CN108203396B - Synthesis of enkephalinase inhibitor - Google Patents

Synthesis of enkephalinase inhibitor Download PDF

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CN108203396B
CN108203396B CN201611177799.7A CN201611177799A CN108203396B CN 108203396 B CN108203396 B CN 108203396B CN 201611177799 A CN201611177799 A CN 201611177799A CN 108203396 B CN108203396 B CN 108203396B
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benzyl
independently selected
acetyl
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CN108203396A (en
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林文清
郑宏杰
刘小波
高晓鹏
朱剑平
沈陈健
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Chongqing Boteng Pharmaceutical Co ltd
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Jiangxi Dongbang Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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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    • C07D207/26—2-Pyrrolidones
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    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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Abstract

The invention discloses a novel synthesis method of an enkephalinase inhibitor (Sacubitril), which comprises the steps of taking L-pyroglutamic acid as a raw material, carrying out multi-step reaction, carrying out epimerization and crystallization to obtain a compound of a formula I which is consistent with the chirality of the Sacubitril, acylating the compound of the formula I, reacting the acylated compound with biphenyl to obtain a compound of a formula II, hydrolyzing and carrying out ring opening to obtain a compound of a formula III, reacting the compound of the formula III with succinic anhydride, and reducing to obtain the Sacubitril. The invention adopts a new chiral control strategy, and constructs a new chiral center by a simpler and more reliable method; the control of the chiral key intermediate is placed at the front section of the synthetic line, so that the risk is reduced and the cost is reduced.

Description

Synthesis of enkephalinase inhibitor
Technical Field
The invention belongs to the field of pharmaceutical chemicals.
Background
LCZ696(Entresto, Scheme 1) is an original new compound drug developed by Nowa company. The medicine is prepared by inhibiting Sacubitril and angiotensin receptor blocker Valasartan by enkephalinase in a ratio of 1: 1, approved by the FDA at 7 months of 2015 for marketing in the united states for treatment to reduce the risk of cardiovascular death and hospitalization for heart failure and to reduce ejection fraction in patients with chronic heart failure (NYHA class II-IV). The medicine has good safety and obvious curative effect, is a serious medicine for treating heart failure diseases, is a great breakthrough in the field of heart failure treatment in the past 25 years, and has good market prospect.
Figure 362881DEST_PATH_IMAGE001
Document WO2008083967a2 reports a method (Scheme 2) for synthesizing secubitril by using L-pyroglutamic acid as a starting material, the reaction of the line during methylation requires ultralow temperature conditions, the reaction conditions are harsh, the operation is complicated, the large-scale production is not facilitated, the chiral control is not ideal, and the selectivity is not high.
Figure 342338DEST_PATH_IMAGE002
Document WO2009090251a2 also reports a novel process for the synthesis of secubitril by asymmetric catalytic hydrogenation starting from L-pyroglutamic acid (Scheme 3). The introduction of methyl by the method adopts a brand-new asymmetric catalytic hydrogenation strategy, so that the selectivity is obviously improved, and the effect is good. But because of the adoption of the chiral catalyst with high price and the use of the Grignard reaction, the cost is higher, and the improvement space are provided.
Figure 448308DEST_PATH_IMAGE003
Disclosure of Invention
Aiming at the problems, the invention discloses a novel preparation method of an enkephalinase inhibitor Sacubitril. The method comprises the steps of taking L-pyroglutamic acid as an initial raw material, synthesizing a compound shown in a formula VII through a plurality of steps of reactions, then obtaining a key chiral intermediate shown in a formula I through an epimerization reaction, and obtaining a product Sacubitril through a plurality of steps of reactions such as a Friedel-crafts reaction, a hydrolysis reaction and the like. Because a new chiral control strategy is adopted, a new chiral center is constructed by a simpler and more reliable method, and the control of the chiral key intermediate is placed at the front section of the synthesis line, which is beneficial to reducing the risk and the control cost.
