CN112457231A - Racemization method of larotrytinib intermediate - Google Patents
Racemization method of larotrytinib intermediate Download PDFInfo
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- CN112457231A CN112457231A CN201910849359.9A CN201910849359A CN112457231A CN 112457231 A CN112457231 A CN 112457231A CN 201910849359 A CN201910849359 A CN 201910849359A CN 112457231 A CN112457231 A CN 112457231A
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- pyrrolidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a racemization method of a larotretinib intermediate, which comprises the following steps:
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a racemization method of a larotrytinib (Larotretinib) intermediate.
Background
The chemical name of the larotinib (English name: Larotrectinib) is: (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-a ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide sulfate having the structural formula: is the first Tropomyosin Receptor Kinase (TRKs) inhibitor developed by Loxo Oncology and Bayer, and is clinically used for treating adult and child patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion and without known acquired resistance mutations resulting in solid tumors. N Engl J Med 2018; 378:731-9, the approval of this drug for 17 different cancer treatments is an important milestone in the small molecule therapy ' switch ' from "cancer-based origin in vivo to" tumor-based characteristics ', with epoch-making implications.
The construction of the (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine (R form-I) fragment during the preparation of Ralitinib is the main point in the synthetic route. At present, the main methods for preparing (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine (I) fragments are as follows:
the method comprises the following steps: (CN102264736B and CN103509017B)
This process, although directly producing the desired R form-IThe reaction needs to use expensive (-) -cytisine and Pd (OAc)2And meanwhile, the reaction conditions are harsh, so that the production cost is greatly increased, and the method is difficult to be suitable for industrial mass production.
The second method comprises the following steps: (CN107428760A/US10045991B2/CN109414442A)
The disadvantages of the route are that expensive metal iridium and ligand are needed, the chiral purity of the iridium cannot meet the requirement once, and the iridium needs to be resolved by using D- (+) -malic acid.
The third method comprises the following steps: WO2017201241A1
The method is characterized in that a chiral center is constructed by introducing tert-butylsulfinamide through chiral induction, the yield and chiral purity are good, but the second step of reaction requires a low temperature condition of-30 ℃.
The method four comprises the following steps: (CN107445879A)
The method has the advantages that the price of the used raw materials is high, the atom economy of the route is poor, and the lithium aluminum hydride used in the reaction is predicted to be difficult to treat and purify.
The method five comprises the following steps: (CN 108218754)
The method takes pyrrolidine as a raw material, and then the pyrrolidine is resolved through D-malic acid to obtain a compound with a required configuration, and the utilization rate of the used N-chlorosuccinimide atom is low.
The method six: (CN 108003161A)
The method has the disadvantages of long steps, dangerous tetraethyl titanate used in the third step and the like.
In summary, the currently reported chemical synthesis methods of (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine mainly belong to or are similar to the above methods, but they usually have one or more disadvantages, such as expensive metal catalyst or reagent, long procedure, many side reactions, etc. By comparing the various methods, the racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine is obtained by adopting a series of reaction modes such as a similar method two-format reaction and the like, and then the racemic compound is resolved to obtain the (R) -2- (2, 5-difluorophenyl) -1-pyrrolidine.
So far, no literature report is available on racemization of the compound, and the invention has positive promotion significance on production of the larotretinib.
Disclosure of Invention
The invention provides a racemization method of a compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine, which realizes recycling, makes up for the defect of low yield caused by resolution, avoids using expensive metal catalysts or chiral reagents, has low cost, few reaction steps and high yield, reduces the discharge of three wastes, makes up for the defect of low yield of a resolution route, and is more suitable for industrial production. The present invention has been completed based on this finding.
The invention provides a racemization method of (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (S-I) or S-I-based racemic mixture, which comprises the following steps:
(i) S-I or S-I dominant racemic mixture is heated in solvent under the action of alkali and converted into racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine (II).
In another preferred embodiment, the time of the racemization reaction is 1 to 18 hours.
