CN111560008A - Preparation method of Geragibo intermediate - Google Patents

Abstract

The invention provides a preparation method of a Geragibo intermediate, which relates to the technical field of organic synthesis and comprises the following steps: dehydro-N-methyl-4-piperidone and (S) -tert-butyl sulfinamide are subjected to a dehydration condensation reaction, a product of the dehydration condensation reaction and N-p-toluenesulfonyl-benzimidazolyl-2-lithium are subjected to a Michael addition reaction, the product of the addition reaction is reduced by sodium triacetoxyborohydride, concentrated hydrochloric acid is added into the obtained reduction product for hydrolysis, and alkali is added into the hydrolysis product for neutralization, so that a Glabra intermediate is obtained. According to the synthesis method of the grangible intermediate, the starting raw materials are cheap and easy to obtain, all the steps are conventional reactions, the requirement on equipment is not high, and the production cost of the grangible intermediate can be well reduced.

Description

Preparation method of Geragibo intermediate

Technical Field

The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a grangible intermediate.

Background

Acute Myeloid Leukemia (AML), the most common malignant leukemia in adults, is the one of the lowest survival types of leukemia. Since many adult patients with AML are unable to undergo intensive chemotherapy due to various complications, as well as chemotherapy-related toxicities, more than half of the patients have died. Glargib (glasdegib) was found to be very effective in AML, mainly in treating newly diagnosed patients with age above 75 years, or Acute Myeloid Leukemia (AML) which cannot receive high-intensity chemotherapy due to co-morbidity. [ patent: GB 2519344(GB 2013-18461); ACS med.chem.lett.2012,3, 106-; org.Lett.2014,16,860-863 ]. The new medicine is expected to greatly improve the cure rate of AML patients, especially the AML patients of the old; therefore, the demand for grangil cloth will be more and more increased in the future, and the grangil cloth main synthetic route [ ACS med.chem.lett.2012,3,106-; org.Lett.2014,16,860-863] all require to synthesize a chiral intermediate compound (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine shown as a structural formula 1, and then condense the chiral intermediate compound with a substrate of another segment, wherein the synthetic route is shown as the following formula:

therefore, the method for preparing the intermediate of (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine, namely the glatiribbean intermediate, which has the advantages of cheap and easily obtained raw material source, economic synthetic route and simple and convenient purification steps, has very important significance.

At present, the preparation method of the intermediate of the grahamib is mainly as follows, wherein the first method uses a complex chiral intermediate shown in a structural formula M1 as a starting material, and firstly converts hydroxyl into amino through three steps of hydroxyl activation, azide substitution and reduction to obtain an intermediate shown in a structural formula M2; then protecting amino group, and hydrolyzing ester group to obtain intermediate shown in structural formula M3; the intermediate shown in the structural formula M3 is subjected to condensation reaction with o-phenylenediamine to obtain an intermediate shown in the structural formula M4, then the intermediate shown in the structural formula M5 is prepared through three steps of intramolecular ring closure, deprotection, reductive amination and the like, and finally the target compound shown in the structural formula 1, namely the Geragibb intermediate [ ACSMed. chem. Lett.2012,3, 106-plus 111 ]; specific synthetic routes are given in the following formula:

secondly, taking N- (p-toluenesulfonyl) benzimidazole as a starting material, firstly forming a lithium reagent shown as a structural formula M7 under the action of LDA, then carrying out addition reaction with an intermediate shown as a structural formula M8, then carrying out hydrolysis two-step reaction to obtain an intermediate shown as a structural formula M9, then selectively reducing double bonds of the intermediate shown as a structural formula M9 by using a reducing agent to obtain an intermediate shown as a structural formula M10, then removing a protecting group to obtain an intermediate shown as a structural formula M11, and finally adopting a very key biological enzyme catalyst ATA-36 to carry out one-step chiral amination reduction to obtain a target compound shown as a structural formula 1, namely a Glabra intermediate [ Org.Lett.2014,16,860-863 ]; specific synthetic routes are given in the following formula:

the two synthesis methods have the defects that the first synthesis method has complex initial raw materials, long synthesis steps (up to 10 steps) and low total yield, and relates to highly toxic and explosive substances such as sodium azide, sodium cyanoborohydride and the like in the middle, so that the method brings danger to the production process, is easy to pollute the environment and has no industrial value.

