Process for preparing selective cathepsin cysteine protease inhibitors
阅读说明：本技术 选择性组织蛋白酶半胱氨酸蛋白酶抑制剂的制备方法 (Process for preparing selective cathepsin cysteine protease inhibitors ) 是由 E·沃伊特 C·P·A·查塞恩格 H·P·尼德曼 S·维伊特 C·斯彻伊佩斯 于 2019-08-01 设计创作，主要内容包括：一种式I化合物的制备方法,包括将式A化合物与碱和式B化合物反应以产生式C化合物(A compound of formula I A process for the preparation of (A), which comprises reacting a compound of formula (A) With a base and a compound of formula B Reacting to produce a compound of formula C)
1. a process for the preparation of a compound of formula I,
comprising reacting a compound of formula AWith a base and a compound of the formula BReaction to give the compound of formula C
2. The process according to claim 1, wherein the base is an alkyl lithium, preferably n-butyl lithium.
3. The preparation process according to any one of claims 1-2, wherein the base is added to the compound of formula a at low temperature, preferably below-70 ℃.
4. The preparation process according to any one of claims 1 to 3, wherein the compound of formula B is added at low temperature, preferably below-70 ℃.
5. The preparation method according to any one of claims 1 to 4, further comprising reducing the compound of formula CTo give a compound of the formula D
6. The preparation method of claim 5, further comprising reacting the compound of formula DWith one or more bases and a compound of formula EReaction to give a compound of formula F
7. The process according to claim 6, wherein the one or more bases comprise organolithium reagents, preferably methyllithium and n-butyllithium.
8. The preparation process according to any one of claims 6 to 7, wherein methyllithium is added to the compound of formula D at low temperature, preferably below-65 ℃.
9. The preparation process according to claim 8, wherein after adding methyllithium to the compound of formula D, n-butyllithium is added at low temperature, preferably below-65 ℃.
10. The preparation method according to any one of claims 6 to 9, further comprising reacting the compound of formula F in the presence of a reducing agentWith compounds of the formula GReaction of in which X-Is a counter ion;
to produce a compound of formula H
11. The process of claim 10 wherein the compound of formula G isWherein X-Is hydrogen sulfate or tartrate, preferably tartrate.
12. The production method according to any one of claims 10 to 11, wherein the reducing agent is Zn (BH)4)2。
13. The preparation method according to any one of claims 10 to 12, wherein the reduction is carried out at a low temperature, preferably not higher than-5 ℃.
14. The preparation process of any one of claims 10 to 13, further comprising reacting the compound of formula H in the presence of HATUAnd compounds of formula JOr a salt thereof, to produce a compound of formula I.
15. The process according to claim 14, wherein the reaction of the compound of formula H with the compound of formula J is carried out in N, N-dimethylformamide.
Background
US patent No. 7,407,959 discloses compounds of the formula which are selective cathepsin cysteine protease inhibitors and therefore may be useful in the treatment of diseases such as osteoarthritis or osteoporosis. Methods of making these compounds are also disclosed.
WO2006/017455 discloses a process for diastereoselective reductive amination wherein a perfluorinated ketone or ketal is reacted with an alpha-amino ester to form an imine metal carboxylate salt, which is stereoselectively reduced. Specifically, the synthesis of 4-fluoro-N- { (1S) -2,2, 2-trifluoro-1- [4' - (methylsulfonyl) -biphenyl-4-yl ] ethyl } -L-leucine dicyclohexylamine salt is disclosed (see pages 18-19):
WO2012/148555 discloses an amidation process in which [4- (4-methylsulfonylphenyl) phenyl ] is attached]Radicals or [4- (4-methylsulfinylphenyl) phenyl]Perfluorinated amino acids of the group (such as those described in the previously cited references) are treated with amines in the presence of a coupling agent to give the corresponding amides. Specifically, N- (1-cyanocyclopropyl) -4-fluoro-N is disclosed2- { (1S) -2,2, 2-trifluoro-1- [4' - (methylsulfonyl)) Biphenyl-4-yl]Synthesis of ethyl } -L-leucinamide (see pages 8-9):
isabel et al, bioorg.Med.chem.Lett.2010,20(3),887-892 discloses the discovery of an orally bioavailable cathepsin K inhibitor MK-0674. Unlike what is described in the previously cited references, the synthesis of this compound is carried out around a key Suzuki coupling step between a highly functionalized boronic ester and an aryl bromide or chloride:
wherein Ar especially comprisesThe synthetic route towards the final product involves seven steps and the use of expensive palladium catalysts is repeated.