The preparation method of Sacubitril is as follows:
Figure 905834DEST_PATH_IMAGE004
Figure 533256DEST_PATH_IMAGE005
the method uses L-pyroglutamic acid as a starting material, and obtains a compound V by adding a protecting group, wherein R1 is independently selected from H or amino protecting groups such as tert-butyl formate, acetyl, benzyl formate, benzyl and the like. The compound V is further prepared to obtain a compound VI, and the compound VII is prepared by Pd/C reduction. Compounds of formula VII are prepared in the presence of DBU (diazabicyclo) to provide compounds I.
The compound I is prepared by the following steps:
a: dissolving the compound of formula I in an organic solvent, dropwise adding an acylating agent, such as oxalyl chloride, reacting completely, and reacting with biphenyl to obtain the compound of formula II.
B: the compound of formula II is hydrolyzed to open the ring under the action of acid, such as hydrochloric acid, to obtain the compound of formula III, wherein R2 is independently selected from H or alkyl of C1-C4.
C: and reacting the compound shown in the formula III with succinic anhydride to obtain a compound shown in the formula IV.
D: and carrying out reduction reaction on the compound shown in the formula IV to obtain the Sacubitril.
In the step B, the product after hydrolytic ring opening is separated and purified by a 732 type cation exchange resin column and concentrated to obtain the compound shown in the formula III.
And in the step B, adding sodium chloride into the product after the hydrolytic ring opening, cooling, crystallizing and drying to obtain the compound shown in the formula III.
In the step C, dissolving the compound of the formula III in absolute ethyl alcohol, dropwise adding acetyl chloride, carrying out reflux reaction for 12h, cooling to room temperature, dropwise adding a 50% sodium carbonate solution, adjusting the pH value to be alkalescent, continuously cooling to about 5 ℃, adding succinic anhydride in batches, carrying out reduced pressure evaporation to remove ethanol after complete reaction, adjusting the pH value to 3-4 by using dilute hydrochloric acid, and carrying out extraction concentration to obtain the compound of the formula IV.
And C, dissolving the compound shown in the formula III in absolute ethyl alcohol, dropwise adding acetyl chloride, performing reflux reaction for 12 hours, performing reduced pressure distillation to remove the ethyl alcohol, then adding the absolute ethyl alcohol, triethylamine and succinic anhydride again, removing the solvent after the reaction is completed, recrystallizing the residue with the ethyl alcohol and water, and drying to obtain the compound shown in the formula IV.
In step D, the catalyst used for the reduction reaction is selected from the Pd/C or HSiEt3/BF3 system.
Meanwhile, intermediate compounds II, III and IV in the reaction process,
Figure 418035DEST_PATH_IMAGE006
Figure 996653DEST_PATH_IMAGE007
Figure 195553DEST_PATH_IMAGE008
wherein R1 is independently selected from H or amino protecting groups such as tert-butyl formate, acetyl, benzyl formate, benzyl and the like; r2 is independently selected from H or C1-C4 alkyl.
Detailed Description
Example 1: synthesis of compound V (R1= Ac)
Reference is made to the method of the synthesis of compound V (R1= Ac) (Journal of Organic Chemistry, 1986, vol. 51, p. 3494-3498). 104g (0.80 mol, 1eq) of L-pyroglutamic acid and 300g (2.88wt.) of methanol were added to a three-necked flask, and 138g (2.2eq) of acetyl chloride was added dropwise. After the dropwise addition is finished, the temperature is raised to 55-65 ℃ until the raw materials react completely. The solvent was distilled off under reduced pressure to obtain a white solid, 300g (2.88wt) of toluene was added, 178g (2.2eq) of triethylamine was added dropwise, 69g (1.1eq) of acetyl chloride was added dropwise after the reaction, 160g of water was added, the layers were separated by stirring, the organic phase was washed with dilute hydrochloric acid, a sodium hydrogencarbonate solution and water in turn, and 122g of a white solid was obtained after concentration.
