CN107629039B

CN107629039B - The preparation method and intermediate of deuterated acrylamide

Info

Publication number: CN107629039B
Application number: CN201710949642.XA
Authority: CN
Inventors: 常俊标; 杜锦发
Original assignee: Henan Real Biological Science And Technology Co Ltd
Current assignee: Henan Genuine Biotech Co Ltd
Priority date: 2017-10-12
Filing date: 2017-10-12
Publication date: 2019-09-20
Anticipated expiration: 2037-10-12
Also published as: CN107629039A

Abstract

The invention discloses the preparation methods and intermediate of a kind of deuterated acrylamide, belong to organic synthesis field.The structure of the deuterated acrylamide is shown in formula I.The preparation method includes the steps that route shown below: compound a -1 reacts to obtain compound a -2 with diethoxy oxygen phosphorus acetic acid in the presence of a base, and compound a -2 reacts to obtain compound I with two deuterated polyformaldehyde or two deuterated formaldehyde in the presence of a base.Compound a -2 can also react to obtain compound a -3 with halogenated acetic acids or haloacetyl chloride by compound a -1, and gained Haloacetamide reacts to obtain with triethyl phosphite again.Described the method for preparing compound of formula I has many advantages, such as that high income, purity is high, process repeatability are good.

Description

Preparation method and intermediate of deuterated acrylamide

Technical Field

The invention relates to a preparation method and an intermediate of deuterated acrylamide, belonging to the field of organic synthesis.

Background

Deuterated compounds have a number of important uses in pharmaceutical research. They can be used not only as substitute drugs for non-deuterated drugs, but also as isotope standards for drug metabolism studies. The acrylic acid derivatives have many medical uses, such as third generation irreversible selective EGFR mutation inhibitor AZD9291 and other EGFR inhibitors containing acrylamides (such as DY3002, WZ4002, CI-1033, CO-1688, EGF816, ASP8273, PF-06747775, etc.). AZD9291 has been approved by the FDA in the united states for the treatment of lung cancer. The use of deuterated acrylic acid and derivatives thereof in industry and medicine is increasing. But the synthesis methods of deuterated acrylic acid and derivatives thereof are rarely reported. U.S. Pat. No. 4,487,4890 discloses the use of RuCl₃The catalyst, deuterium gas or heavy water directly replaces hydrogen on double bonds to prepare the deuterated acrylic compound. The activity sequence of compound A deuteration is (a) ═ b>(c) In that respect However, in RuCl₃In the presence of this, the deuteration reaction reached 45%. The mixtures produced are in most cases of no practical significance.

Yang in U.S. Pat. No. 8829238 discloses the preparation of 2,3, 3-trideuteroacrylic acid. The preparation method comprises the steps of using propiolic acid II as a raw material, exchanging heavy water into deuterated sodium propiolate III in the presence of alkali, and carrying out catalytic deuteration by using a Lindlar catalyst under deuterium gas to obtain a required product of sodium 2,3, 3-tri-deuterated acrylate IV. However, both the quality and reaction time of the Lindlar catalyst can affect the purity of the product.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a preparation method of deuterated acrylamide with the structure shown in the formula I, so that the deuterated acrylamide can be produced with high yield and high purity.

Wherein,

r is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the substituents are selected from the group consisting of halogen, hydroxy, amino optionally substituted with alkyl, amino acid group, amino acid ester group, alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkylthio, heterocyclyl, aryl, aryloxy, arylthio, heteroaryl, nitro, cyano, -N₃Sulfonyl, sulfate, phosphonyl, phosphate, phosphonoxy;

the alkyl in the alkyl, alkoxy and alkylthio groups is respectively and independently straight-chain or branched C₁～C₂₀Alkyl, optionally straight or branched C₁～C₁₆Alkyl, optionally straight or branched C₁～C₁₀Alkyl, optionally straight or branched C₁～C₆Alkyl, optionally straight or branched C₁～C₄An alkyl group;

the cycloalkyl in the cycloalkyl, the cycloalkoxy and the cycloalkylthio is respectively and independently C₃～C₂₀Monocyclic or polycyclic alkyl, optionally C₃～C₁₅Monocyclic or polycyclic alkyl, optionally C₃～C₁₀Monocyclic or polycyclic alkyl, optionally C₃～C₇Monocyclic or polycyclic alkyl;

the heterocyclic group is a group in which 1 to 3 carbon atoms in the cycloalkyl group are replaced by one or more heteroatoms selected from O, S, N;

