WO2019029507A1 - Preparation method for imidazoisoindole derivatives - Google Patents

Preparation method for imidazoisoindole derivatives Download PDF

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WO2019029507A1
WO2019029507A1 PCT/CN2018/099113 CN2018099113W WO2019029507A1 WO 2019029507 A1 WO2019029507 A1 WO 2019029507A1 CN 2018099113 W CN2018099113 W CN 2018099113W WO 2019029507 A1 WO2019029507 A1 WO 2019029507A1
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compound
preferably
selected
formula
pd
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PCT/CN2018/099113
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French (fr)
Chinese (zh)
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黄建
尤凌峰
姜威
罗扬
王军政
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The present invention relates to a process for the preparation of imidazoisoindole derivatives. The invention particularly relates to a process for the preparation of imidazoisoindole derivatives represented by the formula (I). The process comprises: dissolving a compound represented by formula (II) to obtain a compound represented by formula (III) with high optical purity; and using the compound represented by formula (III) as a raw material for carrying out chemical reactions. The final product obtained has high optical purity at low cost, and is therefore more economical and more suitable for production on an industrial scale.

Description

Preparation method of imidazoisoindole derivatives Technical field

The invention belongs to the field of medicine and relates to a preparation method of an imidazoisoindole derivative.

Background technique

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein. A large number of studies have shown that IDO is highly expressed in leukemia cells. The local T cell proliferation is inhibited, the T-cell-mediated immune response is inhibited, and the T-cell activation signal transduction is blocked, thereby mediating the attack of the tumor cells to escape the immune system. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.

IDO inhibitors have good application prospects in the pharmaceutical industry as drugs. WO2016169421 discloses a novel IDO inhibitor whose compound structure is as shown in formula (I).

Figure PCTCN2018099113-appb-000001

This compound showed excellent IDO inhibition. At present, the synthesis of such compounds is mainly carried out by reacting a halophenylpyrazole with piperidinyl imidazolium and then subjecting it to chiral resolution.

Figure PCTCN2018099113-appb-000002

In the preparation process, we found that the chiral resolution of the final step is very low, especially when using chiral column resolution, because the solubility of the racemate and product in the eluent is not high, it is easy to precipitate during the preparation process. The chiral column is blocked, which seriously affects the efficiency of the separation.

Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel process for the preparation of imidazoisoindole derivatives.

In one aspect, the invention provides a novel reaction intermediate, such as a compound of formula III,

Figure PCTCN2018099113-appb-000003

a compound of formula IV,

Figure PCTCN2018099113-appb-000004

Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO 2 R, R is C 1 -C 6 alkyl; preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.

a compound of formula VII,

Figure PCTCN2018099113-appb-000005

Wherein R 2 is selected from a hydroxy protecting group;

And a compound of formula d,

Figure PCTCN2018099113-appb-000006

Another aspect of the invention provides a process for the preparation of a compound of formula III, including the step of chiral resolution of a compound of formula II,

Figure PCTCN2018099113-appb-000007

The chiral resolution method may be chemical resolution, membrane resolution, chromatographic resolution, capillary electrophoresis resolution, and biological resolution.

In certain embodiments, the method of chiral resolution is chromatographic resolution.

In certain embodiments, the method of chiral resolution is chemical resolution. The resolving agent used may be an organic acid or the like, such as L-tartaric acid, D-tartaric acid, dibenzoyl-L-tartaric acid (L-DBTA), dibenzoyl-D-tartaric acid (D-DBTA), two pairs. Toluyl-L-tartaric acid (L-DTTA) or di-p-toluoyl-D-tartaric acid (D-DTTA), R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, etc., preferably L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, L- Aspartic acid, D-aspartic acid, more preferably D-DTTA.

The molar ratio of the resolving agent to the compound of formula II may be from 1:1 to 4:1.

The process of resolving the compound of the formula II by a resolving agent can be carried out in a conventional solvent, and preferred solvents include water or a hydrophilic organic solvent (for example, C 1 -C 6 alcohols such as methanol and ethanol; ketones, For example, acetone and methyl ethyl ketone; ethers such as tetrahydrofuran and dioxane; acetonitrile; N,N-dimethylformamide; and N,N-dimethyl sulfoxide; or a mixed solvent thereof, more preferably methanol Or ethanol.