Figure 926749DEST_PATH_IMAGE009
Example 2: compound VI (R)1Synthesis of = Ac)
Compound VI (R)1= Ac) Synthesis reference (Synthesis, 1997, 863-865) method. 50g (0.27mol, 1.0eq) of Compound V (R)1= Ac, product in example 1), 70.6g (1.5eq) tert-butoxybis (dimethylamino) methane (Bredereck reagent), 200mL ethylene glycol dimethyl ether were added to the reaction flask and heated to 68-70 ℃ for reaction for 10 h. Cooling, crystallizing, filtering, washing the filter cake with a small amount of solvent, and drying to obtain compound VI (R)1= Ac), weight 46.3 g.
Figure 795479DEST_PATH_IMAGE010
Example 3: compound VII (R)1Synthesis of = Ac)
Compound VII (R)1= Ac) according to the literature (Synthesis, 1997, 863-865).
Example 3.1: 24g (0.1mol, 1.0eq) of Compound VI (R)1= Ac, product in example 2), 2.4g of 10% palladium on carbon, 260mL of isopropanol were added to a reaction flask, and hydrogen gas was introduced to react until the reaction was complete. Filtering and concentrating to obtain a product VII (R)1= Ac, HPLC analysis shows VII as a mixture of VII-1 and VII-2 in a ratio VII-1/VII-2= 83/17).
Example 3.2: 12g (0.05mol, 1.0eq) of Compound VI (R)1= Ac, product in example 2), 1.2g of 10% palladium on carbon, 80mL of isopropanol are added into a reaction kettle, the air in the kettle is replaced by hydrogen, hydrogen is filled to 2.0MPa, the temperature is raised to 40-50 ℃ for reaction, and the temperature and pressure are maintained until the reaction is complete. Filtering and concentrating to obtain a product VII (R)1= Ac, HPLC analysis shows VII as a mixture of VII-1 and VII-2 in a ratio VII-1/VII-2= 68/32).
Figure 864322DEST_PATH_IMAGE011
Example 4: compound I (R)1Synthesis of = Ac)
Example 4.1: reference is made to the method of the literature for the synthesis of compound I (Tetrahedron, 2004, 60, 10277-10284). 12g (0.06 mol, 1.0eq) of Compound VII (R)1= Ac, dr =68/32, product from example 3.2), 100mL of dichloromethane were added to the flask, cooled to 0-5 ℃, and 17g (4.0eq) of DBU were added dropwise. Heating to 20-30 deg.C, reacting for 48 hr, adding dilute hydrochloric acid to adjust pH to 5-6, layering, concentrating organic layer, adding 2M LiOH aqueous solution into residue, and stirring to react completely. Adjusting pH to 2-3 with dilute hydrochloric acid, and extracting with ethyl acetate. Distilling under reduced pressure to remove ethyl acetate, and recrystallizing the residue with isopropanol/water to obtain compound I (R)1= Ac), weight 4.6g (de)>99%)。
Example 4.2: 12g (0.06 mol, 1.0eq) of Compound VII (R)1= Ac, dr =68/32, product from example 3.2), 100mL of methanol were added to the flask, and 20.7g (2.5eq) of potassium carbonate were added. Heating to 20-30 deg.C, reacting for 72 hr, filtering, and adding dilute hydrochloric acid to the filtrate to adjust pH to 2-3. Concentrating, adding methanol to the residue, distilling with water, adding anhydrous methanol to the residue, stirring, filtering, concentrating the filtrate, and recrystallizing the residue with isopropanol/water to obtain compound I (R)1= Ac), weight 5.1g (de)>99%).