In another preferred embodiment, the time of racemization reaction is 1-8 hours.
In another preferred embodiment, the base is selected from: sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium alkoxide, or combinations thereof.
In another preferred embodiment, the alkali is potassium hydroxide.
In another preferred embodiment, the base is sodium alkoxide, preferably sodium methoxide or sodium ethoxide.
In another preferred embodiment, the solvent is selected from: n, N-Dimethylformamide (DMF), N-dimethylacetamide (dme), Dimethylsulfoxide (DMSO), water, ethanol, isopropanol, ethylene glycol monomethyl ether, or a combination thereof.
In another preferred embodiment, the solvent is DMSO.
In another preferred embodiment, the reaction temperature is from 80 ℃ to 165 ℃.
In another preferred embodiment, the reaction temperature is 100-140 ℃.
In another preferred embodiment, the molar ratio of the alkali to the S-type I is 1:1 to 4: 1.
In another preferred embodiment, the method further comprises one or more purification steps selected from the group consisting of: and (3) performing extraction, washing, drying, concentration and recrystallization.
In another preferred embodiment, the method further comprises the steps of:
(ii) and (3) resolving the compound II to obtain R-type-I and S-type-I.
In another preferred embodiment, the resolving agent is D-malic acid.
In another preferred embodiment, form R-I obtained by the resolution can be used for preparing the erlotinib.
In another preferred embodiment, said S form-I obtained in step (ii) can be recycled to carry out the above reaction.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the present invention has extensively and deeply studied, and unexpectedly found a method for racemizing a compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine with high efficiency by using solvents such as DMSO and the like under the action of alkali, thereby realizing the recycling of (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine, making up the defect of low yield caused by resolution, reducing the discharge of three wastes, and being more suitable for industrial production.
The term "racemic mixture" as used herein refers to a compound containing S-form-I and R-form-I.
Racemization method of (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (S-type-I) or S-type-I-based racemic mixture
Which comprises the following steps:
(i) in a solvent, the compound S-I or S-I-based racemic mixture is converted into the racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine (II) under the action of alkali.
The base used in the present invention includes one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium hydride, sodium alkoxides (sodium methoxide and sodium ethoxide), and potassium hydroxide is particularly preferred.
In the present invention, the solvent used in the racemization reaction may be a solvent commonly used in such reactions in the art, and in the present invention, one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMF), Dimethylsulfoxide (DMSO), water, ethanol, isopropanol, ethylene glycol, and ethylene glycol monomethyl ether are particularly preferred, and dimethylsulfoxide is more preferred.
In the invention, the temperature of the racemization reaction can be the temperature commonly used in the racemization reaction in the field, and the temperature is particularly preferably 80-165 ℃, and most preferably 100-140 ℃.
In the invention, the molar ratio of the alkali reagent to S-type-I in the racemization reaction is preferably 1: 1-4: 1.
In the invention, the raw material of the racemization reaction is (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (S type-I) or a racemic mixture with S type-I as the main component.
After the racemization reaction is finished, the pure racemized compound (II) can be prepared by simple post-treatment, such as extraction and extinction, extraction, washing, drying, concentration, recrystallization and the like.
The racemic compound II can be prepared into (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine by a D-malic acid resolution method for preparing larotinib (larotretinib); for example, the preparation of larotretinib can be performed by methods described in the literature relating to methods one and two of the background of the present application.
In the present invention, 2- (2, 5-difluorophenyl) -1-pyrrolidine (II) can be obtained according to the prior art, such as CN 108218754.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the present invention, the reaction conditions in each step can be carried out according to the conditions in such reactions in the art, except those specifically mentioned above.
The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
Compared with the prior art, the invention has the main advantages that:
1. racemizing (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine to realize the recycling of (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine.
2. The racemization method avoids using expensive metal catalysts or chiral reagents, has low cost, few reaction steps and high yield, reduces the discharge of three wastes, makes up the defect of low yield of a resolution route, and is more suitable for industrial production.