Following a similar strategy but reversing the reactive groups of the Suzuki coupling partner, O' shear, et al, j. org. chem.2009,74(4),1605-1610 discloses enantioselective synthesis of odacadii (odanacatib) by Suzuki coupling of highly functionalized bromides with aryl borates; functionalized bromides are prepared by stereoselective nucleophilic substitution of α -trifluoromethylbenzyltriflate.
WO2006/133559 discloses (1R) -1- (4 '-bromobiphenyl-4-yl) -2, 2-difluoroethanol and 1- {4' - [ (1R) -2, 2-1-hydroxyethyl ] biphenyl-4-yl } -2,2, 2-trifluoroacetone (see examples 65 and 66, respectively), which may be necessary to carry out part of the chemical reactions disclosed in the aforementioned references.
The document Dolman, et al, Tetrahedron 2006,62,5092-5098 discloses a selective metal-halogen exchange of 4, 4' -dibromobiphenyl mediated by lithium tributylmagnesium (tributylmagnasite).
The document Fujisawa, et al, Tetrahedron 1998,54,4267-4276 discloses the preparation of 4-bromo-4 '- (trifluoroacetyl) biphenyl by trifluoroacetylation of 4, 4' -dibromobiphenyl.
WO2013/148554 discloses a process for the preparation and chiral resolution of gamma-fluoroleucine alkyl esters, which are also key components of cathepsin cysteine protease inhibitors, such as those disclosed in US patent No. 7,407,959. Specifically, the synthesis of the following compounds is disclosed:
wherein X is H2SO4L-tartaric acid, D-BOC proline, D- (+) -10-camphorsulfonic acid or N-acetyl-D-phenylalanine.
N1- (1-cyanocyclopropyl) -N2- ((1S) -1- {4' - [ (1R-2, 2-difluoro-1-hydroxyethyl)]Biphenyl-4-yl } -2,2, 2-trifluoroethyl) -4-fluoro-L-leucine amide (MK-0674) is an orally bioavailable cathepsin K inhibitor compound having the structure of formula Ia.
The IUPAC name for this compound is (2S) -N- (1-cyanocyclopropyl) -2- [ [ (1S) -1- [4- [4- [ (1R) -2, 2-difluoro-1-hydroxy-ethyl ] phenyl ] -2,2, 2-trifluoro-ethyl ] amino ] -4-fluoro-4-methyl-pentanamide.
The synthesis of this compound in the prior art focuses on individually functionalizing each benzene ring and coupling the resulting highly substituted aromatic intermediates to form the biphenyl nucleus (see scheme 1 below).
Disclosure of Invention
The applicant has developed a more advantageous process in which the biphenyl structure is already present in the starting material. Compared to known processes, the process of the present invention has fewer synthesis steps, high overall yields and does not require expensive and ultimately toxic organometallic catalysts (see scheme 2 below).
Applicants have also found that temperature control of the reaction sequence can affect the yield and optical purity of the reaction scheme.
One embodiment of the present invention is a process for the preparation of a compound of formula IComprising reacting a compound of formula AWith a base and a compound of formula BReacting to produce a compound of formula C
Detailed Description
Definition of
The Dean-Stark apparatus refers to a laboratory glassware configuration for collecting water or other liquids from the reactor.
THF means tetrahydrofuran.
TMEDA represents N, N' -tetramethylethane-1, 2-diamine.
MTBE is methyl tert-butyl ether.
NMM is N-methylmorpholine, also known as 4-methylmorpholine.
HATU is O- (7-azobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate, also known as 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridine 3-oxide Hexafluorophosphate or azabenzotriazolylurea Hexafluorophosphate (hexafluophosphate Azabenzotriazole urea).
DMF means N, N-dimethylformamide.
Alkyl lithium compounds and organolithium reagents are reagents that contain a lithium carbon bond. Examples are methyllithium and n-butyllithium.
DCHA is dicyclohexylamine.
The counter ion is an ion that accompanies the ionic species to maintain electrical neutrality.
The tartrate salt is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The molecular formula of tartrate dianion is O-OC-CH(OH)-CH(OH)-COO-Or C4H4O6 2-。
The bisulfate salt is a salt of sulfuric acid containing HSO4 -A group.
In another embodiment of the invention, the base added to the compound of formula a is an alkyl lithium, preferably n-butyl lithium.
In an alternative embodiment, the base is added to the compound of formula a at low temperature, preferably below-70 ℃.
In an alternative embodiment, the compound of formula B is added at low temperature, preferably below-70 ℃.
In another embodiment, the process of the invention further comprises reducing the compound of formula CTo produce a compound of formula D
In another embodiment, the method of the present invention further comprisesComprising the step of reacting a compound of formula DWith one or more bases and a compound of formula EReacting to produce a compound of formula F
In alternative embodiments, the one or more bases added to the compound of formula D include organolithium reagents, preferably methyllithium and n-butyllithium.