Figure 601334DEST_PATH_IMAGE012
Example 5: compound II (R)1Synthesis of = Ac)
5g (0.027mol, 1.0eq) of Compound I (R)1= Ac, product in example 4), 100mL dichloromethane, 0.2g (0.1eq) DMF were added to a three-necked flask, then 4.2g (1.2eq) oxalyl chloride in 10mL dichloromethane was added dropwise, and after completion of the addition, the reaction was carried out at room temperature for 2 h. Cooling to-5-0 deg.C, adding 7.9g (2.5eq) of anhydrous aluminum trichloride, adding 4.2g (1.0eq) of biphenyl, and stirring until the reaction is complete. Quenching the reaction with 2N diluted hydrochloric acid, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating to obtain 6.5g of Compound II (R)1= Ac) the product was used in the next reaction without purification.
Figure 187036DEST_PATH_IMAGE013
Example 6: compound III (R)1=H，R2Synthesis of = H)
Example 6.1: 5.5g of Compound II (R)1= Ac, product in example 5), 30mL of 4M hydrochloric acid was added to the flask and heated to reflux for 24 h. Concentrating the reaction solution to about 10mL, separating and purifying with 732 type cation exchange resin column, and collecting the extract containing compound III (R)1=Ac，R2H) and concentrating the eluate to obtain compound III (R)1=H，R2= H), weight4.15g。
Example 6.2: 5.2g of Compound II (R)1= Ac, product in example 5), 35mL of 4M hydrochloric acid was added to the flask and heated to reflux for 24 h. Adding 6g of sodium chloride into the reaction solution, cooling to 0-5 ℃, crystallizing, filtering and drying to obtain a compound III (R)1=H，R2= H), weight 4.7 g.
Figure 429930DEST_PATH_IMAGE014
Example 7: compound IV (R)2Synthesis of = Et)
Example 7.1: 15g (0.05mol, 1.0eq) of Compound III (R)1=H，R2= H, product in example 6), 60mL absolute ethanol, added to three-necked flask, added dropwise with 8.8g (2.2eq) acetyl chloride, and reacted for 12H under reflux. Cooled to room temperature, and about 15mL of 50% sodium carbonate solution was added dropwise to adjust the pH of the solution to 8-9. Cooling the solution to about 5 ℃, adding 5g (1.0eq) succinic anhydride in batches, stirring until the reaction is completed, evaporating ethanol under reduced pressure after the reaction is completed, then adjusting the pH value of the solution to 3-4 by using dilute hydrochloric acid, extracting with methyl tert-ether, and concentrating to obtain a compound IV (R)2= Et), weight 18.7 g.
Example 7.2: 15g (0.05mol, 1.0eq) of Compound III (R)1=H，R2= H, product in example 6), 60mL absolute ethanol, added to three-necked flask, added dropwise with 8.8g (2.2eq) acetyl chloride, and reacted for 12H under reflux. Distilling under reduced pressure to remove ethanol, adding 60mL of anhydrous ethanol, adding dropwise 11.0g (2.1 eq) of triethylamine, adding 5g (1.0eq) of succinic anhydride, stirring until the reaction is complete, distilling to remove the solvent, recrystallizing the residue with ethanol and water, filtering, and drying to obtain a product IV (R)2= Et), weight 15.3g.
Figure 733872DEST_PATH_IMAGE015
Example 8: synthesis of Sacubtril
Example 8.1: 10.3g (0.025mol) of Compound IV (R)2= Et, product in example 7), 0.5 g glacial acetic acid, 50mL ethanol added to the reaction flask, 0.1g 10% palladium on carbon added under protection of N2. The air in the bottle is changed by hydrogen, and the bottle is heated to 40-50 ℃ for reaction for 12 h. Filtering, concentrating to obtain crude product 10g, and recrystallizing with isopropanol to obtain the final product>99.5% of the product.