3. The post-treatment is simple, the product yield is high, the chemical purity is more than 99%, the chiral purity is more than 96-98 ee%, the method can be smoothly used for synthesizing the erlotinib, and the method is suitable for industrial production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1:
73.5g of the compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (R configuration: S configuration: 25:75) was added, DMSO (514ml) and potassium hydroxide (45g,2eq) were heated to 120 ℃ and stirred for reaction for 2.5h, heating was stopped, the reaction mixture was poured into water (3L), dichloromethane was added to extract (400ml), the organic phase was separated, the aqueous phase was extracted three times (400 ml. x.3) with dichloromethane, the organic phases were combined, washed with saturated sodium chloride water to neutrality, dried over anhydrous sodium sulfate and concentrated to obtain 65g of the racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine with a yield of 88.43%.
The racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine, which was the product described above, was taken 64g, 95% ethanol (640 ml) was added, D-malic acid (47g,1eq) was added to the mixture to conduct resolution and crystallization, and the obtained product was crystallized from 95% ethanol to obtain (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine D-malate salt in 34.33% yield, which was detected by chiral HPLC to show that ((2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine ═ 99.01: 0.99).
Example 2:
taking 20g of compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (R configuration: S configuration is 30:70), adding DMSO (150ml) and sodium hydroxide (11g,3eq), heating to 130 ℃, stirring for reaction for 5.5h, stopping heating, pouring the reaction liquid into water (900ml), adding dichloromethane for extraction (150ml), separating an organic phase, extracting an aqueous phase with dichloromethane three times (150ml × 3), combining the organic phases, washing with saturated sodium chloride water to neutrality, drying with anhydrous sodium sulfate, and concentrating to obtain 17g of racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine with yield of 85%.
The product racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine, 17g, was taken, 95% ethanol (170 ml) was added, D-malic acid (1eq) was added for resolution and crystallization, and the obtained product was crystallized with 95% ethanol to obtain the D-malate salt of (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine in a yield of 32.51%, and the salt was detected by chiral HPLC to show that ((2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine ═ 98.92: 1.08).
Example 3:
taking 10g of compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (R configuration: S configuration: 25:75), adding DMSO (100ml), dropwise adding a solution of cesium hydroxide (16g,1.95eq) in DMF (50ml) under stirring at room temperature, heating to 115 ℃, stirring for reacting for 4h, stopping heating, cooling to room temperature, slowly pouring the reaction solution into ice water (600ml), adding dichloromethane (150ml) for extraction, separating an organic phase, extracting an aqueous phase three times (150ml × 3) with dichloromethane, combining the organic phases, washing with saturated sodium chloride water to neutrality, drying with anhydrous sodium sulfate, and concentrating to obtain 8g of racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine with the yield of 86%.
The racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine, which was the product described above, was taken 8g, 95% ethanol (80 ml) was added, D-malic acid (1eq) was added to the mixture to conduct resolution crystallization, and the obtained product was crystallized from 95% ethanol to obtain (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine D-malate salt in 30.02% yield, which was then detected by chiral HPLC to show that ((2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine ═ 98.02: 1.98).
Example 4:
taking 12.5g of compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (R configuration: S configuration: 25:75), adding DMSO (120ml), adding solid sodium ethoxide (11.6g,2.5eq), heating to 135 ℃, stirring for reaction for 7h, stopping heating, slowly pouring the reaction liquid into water (600ml), adding dichloromethane (150ml) for extraction, separating an organic phase, extracting an aqueous phase for three times (150ml × 3) by using dichloromethane, combining the organic phases, washing the aqueous phase by using saturated sodium chloride until the aqueous phase is neutral, drying the aqueous phase by using anhydrous sodium sulfate, and concentrating to obtain 9.7g of racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine with the yield of 84.44%.