The second synthesis method comprises 6 steps, wherein tert-butoxy lithium hydrogen is used in selective reduction of unsaturated double bonds, the substance is easy to emulsify to form colloid in post-treatment, the amplification reaction is not friendly, the separation and purification of post-treatment products are inconvenient, a special chiral bio-enzyme catalyst is needed in the most critical reaction for chiral formation, the substance is not easy to obtain and expensive, the bio-enzyme catalytic chiral synthesis has the defect of difficult separation at the level above a pilot plant test, the amplification reaction is not easy to carry out, and the later-stage large-scale production has great challenges.

In view of this, it is an urgent need to solve the problem of establishing a preparation method of a glatirib intermediate with easily available raw materials and simple and convenient steps.

Disclosure of Invention

The technical problem solved by the invention is that the raw materials required by the existing preparation method of the grangible intermediate are complex and are not easy to obtain.

In order to solve the problems, the invention provides a preparation method of a grangibib intermediate, which comprises the following steps:

s1: carrying out dehydration condensation reaction on the dehydrogenated N-methyl-4-piperidone and (S) -tert-butyl sulfinamide to obtain (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with chiral auxiliary group;

s2: carrying out Michael addition reaction on the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide and N-p-toluenesulfonyl-benzimidazolyl-2-lithium to obtain (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide;

s3: reducing the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide by sodium triacetoxyborohydride to obtain (2R,4R) -N-methyl-2- (N-p-toluenesulfonyl benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide;

s4: and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butyl sulfenamide is hydrolyzed by adding concentrated hydrochloric acid, and the hydrolysate is neutralized by adding alkali to obtain the Glabra gibb intermediate.

For ease of description, the glatiramer intermediate is represented herein as compound 1, wherein the structural formula of the glatiramer intermediate is represented by the following formula:

in order to prepare the compound 1, the dehydro-N-methyl-4-piperidone shown as a compound 2 is used as a starting material, the dehydro-N-methyl-4-piperidone firstly undergoes a dehydration condensation reaction with (S) -tert-butyl sulfinamide, and the (S) -tert-butyl sulfinamide is used as a chiral auxiliary agent to induce and generate a chiral target product, namely, (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with a chiral auxiliary group shown as a compound 3.

Then, the lithium reagent shown as compound 4, N-p-toluenesulfonyl-benzimidazolyl-2-lithium, is subjected to Michael addition reaction with compound 3, and compound 4 can only attack from the back side of compound 3 due to the presence of the tert-butyl chiral auxiliary group in compound 3, so as to obtain the chiral target product shown as compound 5, namely (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide.

The resulting compound 5 was then reduced with sodium triacetoxyborohydride, again due to the presence of a chiral prosthetic group, and triacetoxyborohydride was able to attack only from the back of the tert-butyl group, thus giving (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide, shown as compound 6.

Finally, the two sulfone groups of the compound 6 are hydrolyzed and removed under the condition of concentrated hydrochloric acid, and then are neutralized by alkali to obtain (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine, namely a Glabra intermediate, which is shown in the formula in the specification, wherein the synthesis route is shown in the following formula:

according to the synthesis method of the grangible intermediate, the initial raw materials are cheap and easy to obtain, chiral sulfoxide is selected as a chiral source, a substrate is used for inducing to form a chiral center, a main product can be conveniently separated and purified, the problem of enantiomer selectivity does not exist, all steps are conventional reactions, the requirement on equipment is not high, a complex separation and purification means is not needed, the production cost of the grangible intermediate can be well reduced, and the grangible intermediate has good industrial potential and commercial value.

Optionally, step S1 includes:

s11: dissolving the dehydro-N-methyl-4-piperidone in a benzene solvent, adding pyridinium p-toluenesulfonate and the (S) -tert-butyl sulfinamide, and refluxing and water dividing for 15-20 h at 110-130 ℃ to obtain a dehydration condensation reaction solution;

s12: concentrating the dehydration condensation reaction solution under reduced pressure to obtain a dehydration condensation crude product;

s13: dissolving the crude dehydration condensation product by using dichloromethane, and taking a dehydration condensation organic phase;

s14: and sequentially carrying out water washing, anhydrous sodium sulfate drying and concentration on the dehydration condensation organic phase, and then recrystallizing by an ester solvent to obtain the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfenimide.