The process of splitting the salt with a free intermediate is conventional and can be carried out using a base. The base used for the free is preferably an aqueous alkali metal hydroxide solution, preferably an aqueous sodium hydroxide solution; the solvent may be a conventional solvent such as dichloromethane. Tetrahydrofuran, chloroform, and the like.

In order to increase the optical purity of the compound III obtained by the resolution, the intermediate split salt obtained by the resolution may be recrystallized. The process of splitting into a salt in the present invention can be generally carried out at a normal temperature, and if necessary, under heating, and the step of recrystallization can generally be carried out under heating, and heating is first carried out to cause a split salt in the said Dissolve in the solvent and then slowly complete the recrystallization process at room temperature.

The present invention also provides a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula III according to the process of the invention.

Figure PCTCN2018099113-appb-000008

Further, the method for producing a compound of the formula I or a pharmaceutically acceptable salt thereof according to the invention further comprises the step of preparing a compound of the formula IV by using the compound of the formula III as a reactant.

Figure PCTCN2018099113-appb-000009

Wherein X is a leaving group selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate And -SR, -SO 2 R, R is a C 1 -C 6 alkyl group; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.

The method may be a one-step reaction (e.g., Buckwald coupling) or a multi-step reaction (e.g., first reacting with cyclohexanedione to form a piperidinylphenol intermediate, and then synthesizing compound IV).

Further, the method further comprises the step of preparing a compound of the formula VI by a coupling reaction of a compound of the formula IV with a compound of the formula V in the presence of a catalyst.

Figure PCTCN2018099113-appb-000010

Wherein Y is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X';

R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from C 1 -C 6 alkyl, X' is selected from -Cl, -Br, -I;

m is an integer of 0, 1, 2, 3 or 4;

R 1 is selected from hydrogen or a hydroxy protecting group.

In certain preferred embodiments, Y is selected from BF 3 K and BR a R b, the BR a R b wherein R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is pinacol borate, ie

Figure PCTCN2018099113-appb-000011

The catalyst may include PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II) L p , Pd(0), NiCl 2 L p , Ni ( COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy), wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, and the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb, p is an integer selected from 0, 1, 2, 3 or 4.

For example, the catalyst may be Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , NiCl 2 (dppf), NiCl 2 (PPh 3 ) 2 , Ni{P(OMe) 3 } 2 Cl 2 , NiCl 2 (PCy 3 ) 2 , NiCl 2 (dppe), NiCl 2 (dppb), NiCl 2 (NEt 3 2 ) NiCl 2 (bipy), NiCl 2 ·6H 2 O, NiCl 2 , or Ni(COD) 2 , preferably Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , more preferably Pd(PPh 3 ) 2 Cl 2 .

In certain embodiments, the reaction is carried out in the presence of a basic material, wherein the basic material is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , Cs 2 CO 3 , K 2 or more of CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C 1 ~ C 6 alkyl. Wherein NaOR, KOR or TlOR can be, for example, NaOMe, NaOEt, KOtBu or TlOEt. The alkaline substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .

The solvent of the reaction may be a conventional solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, dimethyl ether, isopropanol. One or more of ethanol, water, and water, preferably one or more of dimethylformamide, dimethyl ether, dioxane, and water. The reaction temperature may be from 60 ° C to 150 ° C.

In certain embodiments, R 1 is a hydroxy protecting group, and the method further comprises the step of deprotecting a compound of formula VI to provide a compound of formula I.

The invention obtains high optical purity compound III by resolving compound II, and the obtained subsequent product always maintains high optical purity, and the product in the latter coupling reaction is not racemized, and the obtained final product has high optical purity, avoiding The final chiral preparation of the problem of blocking the column, the process is stable and easy to reproduce. In addition, the splitting at compound II is low cost, more economical, and more suitable for industrial production.

When the compound II is resolved, both the chromatographic resolution and the chemical resolution can be used to effectively separate the compound III. When the disintegrator is used for separation, the reaction is rapid, the post-treatment is simple, and the by-product can be recycled and reused, and the obtained compound III has high optical purity, which is very suitable for industrial scale production.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups having a conjugated π-electron system, preferably a 6 to 10 membered aryl group, Phenyl and naphthyl are more preferred, and phenyl is most preferred. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane. Base amino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfur based.