the aryl in the aryl, aryloxy and arylthio is respectively and independently C₆～C₁₈Monocyclic or polycyclic aryl, optionally C₆～C₁₄Monocyclic or polycyclic aryl, optionally C₆～C₁₀Monocyclic or polycyclic aryl;

the heteroaryl is a 5-20 membered monocyclic or polycyclic heteroaryl containing 1-3 heteroatoms selected from N, O, S, optionally a 5-15 membered monocyclic or polycyclic heteroaryl, optionally a 5-10 membered monocyclic or polycyclic heteroaryl;

the halogen is selected from: F. cl, Br, I;

preferably, the alkyl group may optionally be substituted by halogen, hydroxy, -N (R)¹)(R²)、C_1-5Alkoxy group of (C)_3-6Cycloalkoxy, phenoxy, C_1-5Alkylthio of, C_3-5Cycloalkylthio, phenylthio, nitro, cyano, -N₃One or more than one substitution;

preferably, said cycloalkyl, heterocyclyl, aryl, heteroaryl may optionally be substituted by halogen, C_1-5Alkyl, hydroxy, -N (R)¹)(R²)、C_1-5Alkoxy group of (C)_3-6Cycloalkoxy of (A), C_1-5Alkylthio of, C_3-5Cycloalkylthio, phenoxy, phenylthio, nitro, cyano, -N₃Sulfonyl, sulfatoOne or more of phosphono, phosphate and phosphonoxy;

R¹、R²each independently is hydrogen, alkyl;

preferably, R is a group represented by i:

wherein each R is₃Independently is alkyl, preferably C₁-C₃Alkyl, optionally deuterated;

preferably, R is a group represented by i-1:

preferably, the compound of formula I as described above is a compound of formula Ia:

the present investigators have compared several methods for preparing compounds of formula I as follows:

wherein R is as defined above.

The method comprises the following steps:

reacting the compound 1 with pyruvic acid or acetone acyl chloride to generate a compound 2, carrying out deuterium exchange in heavy water in the presence of alkali or a catalyst to obtain a compound 3, then reducing the compound 3 with sodium borohydride to generate a compound 4, and treating the compound 4 with sulfonyl chloride in the presence of alkali to obtain a compound I. However, the deuterated product 3 is unstable, and it is difficult to obtain a stable and highly deuterated target product.

The second method comprises the following steps:

deuterating pyruvic acid 5 in heavy water in the presence of alkali to obtain compound 6, reducing compound 6 with sodium borohydride to obtain compound 7, and dewatering with concentrated hydrochloric acid to obtain compound 8₂The reaction produces compound I. In the synthetic route, the deuterated acrylic acid 8 has small molecules and is difficult to separate and purify, so the synthetic route is not easy to be used for large-scale preparation.

The third method comprises the following steps:

the compound a-1 reacts with diethoxyphosphorylacetic acid in the presence of a condensing agent to generate a compound a-2; the compound a-2 reacts with dideutero polyformaldehyde or dideutero formaldehyde in the presence of alkali to obtain a compound I. The compound a-2 can also be prepared by reacting the compound a-1 with halogenated acetic acid or halogenated acetyl chloride to obtain a compound a-3, and reacting the obtained halogenated acetamide a-3 with triethyl phosphite.

In the test, the compound a-1 reacts with diethoxy oxyphosphorylacetic acid in the presence of a condensing agent to generate a compound a-2, which is an exothermic reaction, and when the 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) condensing agent is added, the reaction temperature is controlled to be 0-50 ℃, preferably 0-25 ℃, otherwise, side reactions are increased. The yield is lowered and the purification is difficult.

The compound a-2 reacts with dideutero polyformaldehyde or dideutero formaldehyde in the presence of alkali to obtain a compound I, KOH is used as alkali, and LiCl is added to react to obtain a product with better quality and yield. Experiments show that the alkalinity of the reaction solution is very important, preferentially, the pH is controlled to be 10-12, and when the pH is less than 10, the alkalinity of the reaction solution is not enough to deprotonate to initiate the Wittig reaction. However, if the basicity is too high (pH >12), other side reactions such as amide hydrolysis may be caused.

The compound a-1 is reacted with a haloacetic acid in the presence of HATU to give a compound a-3, and this condensation reaction is also an exothermic reaction, preferably, the reaction temperature is controlled to be 25 ℃ or lower to improve the reaction yield.

Reacting the compound a-1 with a haloacetyl chloride in the presence of a base to form a compound a-3, wherein the base is preferably selected from organic bases such as pyridine, triethylamine and the like; preferably, the reaction temperature is controlled to be 25 degrees celsius or less.