The names of the dehydration condensation reaction liquid, the dehydration condensation crude product, the dehydration condensation organic phase, the addition reaction liquid, and the methal organic phase in the present application are only used to distinguish the reactants, the products, and the like in the respective reaction steps, and do not limit the specific substances.

In the step S12, the benzene solvent can be recovered during the vacuum concentration of the dehydration condensation reaction solution, and the recovered solvent can be reused after being re-evaporated, so as to reduce the cost and pollution.

Optionally, the mole ratio of the dehydro-N-methyl-4-piperidone, the pyridinium p-toluenesulfonate and the (S) -tert-butylsulfinamide in the step S11 is (25-75): 1: 50; so as to obtain higher yield while the dehydration condensation reaction is smoothly carried out.

Alternatively, the dehydro-N-methyl-4-piperidone is prepared from N-methyl-4-piperidone by oxidation.

Therefore, the compound 2 can be prepared from a cheap and easily available commercial reagent N-methyl-4-piperidone (see the literature Chemical Communications (Cambridge, United Kingdom),2016,52(99), 14314-.

Optionally, step S2 includes:

s21: dissolving the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfimide in an ether solvent, cooling to-50 to-30 ℃, adding the N-p-toluenesulfonyl-benzimidazolyl-2-lithium under the stirring condition, stirring for 15min, heating to-30 to-10 ℃, and continuing stirring for addition reaction for 15 to 20 hours to obtain an addition reaction solution;

s22: adding an ammonium chloride solution into the addition reaction liquid to quench the reaction, and separating an addition organic phase; extracting the aqueous phase by using ethyl acetate, and combining the organic phase obtained by extraction with the addition organic phase;

s23: and (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinyl imine is obtained by sequentially washing the addition organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and recrystallizing with an alcohol solvent.

The synthesis process of the part is shown as the following formula:

alternatively, the molar ratio of (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide to the N-p-toluenesulfonyl-benzimidazolyl-2-lithium in step S21 is 1: (0.8 to 1.2); so as to obtain higher yield while the addition reaction is smoothly carried out.

Alternatively, the N-p-toluenesulfonyl-benzimidazolyl-2-lithium is prepared in situ from N- (p-toluenesulfonyl) benzimidazole and lithium diisopropylamide.

Optionally, step S3 includes:

s31: dissolving the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butyl sulfinimide in a halogenated hydrocarbon solvent, adding sodium triacetoxyborohydride in batches under stirring at room temperature, and stirring for 4-24 h at the temperature of 0-10 ℃ to obtain a reduction reaction solution;

s32: adding water to dilute the reduction reaction solution, and separating and reducing an original organic phase; extracting the reduction water phase by using dichloromethane, and combining the obtained organic phase with the reduction organic phase; and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide is obtained by sequentially washing the reduced organic phase with water, drying with anhydrous sodium sulfate and concentrating.

Alternatively, the molar ratio of the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide to the sodium triacetoxyborohydride in step S31 is (0.8-1.2): 1; so as to obtain higher yield while ensuring the smooth proceeding of the reduction reaction.

Optionally, step S4 includes:

s41, dissolving the (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide in an ether solvent, adding concentrated hydrochloric acid, raising the reaction temperature to 30-50 ℃, and stirring for 10-14 h to obtain a hydrolysis reaction solution;

s42: cooling the hydrolysis reaction liquid in an ice bath, adding sodium hydroxide solution for neutralization, and performing suction filtration on the neutralized hydrolysis reaction liquid to obtain a solid product;

s43: washing the solid product with n-hexane and diethyl ether to obtain a crude product of the grangib intermediate;

s44: recrystallizing the crude product by using an alcohol solvent to obtain the Geragibo intermediate.

Compared with the prior art, the preparation method of the Geragibo intermediate provided by the invention has the following advantages:

according to the synthesis method of the grangible intermediate, the initial raw materials are cheap and easy to obtain, chiral sulfoxide is selected as a chiral source, a substrate is used for inducing to form a chiral center, a main product can be conveniently separated and purified, the problem of enantiomer selectivity does not exist, all steps are conventional reactions, the requirement on equipment is not high, a complex separation and purification means is not needed, the production cost of the grangible intermediate can be well reduced, and the grangible intermediate has good industrial potential and commercial value.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, specific embodiments thereof are described in detail below.