In an alternative embodiment, methyllithium is added to the compound of formula D at low temperature, preferably below-65 ℃.
In an alternative embodiment, after methyllithium is added to the compound of formula D, n-butyllithium is added at low temperature, preferably below-65 ℃.
In another embodiment, the method further comprises reacting the compound of formula F in the presence of a reducing agentWith compounds of the formula GReaction of in which X-Is a counter ion; to produce a compound of formula H
In an alternative embodiment, the compound of formula G isWherein X-Is hydrogen sulfate or tartrate, preferably tartrate.
In an alternative embodiment, the reducing agent is Zn (BH)4)2。
In an alternative embodiment, the reduction is carried out at a low temperature, preferably not higher than-5 ℃.
In another embodiment, the methods of the invention further comprise reacting a compound of formula H in the presence of HATUAnd compounds of formula JOr a salt thereof, to produce a compound of formula I.
In an alternative embodiment, the reaction of the compound of formula H with the compound of formula J is carried out in N, N-dimethylformamide.
In another embodiment, the invention is the preparation of a compound of formula IThe method of (1), comprising:
a) reacting a compound of formula AWith a base and a compound of formula BReaction to give a compound of formula C
b) Reducing a compound of formula C to produce a compound of formula D
c) Reacting a compound of formula D with one or more bases and a compound of formula EReaction to give a compound of formula F
d) In the presence of a reducing agentCompounds of formula F and GReaction of in which X-Is hydrogen sulfate or tartrate, preferably tartrate, to produce a compound of formula H
e) Reacting a compound of formula H with a compound of formula J in the presence of O- (7-azobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU)Or a salt thereof, to produce a compound of formula I.
In a further embodiment, the base added to the compound of formula a in step a) is an alkyl lithium, preferably n-butyl lithium.
In a further embodiment, in step a), the base is added to the compound of formula a at a low temperature, preferably below-70 ℃.
In a further embodiment, in step a), the compound of formula B is added at low temperature, preferably below-70 ℃.
In a further embodiment, in step c), the one or more bases added to the compound of formula D comprise organolithium reagents, preferably methyllithium and n-butyllithium.
In a further embodiment, in step c), methyllithium is added to the compound of formula D at low temperature, preferably below-65 ℃.
In a further embodiment, in step c), after the methyllithium is added to the compound of formula D, n-butyllithium is added at low temperature, preferably below-65 ℃.
In a further embodiment, in step d), X-Is tartrate.
In a further embodiment, in step d), the reducing agent is Zn (BH)4)2。
In a further embodiment, in step d), the reduction is carried out at a low temperature, preferably not higher than-5 ℃.
In a further embodiment, in step e), the reaction of the compound of formula H with the compound of formula J is carried out in N, N-dimethylformamide.
An alternative embodiment of the present invention is the preparation of a compound of formula IaThe method of (1), comprising:
a) reacting a compound of formula AWith a base and a compound of formula BReaction to give a compound of formula C
b) Reducing the compound of formula C to obtain a compound of formula Dd
c) Mixing a compound of formula Dd with one or more bases and a compound of formula EReacting to obtain the compound of formula Ff
d) Reacting a compound of formula Ff with a compound of formula GgIn the presence of a reducing agent, wherein X-Is hydrogen sulfate or tartrate, preferably tartrate, to give compounds of formula Hh
e) Reacting a compound of formula Hh with a compound of formula J in the presence of a coupling reagentOr a salt thereof, to give a compound of formula Ia.
In a further embodiment, in step a), the base added to the compound of formula a is an alkyl lithium, preferably n-butyl lithium.
In a further embodiment, in step a), the base is added to the compound of formula a at a low temperature, preferably below-70 ℃.
In a further embodiment, in step a), the compound of formula B is added at low temperature, preferably below-70 ℃.
In a further embodiment, in step b), by using N, N-diethylaniline-borane complex and a catalyst of formula KTo complete the reduction.
In a further embodiment, in step b), the reduction is carried out at low temperature, preferably below 0 ℃, more preferably below-5 ℃.
In a further embodiment, in step c), the one or more bases added to the compound of formula Dd include organolithium reagents, preferably methyllithium and n-butyllithium.
In a further embodiment, in step c), methyllithium is added to the compound of formula Dd at low temperature, preferably below-65 ℃.
In a further embodiment, in step c), after the addition of methyllithium to the compound of formula Dd, n-butyllithium is added at low temperature, preferably below-65 ℃.
In a further embodiment, in step d), X-Is tartrate.