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan. The heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carbonyl group, a -carboxylic acid or a carboxylic acid ester.

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.

"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group. Thio group, alkylamino group, halogen, thiol, hydroxyl group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide A heterocyclic alkylthio group, a carbonyl group, a carboxylic acid or a carboxylic acid ester. "Hydroxy" refers to an -OH group.

"Hydroxy protecting group" is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts). As an example, preferably, the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl, allyl, benzyl , methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; may be (C 1-10 alkyl or aryl) acyl, for example: formyl, acetyl , benzoyl, etc.; may be (C 1-6 alkyl or C 6-10 aryl)sulfonyl; may also be (C 1-6 alkoxy or C 6-10 aryloxy)carbonyl.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

Detailed ways

The invention will be explained in detail below with reference to specific examples, which are to be understood by those skilled in the art.

Example 1

Figure PCTCN2018099113-appb-000012

Compound a (177 g, 0.495 mol, prepared according to the method disclosed in WO2016169421) was dissolved in 1.5 L of dichloromethane, 300 mL of 1,4-dioxane was added, and the mixture was cooled with ice water, and concentrated hydrochloric acid (412 mL, 4.95 mol) was added dropwise. The temperature was raised to room temperature and the reaction was stirred for 2 hours. After completion of the reaction, 600 mL of water was added to the reaction mixture to extract and separate the aqueous phase. Sodium hydroxide (215 g, 5.38 mol) was dissolved in 215 mL of water, and the aqueous phase was slowly added dropwise to pH 8-9, the aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound II 144.8 g.

Example 2

Figure PCTCN2018099113-appb-000013

Chiral preparation of compound II 128.6 g (separation conditions: chiral preparation column Superchiral S-AY (Chiralway), 2 cm ID*25 cm Length, 5 um; mobile phase: CO 2 /EtOH/DEA=60/40/0.05 (v /v/v), flow rate: 50 g/min), the target component was collected, and no clogging occurred in the preparation column during the process, and concentrated under reduced pressure to obtain 63.6 g of compound III, optical purity: 99.4%, and chemical purity: 99.2%.

Example 3

Compound II (35.1 g) was dissolved in 600 mL of ethanol at 25-30 ° C, 600 ml of D-DTTA 142 g of ethanol solution was added, and stirred at 25-30 ° C for 16 hours, a large amount of pale yellow solid appeared, and the filter cake was filtered. Add 600 mL of ethanol, heat to reflux, then cool to 25-30 ° C, filter, filter cake to obtain 51.5g white solid, add solid to 750mL of dichloromethane and water 500mL, adjust the pH value with 2N sodium hydroxide solution under stirring To 10-11. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL*3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated %.

Example 4

Figure PCTCN2018099113-appb-000014

first step

Compound III (75 g, 292 mmol) was dissolved in 2 L of ethanol, and compound c (49.1 g, 438 mmol) and 10% Pd/C 7.5 g were sequentially added, and the mixture was heated to 75 ° C, and the mixture was stirred for 28 hours. After completion of the reaction, Pd/C was removed by filtration, and the filter cake was rinsed with methanol. The filtrate was concentrated under reduced pressure and dried in vacuo to give compound d 54.1 g.

Second step

Compound d (54.1 g, 0.155 mol) was dissolved in 700 mL of dichloromethane. The temperature was lowered to 0 ° C, pyridine (61.3 g, 0.775 mol) was added, and then Tf 2 O (56.8 g, 0.201 mol) was added dropwise. The temperature was raised to room temperature, and the reaction was stirred for 1 hour. After the reaction was completed, 60 mL of water was added to the reaction mixture, and the pH was adjusted to 2 with 1 M hydrochloric acid. The mixture was separated and separated, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The organic layer was concentrated under reduced pressure. EtOAcjjjjjjj