Example one

The embodiment provides a preparation method of a glatirib intermediate, which comprises the following steps:

s1: in a single-neck flask with a magnetic stirrer and a capacity of 1000 ml, 55.5 g (500 mmol) of compound 2 was added, 500 ml of toluene was added to dissolve compound 2, 10 mmol of pyridinium p-toluenesulfonate and 60.6 g (500 mmol) of (S) -tert-butylsulfenamide were added, a water separator was connected, and water was distributed under reflux at 110 ℃; after refluxing and water dividing reaction for 18 hours, the reaction is complete, and the water divider is removed; cooling the reaction solution to room temperature, and then removing the toluene solvent through reduced pressure concentration (the toluene can be recovered, steamed again, dried and recycled); the remaining crude solid was dissolved in 500 ml of dichloromethane and the organic phase was washed twice with water; the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by decompression, and the crude product is recrystallized by ethyl acetate solvent to obtain 101.7 g of white solid which is the pure chiral imine compound 3; the yield of this step was calculated to be 95%.

The obtained product was characterized by the following data:

¹H NMR(400MHz,CDCl₃):5.06(d,J＝7.8Hz,1H),7.08(d,J＝ 7.8Hz,1H),3.79(t,J＝7.2Hz,2H),3.06(s,3H),2.35(t,J＝7.2Hz, 2H),1.29(s,9H).

¹³C NMR(75MHz,CDCl₃):165.3,146.8,95.5,60.6,48.4,43.8, 34.0,27.2.

ESI–MS:m/z 215([M+H]).HRMS(EI):m/z 215.1216.Calcd.for C₁₀H₁₉N₂OS⁺:215.1213.

the analysis of the characterization data confirmed that the product was (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinylimide represented by Compound 3.

S2: under the nitrogen atmosphere, 21.4 g (100 mmol) of compound 3 is added into a double-neck bottle with the magnetic stirring capacity of 500 ml, then 100 ml of anhydrous tetrahydrofuran is added to dissolve the compound 3, and then the reaction system is cooled to-40 ℃; under stirring, 105 mmol of a lithium reagent represented by compound 4 was added dropwise from an isopiestic dropping funnel (as is currently done, the preparation procedure is as follows: in a 250 ml single-neck flask equipped with an isopiestic dropping funnel, 28.6 g (105 mmol) of N- (p-toluenesulfonyl) benzimidazole was added, then 100 ml of anhydrous tetrahydrofuran was added to dissolve N- (p-toluenesulfonyl) benzimidazole, the reaction solution was cooled to-20 ℃, then 63 ml (2.0 mol/l, LDA is a commercial reagent) of tetrahydrofuran/heptane/ethylbenzene solution of LDA (lithium diisopropylamide) was added dropwise from the isopiestic dropping funnel, after the addition, the reaction solution was stirred at the temperature for 15 minutes, this was a prepared lithium reagent represented by compound 4, compound 4 was carefully transferred to the isopiestic dropping funnel), then the reaction solution was heated to-20 ℃, keeping the temperature at minus 20 ℃ until the reaction is finished after stirring for 16 hours; after the reaction is finished, adding 500 ml of saturated ammonium chloride solution to quench the reaction, and separating an organic phase; extracting the water phase with ethyl acetate, combining the organic phases, washing the organic phases with a saturated sodium chloride solution, and then drying the organic phases with anhydrous sodium sulfate to obtain a crude product; the solvent in the crude product was removed by concentration under reduced pressure, and then recrystallized from ethanol to give 37.9 g of a yellow solid, which was pure compound 5; the yield in this step was calculated to be 78%.

The obtained product was characterized by the following data:

¹H NMR(400MHz,CDCl₃):7.77-7.59(m,4H),7.45-7.27(m, 4H),4.66(dd,J＝7.2,4.8Hz,1H),3.04(m,1H),2.80–2.74(m,2H), 2.66–2.58(m,2H),2.40(m,1H),2.39(s,3H),2.26(s,3H),1.32(s,9H)；

¹³C NMR(75MHz,CDCl₃):164.5,143.9,141.6,135.7,132.9, 130.1,126.9,125.6,124.9,120.8,116.8,114.0,60.1,59.2,51.3,43.5, 41.5,39.2,27.1,21.3.

.ESI–MS m/z 487([M+H]).HRMS(EI):m/z 487.1830.Calcd.For C₂₄H₃₁N₄O₃S₂ ⁺:487.1832.

the characterization data were analyzed to confirm that the product was (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide represented by Compound 5.