In a further embodiment, in step d), the reducing agent is Zn (BH)4)2。
In a further embodiment, in step d), the reduction is carried out at a low temperature, preferably not higher than-5 ℃.
In a further embodiment, in step d), the compound of formula Hh may be isolated as a salt by addition of a base, preferably a dialkylamine, most preferably diisopropylethylamine.
In a further embodiment, in step e), the reaction of the compound of formula Hh with the compound of formula J is carried out in N, N-dimethylformamide.
In a further embodiment, the process of the invention further comprises isolating the compound of formula Ia from the reaction mixture by:
i. adding phosphoric acid at a temperature above 25 ℃, preferably 60 ℃, and then
Adding water at a temperature above 25 ℃, preferably between 50 and 55 ℃, and then
Cooling the mixture to 20 to 25 deg.C
In an alternative embodiment of the invention, in the reaction of step a),
i. keeping the temperature below-70 ℃ and adding n-butyllithium; and
adding also the compound of formula B while maintaining the temperature below-70 ℃.
In a further embodiment, the reduction of step c) is carried out by using a catalyst of the formula KTo complete.
In an alternative embodiment of the invention, the compound of formula H is
In another embodiment, the compound has the formula Hh
Detailed Description
Examples
Step 1.1 Synthesis of 1- (4 '-bromo [1,1' -biphenyl ] -4-yl) -2, 2-difluoroethanone
4,4 '-dibromo-1, 1' -biphenyl (460g, 1.48mol) was dissolved in anhydrous tetrahydrofuran (7.35L) under an inert atmosphere. The resulting solution was cooled to-76 ℃ and a 2.5N solution of N-butyllithium in hexane (610mL, 1.53mol) was added over 2.5 hours while maintaining the internal temperature below-70 ℃ and ensuring good dispersion of the N-butyllithium. After a reaction time of 15 minutes, ethyl 2, 2-difluoroacetate (200g, 1.61mol) was added while maintaining the internal temperature below-70 ℃. After a reaction time of 15 minutes, 3.0N aqueous hydrochloric acid (750mL) was added over 4 minutes and a temperature increase to-45 ℃ was observed. The internal temperature was raised to 0 ℃, toluene (1.4L) was added, and the resulting mixture was vigorously stirred for 5 minutes. The mixture was allowed to settle for 10 minutes, the organic phase was separated and the aqueous phase was extracted with toluene (2X 500 mL). Brine (750mL) was added to the combined organic layers; the mixture was stirred for 5 minutes and then allowed to settle for 30 minutes. The organic layer was collected and concentrated under reduced pressure to a volume of about 1L until the onset of crystallization was observed. After addition of n-heptane (4L) to the suspension, the temperature rose to 50 ℃. The suspension was then cooled to room temperature with gentle stirring. The resulting precipitate was filtered, washed with a 1: 9 mixture of toluene and n-heptane (2X 500mL), and dried under vacuum at 40 ℃ to give the desired product (308g, 0.99 mol).
Synthesis of alternative 1- (4 '-bromo [1,1' -biphenyl ] -4-yl) -2, 2-difluoroethanones
4,4 '-dibromo-1, 1' -biphenyl (150g, 0.48mol) was dissolved in anhydrous tetrahydrofuran (2L) under an inert atmosphere. The resulting solution was cooled to-72 ℃ and a 2.5N solution of N-butyllithium in hexane (194mL, 0.48mol) was added over 5.5 hours while maintaining the internal temperature below-70 ℃ and ensuring good dispersion of the N-butyllithium. After a reaction time of 5 minutes, ethyl 2, 2-difluoroacetate (65.7g, 0.53mol) was added over 30 minutes while the internal temperature rose to-60 ℃. After 30 minutes reaction time, 10% aqueous ammonium chloride (750mL) was added over 30 minutes and the temperature was raised to-40 ℃. The internal temperature was raised to-5 ℃, methyl tert-butyl ether (750mL) was added, and the resulting mixture was vigorously stirred for 10 minutes. The mixture was warmed to 20 ℃ and stirred for 20 minutes, then allowed to settle for 30 minutes. The aqueous layer was discarded and the organic phase was washed with 5% aqueous sodium sulfate (4X 750 mL). The organic phase was concentrated under pressure to a volume of about 600mL while the internal temperature was raised to 40 ℃. 2-propanol (520mL) was added dropwise while maintaining the total volume at about 700mL and the internal temperature at 40 ℃. Seeds of the desired product (0.75g, 2.4mmol) were added to the mixture, which was stirred at 40 ℃ for 16 h. To induce more precipitation, 2-propanol (1.5L) was added while maintaining the total volume at about 900mL and the internal temperature at 40 ℃. After stirring at 40 ℃ for 12 hours, the suspension was cooled to 18 ℃ and stirred at this temperature for 24 hours. The resulting precipitate was filtered, washed with 2-propanol (200mL), and dried under vacuum at 40 ℃ to give the desired product (107g, 0.34 mol).