Reacting compound a-3 with triethyl phosphite in the presence of a base selected from the group consisting of organic bases to form compound a-2((j. org. chem.1996,61,7202)); preferably, selected from e.g. pyridine, triethylamine, etc.; in the reaction, an organic solvent is optionally added; preferably, the organic solvent is selected from the group consisting of non-protonated solvents; preferably, the organic solvent is selected from: THF, CH₂Cl₂DMF and the like.

The present invention also provides useful intermediates of formula a-2I and a-3I:

the method for preparing the compound shown in the formula I has the advantages of high yield of more than 30%, high purity of more than 95%, good process repeatability and the like, and is suitable for industrial production.

Detailed Description

The following describes in detail specific embodiments of the present invention. It should be understood that the embodiments described herein are illustrative only and are not limiting.

EXAMPLE 1 Synthesis of Compound Ia

The synthetic route is as follows:

1. preparation of a-2I from Diethoxyoxyphosphonic acid: A-1I (5g,0.011mol), diethoxyphosphonic acid (2.35g,0.012mol) and N, N-diisopropylethylamine (1.68g,0.013mol) were dissolved in tetrahydrofuran (25mL), HATU (4.94g,0.013mol) was slowly added, and after the addition, stirring was continued at 25 ℃ for 5 hours. The reaction was poured into water (50mL) and extracted with ethyl acetate (50 mL. times.2) and the organic phases combined. The organic phase was washed successively with water (50 mL. times.4) and half-saturated brine (50 mL. times. 4), dried over anhydrous sodium sulfate, and concentrated to give a-2I (5g, yield 71.5%) as a pale yellow solid which was used in the next reaction without purification. M.p:113 ℃ and 116 ℃. LCMS (liquid Crystal Module) (M + 1)]⁺:624.4。

¹HNMR(400MHz,CDCl₃):δ1.26(t,J＝7.2Hz,6H),2.65(s,3H),2.83(s,6H),3.89(s,3H),3.91(s,3H),4.11(q,J＝7.2Hz,4H),7.02(s,1H),7.18(d,J＝7.2Hz,1H),7.22‐7.28(m,2H),7.54(d,J＝7.2Hz,1H),8.00(br,1H),8.29‐8.32(m,2H),8.53(s,1H),8.72(s,1H),8.97(br,1H),9.54(s,1H)。

2. Preparation of Compound Ia A-2I (200mg,0.32mmol), deuterated polyoxymethylene (10mg,0.33mmol), lithium chloride (20mg,0.48mmol), potassium hydroxide (89mg,1.6mmol) were dissolved in THF/H₂O (2mL/2mL) solution, pH controlled at 10-12, stirred overnight at room temperature (16 h). Water (20mL) was added to the reaction mixture, which was extracted with ethyl acetate (20mL), and the mixture was washed with water (20mL) and brine (20 mL. times.2) in this order. The organic phase was dried over anhydrous sodium sulfate, concentrated to give a crude product (150mg), and separated by column chromatography (eluent: dichloromethane: methanol ═ 20:1) to give Ia (110mg, yield 68%) as a pale yellow solid. HPLC purity: 99.8%, M.p: 100-. LCMS (liquid Crystal Module) (M + 1)]⁺:502.5。¹HNMR(400MHz,CDCl₃):δ2.28(s,8H),2.71(s,3H),2.91(br,2H),3.89(s,3H),4.00(s,3H),6.79(br,1H),7.20(d,J＝5.2Hz,1H),7.24‐7.30(m,2H)，7.39‐7.41(m,1H)，7.72(s,1H)，8.06(dd,J＝6.8Hz,J＝1.6Hz,1H),8.38(d,J＝5.6Hz,1H),9.10(s,1H),9.85(s,1H),10.14(br,1H)。

Example 2 preparation of compound a-2I from halide:

route A

Route B

Route a was prepared from iodoacetic acid: the method for preparing a-2I by using diethoxyphosphorylacetic acid uses iodoacetic acid to replace the diethoxyphosphorylacetic acid to obtain the compound a-3I. LCMS (liquid Crystal Module) (M + 1)]⁺:614。

Route B preparation of iodoacetyl chloride: compound a-1I (445mg,1.0mmol) and triethylamine (303mg,3.0mmol) were dissolved in CH₂Cl₂(10 mL). Iodopetyl chloride (204.4mg,1.0mmol) was added slowly via syringe at 0 deg.C and after addition the reaction mixture was stirred at room temperature for 2 h. Water (10mL) was added, the mixture was extracted with EtOAc (10mL x3), Na₂SO₄Drying and evaporating the solvent to obtain the product a-3I which is directly used for the next reaction without purification.