S3: in an open flask with a magnetic stirring capacity of 500 ml, 24.3 g (50 mmol) of Compound 5 are added, 100 ml of dichloromethane are added to dissolve Compound 5, the reaction mixture is cooled to 0 ℃ to 5 ℃, and 10.6 g (50 mmol) of NaBH (OAc) are added in one portion with stirring₃Solid, keeping stirring for 0.5 hour under the condition of 0-10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) was further added to the reaction solution₃Continuously stirring and reacting the solid for 0.5 hour at the temperature of between 0 and 10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) were added₃And (3) continuously stirring the solid at the temperature of 0-10 ℃ for 4 hours, adding 250 ml of water to quench after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, washing the organic phase by water, drying the organic phase by using anhydrous sodium sulfate, and then concentrating under reduced pressure to remove the solvent to obtain a yellow solid, wherein the yellow solid is a crude product of the compound 6, and the crude product is directly used as a raw material for the next hydrolysis reaction without purification.

S4: the crude compound 6 in S3 was put into a 500 ml open-top flask with magnetic stirring, 100 ml tetrahydrofuran was added, and then 50 ml concentrated hydrochloric acid (10mol/L, 500 mmol) was added and reacted at 40 ℃ for 12 hours; after the reaction is completed, cooling the reaction solution to 0-5 ℃ (ice bath), then dropwise adding an aqueous solution (5mol/L) of sodium hydroxide to a pH value of 10-12, generating a large amount of precipitates, performing suction filtration, washing a solid with n-hexane and diethyl ether, wherein the solid is a crude product of a compound 1, and recrystallizing the crude product of the compound 1 with ethyl acetate to obtain 8.6 g of a yellow solid, which is a target intermediate compound 1, namely a grangian intermediate; the yield in this step was calculated to be 75%.

The obtained product was characterized by the following data:

¹H NMR(400MHz,CD₃OD):7.72-7.58(m,3H),7.26-7.14(m, 2H),3.88-3.80(m,1H),3.48-3.41(m,1H),2.68(dt,J＝12.0,4.0Hz,1H), 2.20(td,J＝12.0,3.2Hz,1H),2.03(s,3H),1.98–2.10(m,1H),1.91– 1.83(m,2H),1.72-1.68(m,1H)；

¹³C NMR(75MHz,CD₃OD)153.8,136.9,136.3,122.8,122.6, 118.5,117.9,58.6,49.9,43.7,42.4,36.0,29.8.

ESI–MS m/z 231([M+H]).HRMS(EI):m/z 231.1606.Calcd.For C₁₃H₁₉N₄ ⁺:231.1604.

the analysis of the characterization data confirmed that the product formed was a glatirib intermediate as shown in compound 1.

Example two

The embodiment provides a preparation method of a glatirib intermediate, which comprises the following steps:

s1: 28 g (250 mmol) of Compound 2, and then 500 ml of toluene were added to dissolve Compound 2 in a 1000 ml single-neck flask with magnetic stirrer, and then 10 mmol of pyridinium p-toluenesulfonate and 60.6 g (500 mmol) of (S) -tert-butylsulfinamide were added, followed by a water separator and reflux at 120 ℃ for water diversion; after refluxing and water dividing reaction for 20 hours, the reaction is complete, and the water divider is removed; cooling the reaction solution to room temperature, and then removing the toluene solvent through reduced pressure concentration (the toluene can be recovered, steamed again, dried and recycled); the remaining crude solid was dissolved in 500 ml of dichloromethane and the organic phase was washed twice with water; the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was recrystallized from ethyl acetate solvent to give 49.8 g of a white solid in 93% yield, which was pure chiral imine compound 3.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The analysis of the characterization data confirmed that the product was (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinylimide represented by Compound 3.