Step 2.4 Synthesis of bromo- α - (difluoromethyl) - (α R) - [1,1' -biphenyl ] -4-methanol
Step 2a preparation of- (R) - (+) -Ph-OAB catalyst
Under an inert atmosphere, (R) - (+) -diphenyl (pyrrolidin-2-yl) methanol (25.6g, 99mmol) and phenylboronic acid (12.94g, 104mmol) were dissolved in toluene (1L). The resulting mixture was refluxed for 20 hours while removing the generated water azeotropically using a Dean-Stark apparatus. Complete conversion of (R) - (+) -diphenyl (pyrrolidinyl-2-yl) methanol was ensured by NMR and the obtained yellow solution was kept under inert atmosphere at room temperature until used as such in the next step.
Step 2 b-1- (4 '-bromo [1,1' -biphenyl)]Asymmetric reduction of (E) -4-yl) -2, 2-difluoroethanone
The toluene solution of (R) - (+) -Ph-OAB obtained in the previous step (497mL, 48.2mmol) was added to a toluene solution of N, N-diethylaniline-borane complex (189mL, 1.06mol) (1.2L), and the resulting mixture was heated to 45 ℃. A solution of 1- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -2, 2-difluoroethanone (300g, 0.96mol) in toluene (1.5L) was added dropwise over 3 hours. After the addition was complete, the reaction mixture was stirred at 45 ℃ for 1 hour. While maintaining the temperature below 55 ℃, 3.0N aqueous hydrochloric acid (1.2L) was added very slowly. After the addition was complete, the mixture was stirred at 45 ℃ for 1 hour. The reaction mixture was cooled to room temperature. The aqueous phase of the reaction mixture was discarded, and the organic phase was washed with brine (600mL) and concentrated under reduced pressure. The crude product was dissolved in a 2:3 mixture of methanol and water (2.85L) and stirred gently at 40 ℃ for 18 h. The resulting solid was filtered and washed with 2:3 mixture (2X 500mL) was washed and dried under vacuum at 40 ℃ to give the desired product (297g, 0.95 mol).
Step 2 c-4 '-bromo-alpha- (difluoromethyl) - (alpha R) - [1,1' -biphenyl]Recrystallization of (E) -4-methanol
4 '-bromo- α - (difluoromethyl) - (α R) - [1,1' -biphenyl ] -4-methanol (546g) was added to anhydrous toluene (1.09L), the temperature was raised to 65 ℃ and heptane (1.64L) was slowly added over 45 minutes while maintaining the temperature at 65 ℃. The heating was stopped and the mixture was cooled to room temperature overnight with gentle stirring. Precipitation began as the mixture was cooled to about 55 ℃. The stirring was stopped and the solid was allowed to settle. After filtration, the resulting filter cake was slurried with a 2:3 mixture of toluene and heptane (2.5L) and then rinsed with n-heptane (4L). The solid was then dried in vacuo to give pure 4 '-bromo- α - (difluoromethyl) - (α R) - [1,1' -biphenyl ] -4-methanol.