Example 5

Figure PCTCN2018099113-appb-000015

Compound e (41 g, 85 mmol) and compound f (40.5 g, 170 mmol, prepared according to the method disclosed in CN 105189461 A) were dissolved in a mixed solvent of 800 mL of 1,4-dioxane and water (V:V=5:1). Sodium carbonate (27 g, 255 mmol) and Pd(dppf)Cl 2 (6.2 g, 8.5 mmol) were sequentially added, and the mixture was warmed to reflux under argon atmosphere, and the reaction was stirred for 3 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, 200 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water, and the filter cake was collected, dispersed with 750 mL of methanol, concentrated hydrochloric acid (22 mL) was added, stirred for 30 min, and concentrated to remove methanol. 1.2L of water, stirred for 30min, filtered, the solid was rinsed with water, the aqueous phase was combined, extracted with ethyl acetate (400mL × 2), the aqueous phase was collected, the pH was adjusted to basic with saturated NaHCO 3 solution, solid was precipitated, and filtered. The solid was washed with water and dried in vacuo to give compound I 23.9 g.

Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.

Claims (14)

  1. a compound of formula III,
    Figure PCTCN2018099113-appb-100001
  2. a compound of formula IV,
    Figure PCTCN2018099113-appb-100002
    Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO 2 R, R is C 1 -C 6 alkyl; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.
  3. a compound of formula VII,
    Figure PCTCN2018099113-appb-100003
    Wherein R 2 is selected from a hydroxy protecting group.
  4. a compound of formula d,
    Figure PCTCN2018099113-appb-100004
  5. A process for the preparation of a compound of formula III, comprising the step of chiral resolution of a compound of formula II,
    Figure PCTCN2018099113-appb-100005
  6. The preparation method according to claim 5, wherein the chiral resolution method is selected from the group consisting of chemical resolution, membrane resolution, chromatographic resolution, capillary electrophoresis resolution, and biological resolution, preferably chemical resolution and Chromatographic resolution.
  7. The preparation method according to claim 6, wherein the resolving agent used in the chemical resolution is selected from the group consisting of L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA or D-DTTA. , R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, preferably L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, more preferably D-DTTA.
  8. The preparation method according to claim 6, wherein a molar ratio of the resolving agent used in the chemical resolution to the compound of the formula II is from 1:1 to 4:1.
  9. The preparation method according to claim 6, wherein the chemically resolved reaction solvent is selected from the group consisting of water, C 1 -C 6 alcohols, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, One or more of N,N-dimethylformamide and N,N-dimethyl sulfoxide, preferably methanol or ethanol.
  10. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, which comprises the step of preparing a compound of formula III according to the process of any of claims 5 to 9.
    Figure PCTCN2018099113-appb-100006
  11. The method according to claim 10, further comprising the step of preparing a compound of the formula IV by using the compound of the formula III as a reactant.
    Figure PCTCN2018099113-appb-100007
    Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO 2 R, R is C 1 -C 6 alkyl; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.
  12. The method according to claim 10, further comprising the step of preparing a compound of the formula VI by coupling a compound of the formula IV with a compound of the formula V in the presence of a catalyst.
    Figure PCTCN2018099113-appb-100008
    Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO 2 R, R is C 1 -C 6 alkyl; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy;
    Y is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X';
    R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from C 1 -C 6 alkyl, X' is selected from -Cl, -Br, -I;
    m is an integer of 0, 1, 2, 3 or 4;
    R 1 is selected from hydrogen or a hydroxy protecting group;
    Said Y is preferably from BF 3 K and BR a R b , wherein R a and R b in said BR a R b are preferably independently selected from -OH, alkyl, alkoxy, or BR a R b Alcohol borate.
  13. The preparation method according to claim 12, wherein the catalyst is selected from the group consisting of PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II)L. p , Pd(0), NiCl 2 L p , Ni(COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy),
    Wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand selected from the group consisting of PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb, and p is independently selected An integer from 0, 1, 2, 3 or 4,
    The catalyst is preferably Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , more preferably Pd (PPh 3 ) 2 Cl 2 .
  14. The production method according to claim 12, wherein the reaction is carried out in the presence of a basic substance, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , one or more of Cs 2 CO 3 , K 2 CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from a C 1 -C 6 alkyl group, and the basic substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .
PCT/CN2018/099113 2017-08-08 2018-08-07 Preparation method for imidazoisoindole derivatives WO2019029507A1 (en)

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