Example 8.2: under nitrogen protection, 4.2g (0.01mol) of compound IV (R)2= Et, product in example 7), 30mL dichloromethane, 10mL acetonitrile, 3.0g (2.5eq) triethylsilane were added to the reaction flask and cooled to 0-5 ℃. 3.7mL (3.0eq) of boron trifluoride/diethyl ether solution is added dropwise, and after the dropwise addition is finished, the temperature is raised to 30-40 ℃ for reaction until the compound IV disappears. After the reaction, the reaction solution was transferred to a cooled saturated aqueous solution of sodium carbonate (60 g), stirred and then layered, the aqueous layer was extracted with 50mL of dichloromethane, the organic phases were combined, washed with water, and then layered after standing, and the organic phase was concentrated to obtain a product (3.5 g).
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.

Claims (10)

1. A preparation method of an enkephalinase inhibitor Sacubitril is characterized by comprising the following steps:
a: reacting the compound of the formula I with biphenyl to prepare a compound of a formula II;
b: opening the ring of the compound of the formula II under the action of acid to obtain a compound of a formula III;
c: reacting the compound shown in the formula III with succinic anhydride to obtain a compound shown in a formula IV;
d: carrying out reduction reaction on the compound shown in the formula IV to obtain Sacubitril;
Figure FDA0002692566460000011
wherein,
r1 in the compound I is independently selected from H or tert-butyl formate, acetyl, benzyl formate and benzyl;
r1 in the compound II is independently selected from H or tert-butyl formate, acetyl, benzyl formate and benzyl;
in the compound III, R1 is independently selected from H or tert-butyl formate, acetyl, benzyl formate and benzyl, R2 is independently selected from H or C1-C4 alkyl;
r2 in the compound IV is independently selected from H or C1-C4 alkyl.
2. The process of claim 1, wherein in step A, the compound of formula I is dissolved in an organic solvent, oxalyl chloride is added dropwise, and after the reaction is completed, the compound of formula II is obtained by reacting with biphenyl.
3. The process of claim 1, wherein in step B, the product of hydrolytic ring opening is separated and purified by a 732 type cation exchange resin column, and concentrated to obtain the compound of formula III.
4. The process of claim 1, wherein in step B, sodium chloride is added into the product after hydrolytic ring opening, and the product is cooled, crystallized and dried to obtain the compound of the formula III.
5. The process as claimed in claim 1, wherein in step C, the compound of formula III is dissolved in absolute ethanol, acetyl chloride is added dropwise, after 12h of reflux reaction, the mixture is cooled to room temperature, 50% sodium carbonate solution is added dropwise to adjust the pH value to be alkalescent, the mixture is continuously cooled to about 5 ℃, succinic anhydride is added in batches, after the reaction is completed, ethanol is evaporated under reduced pressure, dilute hydrochloric acid is used for adjusting the pH value to 3-4, and the compound of formula IV is obtained after extraction and concentration.
6. The process of claim 1, wherein in step C, the compound of formula III is dissolved in absolute ethyl alcohol, acetyl chloride is added dropwise, after 12h of reflux reaction, the ethanol is removed by distillation under reduced pressure, absolute ethyl alcohol, triethylamine and succinic anhydride are added again, after the reaction is completed, the solvent is removed, and the residue is recrystallized by ethanol and water and dried to obtain the compound of formula IV.
7. The process of claim 1, wherein in step D, the catalyst used for the reduction is selected from Pd/C or HSiEt3/BF3And (4) preparing the system.
8. The process of claim 1, wherein the compound of formula I is prepared by the following steps:
Figure FDA0002692566460000021
wherein R1 is independently selected from H or tert-butyl formate, acetyl, benzyl formate, benzyl.
9. The compounds II, III, IV,
Figure FDA0002692566460000022
wherein,
r1 in the compound II is independently selected from tert-butyl formate, acetyl, benzyl formate and benzyl;
in the compound III, R1 is independently selected from H or tert-butyl formate, acetyl, benzyl formate and benzyl, R2 is independently selected from H or C1-C4 alkyl;
r2 in the compound IV is independently selected from H or C1-C4 alkyl.
10. The compound of claim 9, wherein R1 is acetyl in compound II, R1 is H or acetyl in compound III, R2 is H or ethyl; in compound IV, R2 is H or ethyl.
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