Step 3.1 Synthesis of- [4'- [ (1R) -2, 2-difluoro-1-hydroxyethyl ] [1,1' -biphenyl ] -4-yl ] -2,2, 2-trifluoroacetone
Under an inert atmosphere, (R) -1- (4 '-bromo- [1,1' -biphenyl ] -4-yl) -2, 2-difluoroethanol (720g, 2.30mol) was dissolved in anhydrous tetrahydrofuran (3.6L) and the resulting solution was cooled to-70 ℃. 1.6M solution of methyllithium in diethyl ether (1.58L, 2.53mol) was added over 1 hour while maintaining the temperature between-70 and-65 ℃. After a reaction time of 5 minutes, N, N, N ', N' -tetramethylethane-1, 2-diamine (1.15L, 7.59mol) was added over 15 minutes, while a temperature increase from-70 ℃ to-65 ℃ was observed. The resulting mixture was stirred for 5 minutes to cool the temperature again to-70 ℃ and then a 2.5M solution of n-butyllithium in n-hexane (1.012L, 2.53mol) was added and an increase in temperature from-70 ℃ to-65 ℃ was observed. After a reaction time of 10 minutes, ethyl 2,2, 2-trifluoroacetate (360mL, 3.03mol) was added dropwise over 20 minutes and a temperature rise to-50 ℃ was observed. The reaction mixture was stirred at-50 ℃ for 30 minutes and 6N aqueous hydrochloric acid (3.83L) was added over 10 minutes while the temperature was increased from-50 ℃ to 0 ℃. Methyl tert-butyl ether (4L) was added and the resulting mixture was stirred for 10 minutes. The aqueous layer was separated. The organic layer was washed with brine (2.5L) and concentrated under reduced pressure. Methyl tert-butyl ether and petroleum ether 2:3 mixture (800mL) was added to the crude product and the resulting solution was purified by silica gel column chromatography using a gradient of petroleum ether in methyl tert-butyl ether. After collecting the target fraction and concentrating under reduced pressure, the desired product was isolated as a solid (728g, 2.20mol)
Step 4.(2S) -2- [ [ (1S) -1- [4- [4- [ (1R) -2, 2-difluoro-1-hydroxy-ethyl ] -1]Phenyl radical]Phenyl radical]-2,2, 2-trifluoro-ethyl]Amino group]Synthesis of (E) -4-fluoro-4-methyl-pentanoic acid
The reactor was charged with (S) -gamma-fluoroleucine ethyl ester tartrate (688g, 2.1mol), potassium carbonate (1.22kg, 8.74mol) and methanol (1.5L). After addition of a solution of (R) -1- (4'- (2, 2-difluoro-1-hydroxyethyl) - [1,1' -biphenyl ] -4-yl) -2,2, 2-trifluoroacetone (596g, 1.80mol) in methanol (1.9L), water (31.5mL, 1.75mmol) was added with a slight exotherm observed. The resulting mixture was warmed to an internal temperature of 50 ℃ and stirred at that temperature for 9 hours. The temperature was lowered to 10 ℃ and the reaction mixture was stirred at this temperature for a further 18 hours. Zinc (II) chloride (484g, 3.55mol) and 1, 2-dimethoxyethane (2.6L) were added to the second reactor and the resulting mixture was cooled to-20 ℃. Sodium tetrahydroborate (270g, 7.14mol) was added in two portions while a temperature increase from-20 to-6 ℃ was observed. The reaction mixture was cooled to-15 ℃ and stirred at this temperature for 1 hour. Acetonitrile (3.95L) was added, the temperature was adjusted to-15 to-20 ℃ and the mixture was aged for 30 minutes. The temperature of the second reactor was reduced to between-50 and-45 ℃ and the contents of the first reactor, previously cooled to-5 ℃, were added over 30 minutes while maintaining the temperature below-5 ℃. The first reactor was flushed with methanol (500mL) and added to the contents of the second reactor. The temperature was adjusted to-20 to-10 ℃ and the reaction mixture was aged for 90 minutes. Acetone (2.25L) was added over 15 minutes to bring the temperature to-5 ℃. After 30 minutes of aging, the reaction mixture was cooled to-20 ℃ and 3N aqueous hydrochloric acid (5.8L) was added over 30 minutes, maintaining the temperature below 0 ℃. After addition of methyl tert-butyl ether (8.4L) and water (1L), the resulting heterogeneous mixture was stirred for 18 hours. Additional water (1.6L) was added and the resulting suspension was filtered. The filter cake was washed with methyl tert-butyl ether (2L) and added to the filtrate. After separating the aqueous phase, heptane (400mL) was added to the organic layer cooled to 10 ℃ and then extracted with 3N aqueous sodium hydroxide (1.7L) and then with 1N aqueous sodium hydroxide (2X 2.5L). After addition of methyl tert-butyl ether (7.5L) to the combined aqueous layers, the temperature was reduced to 10 ℃ and 6N aqueous hydrochloric acid (2.1L) was added while maintaining the temperature below 15 ℃. After separation from the aqueous phase, the organic phase was washed with water (5 × 2.5L) and concentrated under reduced pressure to a volume of about 5L. The concentrated organic phase was heated to 30 ℃ and n-heptane (7.4L) was slowly added with stirring. The resulting concentrated suspension was cooled to 5 deg.C, filtered and the filter cake washed with a 4: 1 mixture (2.6L) of n-heptane and methyl tert-butyl ether, then dried under vacuum at 40 deg.C to give the desired product (647g, 1.40 mol).
In a further experiment, the above synthesis was carried out using the bisulfate salt of (S) - γ -fluoroleucine ethyl ester. Tartrate and hydrogen sulfate esters were prepared as described in WO 2013148554. In another experiment, the diisopropylammonium salt of the final product was isolated, which resulted in a slightly improved optical purity of the salt relative to the free acid.