S2: under the nitrogen atmosphere, 21.4 g (100 mmol) of compound 3 is added into a double-neck bottle with the magnetic stirring capacity of 500 ml, then 100 ml of anhydrous tetrahydrofuran is added to dissolve the compound 3, and then the reaction system is cooled to-50 ℃; under stirring, 80 mmol of a lithium reagent represented by compound 4 was added dropwise from an isopiestic dropping funnel (as is currently done, the preparation procedure is as follows: in a 250 ml single-neck flask equipped with an isopiestic dropping funnel, 21.8 g (80 mmol) of N- (p-toluenesulfonyl) benzimidazole was added, then 100 ml of anhydrous tetrahydrofuran was added to dissolve N- (p-toluenesulfonyl) benzimidazole, the reaction solution was cooled to-20 ℃, then 48 ml (2.0 mol/l, LDA is a commercial reagent) of tetrahydrofuran/heptane/ethylbenzene solution of LDA (lithium diisopropylamide) was added dropwise from the isopiestic dropping funnel, after the addition, the reaction solution was stirred at the temperature for 15 minutes, this was a prepared lithium reagent represented by compound 4, compound 4 was carefully transferred to the isopiestic dropping funnel), then the reaction solution was heated to-30 ℃, keeping the temperature at minus 30 ℃ and continuing stirring for 20 hours until the reaction is finished; after the reaction is finished, adding 500 ml of saturated ammonium chloride solution to quench the reaction, and separating an organic phase; extracting the water phase with ethyl acetate, combining the organic phases, washing the organic phases with a saturated sodium chloride solution, and then drying the organic phases with anhydrous sodium sulfate to obtain a crude product; the solvent was removed from the crude product by concentration under reduced pressure, followed by recrystallization from ethanol to give 29.7 g of a yellow solid, yield 76.3%, which was pure compound 5.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The characterization data were analyzed to confirm that the product was (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide represented by Compound 5.

S3: 19.4 g (40 mmol) of Compound 5 are added to an open flask with a magnetic stirring capacity of 500 ml, 100 ml of dichloromethane are added to dissolve Compound 5, the reaction mixture is cooled to 0 ℃ to 5 ℃, and 10.6 g (50 mmol) of NaBH (OAc) are added in one portion with stirring₃Solid, keeping stirring for 0.5 hour under the condition of 0-10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) was further added to the reaction solution₃Continuously stirring and reacting the solid for 0.5 hour at the temperature of between 0 and 10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) were added₃Solid, continuously stirring for 10 hours at the temperature of 0-10 ℃, adding water after the reaction is finished250 ml of the mixture is quenched, the organic phase is separated, the aqueous phase is extracted by dichloromethane, the organic phases are combined, the organic phases are washed by water, dried by anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent, so that a yellow solid is obtained, and the yellow solid is a crude product of the compound 6, and the crude product is directly used as a raw material for the next hydrolysis reaction without purification.

S4: the crude compound 6 in S3 was put into a 500 ml open-top flask with magnetic stirring, 100 ml tetrahydrofuran was added, and then 50 ml concentrated hydrochloric acid (10mol/L, 500 mmol) was added and reacted at 50 ℃ for 14 hours; after the reaction is completed, cooling the reaction solution to 0-5 ℃ (ice bath), then dropwise adding an aqueous solution (5mol/L) of sodium hydroxide to a pH value of 10-12 to generate a large amount of precipitates, performing suction filtration, washing the solid with n-hexane and diethyl ether, wherein the solid is a crude product of the compound 1, and recrystallizing the crude product of the compound 1 with ethyl acetate to obtain 8.4 g of a yellow solid, wherein the yield is 72.9%; this is the target intermediate compound 1, the glatiribb intermediate.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The analysis of the characterization data confirmed that the product formed was a glatirib intermediate as shown in compound 1.

EXAMPLE III

The embodiment provides a preparation method of a glatirib intermediate, which comprises the following steps:

s1: a1000 ml single-neck flask with magnetic stirrer was charged with 83.3 g (750 mmol) of Compound 2, 500 ml of toluene was added to dissolve Compound 2, 10 mmol of pyridinium p-toluenesulfonate and 60.6 g (500 mmol) of (S) -tert-butylsulfenamide were added, a water separator was attached, and reflux was carried out at 130 ℃ to effect water diversion; after refluxing and water dividing reaction for 15 hours, the reaction is complete, and the water divider is removed; cooling the reaction solution to room temperature, and then removing the toluene solvent through reduced pressure concentration (the toluene can be recovered, steamed again, dried and recycled); the remaining crude solid was dissolved in 500 ml of dichloromethane and the organic phase was washed twice with water; the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was recrystallized from ethyl acetate solvent to give 100.5 g of a white solid in 93.9% yield, which was pure chiral imine compound 3.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The analysis of the characterization data confirmed that the product was (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinylimide represented by Compound 3.