The resulting a-3I and Et₃N (303mg,3.0mmol) in CH₂Cl₂(10mL), triethoxyphosphine (249mg,1.5mmol) was added at 0 ℃. The reaction was stirred at room temperature for 24 h. Water (10mL) was added, the mixture was extracted with EtOAc (10mL x3), and the organic phase was Na₂SO₄Drying, evaporating to remove solvent, and subjecting the residue to silica gel column chromatography (0-5% methanol in CH)₂Cl₂) Purifying to obtain the compound a-2I. LCMS (liquid Crystal Module) (M + 1)]⁺:624。

Comparative example 1

The synthetic route of 3, 3-dideuteroacrylic acid is shown as follows:

ethylene glycol (9) is selectively protected to provide compound 10. The compound 10 is oxidized by a conventional method to form an aldehyde 11, which is then reacted with a dideuterio Wittig reagent to form 3, 3-dideuteropropene 12. Compound 12 is deprotected and then oxidized to compound 13 to give 3, 3-dideuteroacrylic acid 8. Reaction of compound 8 with the appropriate precursor amine affords the corresponding 3, 3-dideuteroacrylamide I. However, the reaction route is too long, compound 11 is easily over-oxidized to the acid, and the overall yield is low, typically 3-10%.

Comparative example 2

The synthetic route of 3, 3-dideuteroacrylic acid is shown as follows:

malonate 14 reacts with deuterated formaldehyde under the action of alkali to generate compound 15, and then deuterated acrylic acid 8 is generated through hydrolysis. The completion of the hydroxymethylation reaction is not easily controlled, resulting in the product 8 being mixed with the by-product acetic acid and being difficult to purify. The reaction repeatability is poor.

In conclusion, the method for preparing the compound of the formula I through the intermediate a-2I has the advantages of high yield, high purity, good process repeatability and the like.

The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

Claims

1. The preparation method of the deuterated acrylamide is characterized by comprising the following steps:

(1) in an organic solvent, reacting a compound a-1 with diethoxy oxyphosphorylacetic acid at 0-50 ℃ in the presence of a condensing agent to generate a compound a-2, wherein the condensing agent is selected from Dicyclohexylcarbodiimide (DCC) or 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU); the organic solvent is selected from the group consisting of non-protonated solvents;

(2) adding LiCl into the compound a-2 in the presence of alkali in an organic solvent or/and water, and reacting with dideutero polyformaldehyde or dideutero formaldehyde to obtain a compound I; the base is selected from: potassium carbonate, sodium hydroxide, potassium hydroxide; the organic solvent is selected from an aprotic solvent or an alcohol; r is a group represented by i:

each R is₃Independently is C₁-C₃Alkyl, said alkyl being optionally substituted with deuterium.

2. The preparation method of the deuterated acrylamide is characterized by comprising the following steps:

(1) in an organic solvent, reacting the compound a-1 with halogenated acetic acid in the presence of a condensing agent to obtain a compound a-3; the condensing agent is selected from Dicyclohexylcarbodiimide (DCC) or 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU); the organic solvent is selected from the group consisting of non-protonated solvents;

or, in an organic solvent, reacting the compound a-1 with halogenated acetyl chloride in the presence of an organic base to generate a compound a-3, wherein the organic solvent is selected from non-protonized solvents;

(2) reacting compound a-3 with triethyl phosphite in the presence of an organic base in an organic solvent selected from the group consisting of an aprotic solvent to form compound a-2;

(3) adding LiCl into the compound a-2 in the presence of alkali in an organic solvent or/and water, and reacting with dideutero polyformaldehyde or dideutero formaldehyde to obtain a compound I; the base is selected from: potassium carbonate, sodium hydroxide, potassium hydroxide; the organic solvent is selected from an aprotic solvent or an alcohol;

r is a group represented by i:

3. The method of claim 1 or 2, wherein the deuterated acrylamide is obtained by reacting a deuterated acrylamide with a hydrogen-containing compound,

r is a group represented by formula i-1:

4. the method of claim 1 or 2, wherein the deuterated acrylamide is prepared from the group consisting of:

5. the intermediate in the process for the preparation of deuterated acrylamides as described in one of the claims 1 to 4, wherein the structure is as follows:

R¹is CH₂CH₃

Or