Step 5 Synthesis of (2S) -N- (1-cyanocyclopropyl) -2- [ [ ((1S) -1- [4- [4- [ (1R) -2, 2-difluoro-1-hydroxy-ethyl ] phenyl ] -2,2, 2-trifluoro-ethyl ] amino ] -4-fluoro-4-methyl-pentanamide
(2S) -2- [ [ (1S) -1- [4- [4- [ (1R) -2, 2-difluoro-1-hydroxy-ethyl ] phenyl ] -2,2, 2-trifluoro-ethyl ] amino ] -4-fluoro-4-methyl-pentanoic acid (545g, 1.18mol) and 1-aminocyclopropanecarbonitrile hydrochloride (167g, 1.41mol) were dissolved in N, N-dimethylformamide (5L) and the resulting solution was cooled to 0 ℃. 4-methylmorpholine (327mL, 2.94mol) was added over 20 minutes while maintaining the temperature below 2 ℃. To the resulting suspension, O- (7-azobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (547g, 1.41mol) was added in two portions while the temperature was observed to rise from 0 ℃ to 5 ℃. After 7 hours of reaction at 5 ℃, the reaction mixture was allowed to reach room temperature and stirred for a further 18 hours. The temperature of the reaction mixture was raised to 60 ℃ over 90 minutes and 4% aqueous phosphoric acid (6.52L) was added. After the addition was complete, a cloudy mixture was obtained. Water (8.75L) was added at a temperature between 50 and 55 ℃ over 90 minutes and the resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was then cooled to 20 to 25 ℃ over 18 hours. The resulting suspension was filtered and the reactor was washed with water (800mL), which was used to flush the filter cake. The filter cake was sequentially washed with N, N-dimethylformamide and water in a 1: 3 mixture (1.5L) and then washed with water (3 × 3L) and then dried by applying a stream of nitrogen to give the desired product as a white solid (610g, 1.16 mol).
The following numbered examples are specific embodiments of the present invention:
1. a compound of formula IA process for the preparation of (A), which comprises reacting a compound of formula (A)With a base and a compound of formula BReaction to give a compound of formula C
2. The process according to claim 1, wherein the base is an alkyl lithium, preferably n-butyl lithium.
3. The preparation process according to any one of claims 1-2, wherein the base is added to the compound of formula a at low temperature, preferably below-70 ℃.
4. The preparation process according to any one of claims 1 to 3, wherein the compound of formula B is added at low temperature, preferably below-70 ℃.
5. The method of any one of claims 1-4, further comprising reducing the compound of formula CTo give a compound of the formula D
6. The method of claim 5, further comprising reacting a compound of formula DWith one or more bases and a compound of formula EReaction to give a compound of formula F
7. The process according to claim 6, wherein the one or more bases comprise organolithium reagents, preferably methyllithium and n-butyllithium.
8. The preparation process according to any one of claims 6 to 7, wherein methyllithium is added to the compound of formula D at low temperature, preferably below-65 ℃.
9. The preparation process according to claim 8, wherein after adding methyllithium to the compound of formula D, n-butyllithium is added at low temperature, preferably below-65 ℃.
10. The preparation method according to any one of claims 6 to 9, further comprising reacting the compound of formula F in the presence of a reducing agentWith compounds of the formula GThe reaction is carried out in the presence of a catalyst,
wherein X-Is a counter ion; to produce a compound of formula H
11. The process according to claim 10, wherein the compound of formula G isWherein X-Is hydrogen sulfate or tartrate, preferably tartrate.
12. The production method according to any one of claims 10 to 11, wherein the reducing agent is Zn (BH)4)2。
13. The production method according to any one of claims 10 to 12, wherein the reduction is performed at a low temperature, preferably not higher than-5 ℃.
14. The preparation process of any one of claims 10 to 13, further comprising reacting a compound of formula H in the presence of HATUAnd compounds of formula JOr a salt thereof, to produce a compound of formula I.
15. The process according to claim 14, wherein the reaction of the compound of formula H with the compound of formula J is carried out in N, N-dimethylformamide.
16. A compound of formula IThe preparation method comprises the following steps:
a) reacting a compound of formula AWith a base and a compound of the formula BReaction to give a compound of formula C
b) Reducing a compound of formula C to produce a compound of formula D
c) Reacting a compound of formula D with one or more bases and a compound of formula EReaction to give a compound of formula F
d) Reacting a compound of formula F with a compound of formula G in the presence of a reducing agentReaction of in which X-Is hydrogen sulfate or tartrate, preferably tartrate, to produce a compound of formula H
e) Reacting a compound of formula H with a compound of formula J in the presence of O- (7-azobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU)Or a salt thereof, to produce a compound of formula I.