The product racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine was taken 9g, 95% ethanol (90 ml) was added, D-malic acid (1eq) was added for resolution and crystallization, and the obtained product was crystallized with 95% ethanol to obtain the product (D-malate salt of (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine in 29.92% yield, which was detected by chiral HPLC and showed that ((2R) -2- (2, 5-difluorophenyl) -1-pyrrolidine ═ 98.77: 1.23).
The structure of 2- (2, 5-difluorophenyl) -1-pyrrolidine (II) is confirmed:1H NMR(400MHz,CDCl3): δ＝7.27-7.23(m,1H),6.97-6.91(m,1H),6.87-6.81(m,1H),4.39(t,1H),3.18-3.12(m, 1H),3.07-3.01(m,1H),2.27-2.21(m,1H),1.92-1.79(m,3H),1.65-1.56(m,1H)。
comparative example
During the development of the present invention, we tried a number of conditions in the early stages of the search, where the reaction described below is a less effective comparative reaction:
comparative example 1.
The compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (5g) (R configuration: S configuration: 25:75) was taken, dimethyl sulfoxide (50ml) was added, DBU (1, 8-diazabicycloundecen-7-ene) (12.45g,3eq) was added, the mixture was heated to 120 ℃ and reacted for 5h without racemization by chiral HPLC. The results show that the racemization reaction does not proceed smoothly with DBU as a base.
Comparative example 2
The compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (5g) (R configuration: S configuration: 25: 750) was taken, dimethylsulfoxide (50ml) was added, potassium hydroxide (1.22g,2eq) was added, and the mixture was heated to 75 ℃ and reacted for 4 hours, and chiral HPLC detection showed that racemization did not occur very much.
Comparative example 3
Taking the compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (5g) (R configuration: S configuration: 25:75), adding DMF (50ml), adding sodium hydroxide (1.22g,2eq), heating to 110 ℃, reacting for 4h, detecting by chiral HPLC (R configuration: S configuration: 38:62), and then using a mixed solvent of DMSO: DMF (2:1), but the reaction time needs to be prolonged to 12h to successfully carry out racemization. As a result, it was found that the racemization reaction did not proceed smoothly in the case where the reaction solvent was pure DMF.
Comparative example 4
Taking the compound (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (5g) (R configuration: S configuration: 25:75), adding N, N-dimethylacetamide (50ml), adding 60% sodium hydride (1.22g,2eq), heating to 50 ℃, reacting for 6h, and using a mixed solvent of DMSO: N, N-dimethylacetamide (2:1) instead of racemization in chiral HPLC detection, heating to 70 ℃, racemizing smoothly within 7h, but generating more impurities in HPLC detection. The results show that in the case of sodium hydride as base, the racemization reaction time is longer, and the reaction impurities are more, which is not favorable for the subsequent resolution.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (8)
- A process for the racemization of (2S) -2- (2, 5-difluorophenyl) -1-pyrrolidine (S form-I) or of the racemic mixture based on S form-I, comprising the following steps:
(i) S-I or S-I dominant racemic mixture is heated in solvent under the action of alkali and converted into racemic compound 2- (2, 5-difluorophenyl) -1-pyrrolidine (II). - 2. The method of claim 1, wherein the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium alkoxide, or combinations thereof.
- 3. The method of claim 1, wherein the solvent is selected from the group consisting of: n, N-dimethylacetamide, Dimethylsulfoxide (DMSO), water, ethanol, isopropanol, ethylene glycol monomethyl ether, or a combination thereof.
- 4. The process of claim 1, wherein the reaction temperature is from 80 ℃ to 165 ℃.
- 5. The process of claim 1, wherein the molar ratio of base to form S-I is from 1:1 to 4: 1.
- 6. The method of claim 1, further comprising one or more purification steps selected from the group consisting of: and (3) performing extraction, washing, drying, concentration and recrystallization.
- 7. A method as claimed in any preceding claim, wherein the method further comprises the steps of:
(ii) and (3) resolving the compound II to obtain R-type-I and S-type-I. - 8. The process of claim 7, wherein said S form-I from step (ii) is recycled to the process of claim 1.
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