S2: under the nitrogen atmosphere, 21.4 g (100 mmol) of compound 3 is added into a double-neck bottle with the magnetic stirring capacity of 500 ml, then 100 ml of anhydrous tetrahydrofuran is added to dissolve the compound 3, and then the reaction system is cooled to-30 ℃; under stirring, 120 mmol of a lithium reagent represented by compound 4 was added dropwise from an isopiestic dropping funnel (as is currently done, the preparation procedure is as follows: in a 250 ml single-neck flask equipped with an isopiestic dropping funnel, 34.3 g (120 mmol) of N- (p-toluenesulfonyl) benzimidazole was added, then 100 ml of anhydrous tetrahydrofuran was added to dissolve N- (p-toluenesulfonyl) benzimidazole, the reaction solution was cooled to-20 ℃, then 75.6 ml (2.0 mol/l, LDA is a commercial reagent) of tetrahydrofuran/heptane/ethylbenzene solution of LDA (lithium diisopropylamide) was added dropwise from the isopiestic dropping funnel, after completion of the addition, the reaction solution was stirred at the temperature for 15 minutes, this was a prepared lithium reagent represented by compound 4, compound 4 was carefully transferred to the isopiestic dropping funnel, then the reaction solution was heated to-10 ℃, keeping the temperature at minus 10 ℃ and continuing stirring for 15 hours until the reaction is finished; after the reaction is finished, adding 500 ml of saturated ammonium chloride solution to quench the reaction, and separating an organic phase; extracting the water phase with ethyl acetate, combining the organic phases, washing the organic phases with a saturated sodium chloride solution, and then drying the organic phases with anhydrous sodium sulfate to obtain a crude product; the solvent was removed from the crude product by concentration under reduced pressure, followed by recrystallization from ethanol to give 37.5 g of a yellow solid, 77.2% yield, which was pure compound 5.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The characterization data were analyzed to confirm that the product was (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide represented by Compound 5.

S3: in an open flask with a magnetic stirring capacity of 500 ml, 29.2 g (60 mmol) of Compound 5 are added, 100 ml of dichloromethane are added to dissolve Compound 5, the reaction mixture is cooled to 0 ℃ to 5 ℃, and 10.6 g (50 mmol) of NaBH (OAc) are added in one portion with stirring₃Solid, keeping stirring for 0.5 hour under the condition of 0-10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) was further added to the reaction solution₃Continuously stirring and reacting the solid for 0.5 hour at the temperature of between 0 and 10 ℃; then, 10.6 g (50 mmol) of NaBH (OAc) were added₃And (3) continuously stirring the solid at the temperature of 0-10 ℃ for 24 hours, adding 250 ml of water to quench after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, washing the organic phase by water, drying the organic phase by using anhydrous sodium sulfate, and then concentrating under reduced pressure to remove the solvent to obtain a yellow solid, wherein the yellow solid is a crude product of the compound 6, and the crude product is directly used as a raw material for the next hydrolysis reaction without purification.

S4: the crude compound 6 in S3 was put into a 500 ml open-top flask with magnetic stirring, 100 ml tetrahydrofuran was added, and then 50 ml concentrated hydrochloric acid (10mol/L, 500 mmol) was added and reacted at 30 ℃ for 10 hours; after the reaction is completed, cooling the reaction solution to 0-5 ℃ (ice bath), then dropwise adding an aqueous solution (5mol/L) of sodium hydroxide to a pH value of 10-12 to generate a large amount of precipitates, performing suction filtration, washing the solid with n-hexane and diethyl ether, wherein the solid is a crude product of the compound 1, and recrystallizing the crude product of the compound 1 with ethyl acetate to obtain 8.1 g of a yellow solid, wherein the yield is 73.6%; this is the target intermediate compound 1, the glatiribb intermediate.

The obtained product was characterized, and the characterization data refer to the relevant data in example one.

The analysis of the characterization data confirmed that the product formed was a glatirib intermediate as shown in compound 1.

Although the present disclosure has been described above, the scope of the present disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present disclosure, and such changes and modifications will fall within the scope of the present invention.