17. The process according to claim 16, wherein in step a) the base is an alkyl lithium, preferably n-butyl lithium.
18. The preparation process according to any one of claims 16 to 17, wherein in step a) the base is added to the compound of formula a at a low temperature, preferably below-70 ℃.
19. The preparation process according to any one of claims 16 to 18, wherein in step a) the compound of formula B is added at low temperature, preferably below-70 ℃.
20. The process of any one of claims 16-19, wherein in step c) the one or more bases comprise an organolithium reagent, preferably methyllithium and n-butyllithium.
21. The preparation process according to claim 20, wherein in step c), methyllithium is added to the compound of formula D at low temperature, preferably below-65 ℃.
22. The preparation process according to claim 20 or 21, wherein in step c) after the addition of methyllithium to the compound of formula D, n-butyllithium is added at low temperature, preferably below-65 ℃.
23. The method of any one of claims 16-22, wherein in step d), X-Is tartrate.
24. The production method according to any one of claims 16 to 23, wherein, in step d), the reducing agent is Zn (BH)4)2。
25. The production method according to any one of claims 16 to 24, wherein, in step d), the reduction is carried out at a temperature of not higher than 0 ℃, preferably not higher than-5 ℃.
26. The preparation process according to any one of claims 16 to 25, wherein in step e) the reaction of the compound of formula H with the compound of formula J is carried out in N, N-dimethylformamide.
27. A compound of formula IaThe preparation method comprises the following steps:
a) reacting a compound of formula AWith a base and a compound of the formula BReaction to give a compound of formula C
b) Reducing a compound of formula C to obtain a compound of formula Dd
c) Reacting a compound of formula Dd with one or more bases and a compound of formula EReacting to obtain the compound of formula Ff
d) Reacting a compound of formula Ff with a compound of formula GgIn the presence of a reducing agent, wherein X-Is hydrogen sulfate or tartrate, preferably tartrate, to give compounds of formula Hh
e) Combining a compound of formula Hh with a compound of formula J in the presence of a coupling agentArticle (A)Or a salt thereof, to give a compound of formula Ia.
28. The process according to claim 27, wherein in step a) the base is an alkyl lithium, preferably n-butyl lithium.
29. The preparation process according to any one of claims 27 to 28, wherein in step a) the base is added to the compound of formula a at a low temperature, preferably below-70 ℃.
30. The preparation process according to any one of claims 27 to 29, wherein in step a) the compound of formula B is added at low temperature, preferably below-70 ℃.
31. The preparation method according to any one of claims 27 to 30, wherein in step b) the reduction is preferably performed by using N, N-diethylaniline-borane complex and a catalyst of formula KTo complete.
32. The preparation method according to any one of claims 27 to 31, wherein in step b) the reduction is carried out at a temperature lower than 0 ℃ and more preferably lower than-5 ℃.
33. The process of any one of claims 27-32, wherein in step c) the one or more bases comprise an organolithium reagent, preferably methyllithium and n-butyllithium.
34. The preparation process according to claim 33, wherein in step c), methyllithium is added to the compound of formula Dd at low temperature, preferably below-65 ℃.
35. The preparation process according to claim 33 or 34, wherein in step c), after adding methyllithium to the compound of formula Dd, n-butyllithium is added at low temperature, preferably below-65 ℃.
36. The method of any one of claims 27-35, wherein in step d), X-Is tartrate.
37. According to claim27-36, wherein in step d), the reducing agent is Zn (BH)4)2。
38. The production method according to any one of claims 27 to 37, wherein in step d), the reduction is carried out at a temperature of not higher than 0 ℃, preferably not higher than-5 ℃.
39. The preparation process according to any one of claims 27-38, wherein in step d) the compound of formula Hh can be isolated as a salt by addition of a base, preferably a dialkylamine, more preferably diisopropylethylamine.
40. The preparation process according to any one of claims 27 to 39, wherein in step e) the reaction of the compound of formula Hh with the compound of formula J is carried out in N, N-dimethylformamide.
41. The preparation method of any one of claims 27 to 40, further comprising isolating the compound of formula Ia from the reaction mixture by:
i. adding phosphoric acid at a temperature above 25 ℃, preferably 60 ℃, followed by
Adding water at a temperature above 25 ℃, preferably between 50 and 55 ℃, and then
Cooling the mixture to 20 to 25 ℃.
42. The production method according to any one of claims 16 to 41, wherein in the reaction of step a),
i. adding n-butyllithium while maintaining the temperature below-70 ℃; and
adding also the compound of formula B while maintaining the temperature below-70 ℃.
43. The method of any one of claims 16-42, wherein the reduction of step c) is by using a catalyst of formula KTo complete.
44. A compound of formula H
45. The compound of claim 44, wherein the compound has the following formula Hh: