio of 1: 10.
2. The process of claim 1, wherein the reaction is carried out at a reaction temperature of from 20 ℃ to 80 ℃.
3. The process of claim 1, the reaction having a reaction time of 4 hours to 48 hours; or the reaction time is 12 to 40 hours; or the reaction time is 24 hours to 30 hours.
4. The method of claim 1, comprising reacting compound 02 with R-Cl in the presence of a base to produce compound 03,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl;
the alkali is at least one of triethylamine, diisopropylethylamine, pyridine and sodium bicarbonate;
the molar ratio of the compound 02 to the base is 1:2-1: 3;
the molar ratio of the compound 02 to the R-Cl is 1:2-1: 3.
5. The method of claim 4, the reaction temperature of the reaction is from-10 ℃ to 20 ℃; or the reaction temperature is 0-10 ℃.
6. The method according to claim 4, which comprises reacting compound 01 with a reducing agent in a solvent to obtain compound 02,
wherein the reducing agent is at least one of sodium borohydride, potassium borohydride, red aluminum and lithium aluminum hydride;
the molar ratio of the compound 01 to the reducing agent is 1:3-1: 8; or the molar ratio is 1:4-1: 5.
7. The method of claim 6, wherein the solvent is at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran.
8. The process of claim 6, wherein the reaction is carried out at a reaction temperature of-10 ℃ to 10 ℃.
9. A process for producing Compound 05 or a salt thereof, which comprises reacting Compound 04 with an acid to produce Compound 05 or a salt thereof,
wherein the acid is hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or sulfuric acid;
the molar ratio of the compound 04 to the acid is 1:1-1: 6; or the molar ratio is 1:2-1: 5.
10. A compound selected from the group consisting of those of the formula,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
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| CN115894338A (en) * | 2021-08-27 | 2023-04-04 | 华南理工大学 | Method for preparing Ritlecetinib intermediate by coupling chemical enzyme and biological enzyme |
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| CN115894338B (en) * | 2021-08-27 | 2024-02-13 | 华南理工大学 | Method for preparing Ritlecritinib intermediate by chemical-biological enzyme coupling |
| CN114133396A (en) * | 2022-01-04 | 2022-03-04 | 浙江乐普药业股份有限公司 | Synthesis method of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one |
| CN114133396B (en) * | 2022-01-04 | 2023-07-21 | 浙江乐普药业股份有限公司 | Synthesis method of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one |
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