Claims (10)

1. A preparation method of a grangibib intermediate is characterized by comprising the following steps:

s1: carrying out dehydration condensation reaction on the dehydrogenated N-methyl-4-piperidone and (S) -tert-butyl sulfinamide to obtain (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with chiral auxiliary group;

s2: carrying out Michael addition reaction on the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide and N-p-toluenesulfonyl-benzimidazolyl-2-lithium to obtain (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide;

s3: reducing the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide by sodium triacetoxyborohydride to obtain (2R,4R) -N-methyl-2- (N-p-toluenesulfonyl benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide;

s4: and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butyl sulfenamide is hydrolyzed by adding concentrated hydrochloric acid, and the hydrolysate is neutralized by adding alkali to obtain the Glabra gibb intermediate.

2. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S1 comprises:

s11: dissolving the dehydro-N-methyl-4-piperidone in a benzene solvent, adding pyridinium p-toluenesulfonate and the (S) -tert-butyl sulfinamide, and refluxing and water dividing for 15-20 h at 110-130 ℃ to obtain a dehydration condensation reaction solution;

s12: concentrating the dehydration condensation reaction solution under reduced pressure to obtain a dehydration condensation crude product;

s13: dissolving the crude dehydration condensation product by using dichloromethane, and taking a dehydration condensation organic phase;

s14: and sequentially carrying out water washing, anhydrous sodium sulfate drying and concentration on the dehydration condensation organic phase, and then recrystallizing by an ester solvent to obtain the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfenimide.

3. The process for preparing a grangibib intermediate as claimed in claim 2, wherein the molar ratio of the dehydro N-methyl-4-piperidone, the pyridinium p-toluenesulfonate and the (S) -tert-butylsulfinamide in step S11 is (25-75): 1: 50.

4. the process for preparing a grangibib intermediate as claimed in claim 1, wherein the dehydro N-methyl-4-piperidone is prepared by oxidation of N-methyl-4-piperidone.

5. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S2 comprises:

s21: dissolving the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfimide in an ether solvent, cooling to-50 to-30 ℃, adding the N-p-toluenesulfonyl-benzimidazolyl-2-lithium under the stirring condition, stirring for 15min, heating to-30 to-10 ℃, and continuing stirring for addition reaction for 15 to 20 hours to obtain an addition reaction solution;

s22: adding an ammonium chloride solution into the addition reaction liquid to quench the reaction, and separating an addition organic phase; extracting the aqueous phase by using ethyl acetate, and combining the organic phase obtained by extraction with the addition organic phase;

s23: and (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinyl imine is obtained by sequentially washing the addition organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and recrystallizing with an alcohol solvent.

6. The process for preparing a glargib intermediate according to claim 5, wherein the molar ratio of the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide to the N-p-toluenesulfonyl-benzimidazolyl-2-lithium in step S21 is 1: (0.8 to 1.2).

7. The process for preparing a grubbs intermediate according to claim 1, wherein the N-p-toluenesulfonyl-benzimidazolyl-2-lithium is prepared in situ from N- (p-toluenesulfonyl) benzimidazole and lithium diisopropylamide.

8. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S3 comprises:

s31: dissolving the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butyl sulfinimide in a halogenated hydrocarbon solvent, adding sodium triacetoxyborohydride in batches under stirring at room temperature, and stirring for 4-24 h at the temperature of 0-10 ℃ to obtain a reduction reaction solution;

s32: adding water to dilute the reduction reaction solution, and separating and reducing an original organic phase; extracting the reduction water phase by using dichloromethane, and combining the obtained organic phase with the reduction organic phase; and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide is obtained by sequentially washing the reduced organic phase with water, drying with anhydrous sodium sulfate and concentrating.

9. The process for preparing a grubbs intermediate as claimed in claim 8, wherein the molar ratio of (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide to sodium triacetoxyborohydride in step S31 is (0.8 to 1.2): 1.

10. the process for preparing a grangibib intermediate as claimed in claim 1, wherein step S4 comprises:

s41, dissolving the (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide in an ether solvent, adding concentrated hydrochloric acid, raising the reaction temperature to 30-50 ℃, and stirring for 10-14 h to obtain a hydrolysis reaction solution;

s42: cooling the hydrolysis reaction liquid in an ice bath, adding sodium hydroxide solution for neutralization, and performing suction filtration on the neutralized hydrolysis reaction liquid to obtain a solid product;

s43: washing the solid product with n-hexane and diethyl ether to obtain a crude product of the grangib intermediate;

s44: recrystallizing the crude product by using an alcohol solvent to obtain the Geragibo intermediate.