Detailed Description
EXAMPLE 12 Synthesis of allyl- [ (5-chloro-2-pyridine) amino ] -2-oxoacetate hydrochloride
Adding 1000g of acetonitrile into a reaction bottle, adding 200g (1.556mol) of 2-amino-5-chloropyridine, heating to 30-35 ℃, dropwise adding 255g (1.717mol) of oxalyl chloride monoallyl ester, and controlling the temperature not to exceed 50 ℃ in the dropwise adding process; after the dropwise addition, the temperature is kept at 45-50 ℃ for reaction for 3-4 hr. After the reaction is finished, the temperature is reduced to 0-5 ℃ and the temperature is kept for about 2-4 hr. Filtering and collecting solid; adding the obtained wet product into 1500g of water, and pulping at room temperature for 2-3 hr; filtration, rinsing with water, collection of the solid and drying gave about 416g (theoretical amount: 431.1g) of 109A4-10 as a dry product. The yield thereof was found to be 96.5%.
Example Synthesis of allyl 22- [ (5-chloro-2-pyridine) amino ] -2-oxoacetate
Adding 900g of ethyl acetate into the reaction bottle; 100g (360.9mmol) of 109A4-10 was added; adding 40g (395.3mmol) of triethylamine under stirring, heating to 40-45 ℃, and stirring for 3-5 hr under heat preservation; filtering while the solution is hot, and collecting filtrate; the ethyl acetate was concentrated under reduced pressure to give a residue of about 95 g. Adding about 50g of ethyl acetate into the residue, stirring to uniformly disperse the ethyl acetate, adding 300g of petroleum ether, heating to 40-45 ℃, and stirring for about 1 hr; cooling to 0-5 deg.C and maintaining for about 1-2 hr. Filtration was carried out, and the solid was collected and dried to obtain about 77g (theoretical amount: 86.8g) of a dried 109A 4-00. Yield: 88.7 percent.
Example Synthesis of allyl 32- [ (5-chloro-2-pyridine) amino ] -2-oxoacetate
Adding 1500g of ethyl acetate and 300g of water into a reaction bottle; 150g (541.3mmol) of 109A4-10 was added; a solution of 54g (642.8mmol) of sodium bicarbonate in 600g of water is added dropwise and the pH is adjusted to 8; keeping the temperature to be 20-25 ℃, stirring and extracting; separating, and extracting the water phase with 750g of ethyl acetate; the organic phases were combined and washed once with a saturated aqueous salt solution; adding anhydrous sodium sulfate and drying; filtering and collecting filtrate; the ethyl acetate was concentrated under reduced pressure to give a residue of about 136 g. Adding 260g of ethyl acetate into the residue, stirring to uniformly disperse the ethyl acetate, adding 400g of petroleum ether, heating to 40-45 ℃, and stirring for 1 hr; cooling to 0-5 deg.C and maintaining for about 1-2 hr. Filtration, collection of the solid and drying gave 109A4-00 dry matter of about 124g (theoretical amount: 130.3 g). Yield: 95.1 percent.
Example Synthesis of allyl 42- [ (5-chloro-2-pyridine) amino ] -2-oxoacetate
Adding 1200g of ethyl acetate into a reaction bottle, adding 100g (777.8mmol) of 2-amino-5-chloropyridine, adding 83g (820.2mmol) of triethylamine, cooling to 0-5 ℃ by using brine ice, dropwise adding 120g (807.8mmol) of oxalyl chloride monoallyl ester, and controlling the temperature in the dropwise adding process to be not more than 10 ℃; after the dropwise addition, the deicing salt bath is removed, the temperature is naturally returned to the room temperature, and the mixture is stirred overnight. After the reaction, 600g of water is added, stirring and washing are carried out, an organic phase is separated out, and the organic phase is washed once by saturated saline solution; adding anhydrous sodium sulfate and drying; filtering and collecting filtrate; the ethyl acetate was concentrated under reduced pressure to give a residue of about 145 g. Adding 500g of petroleum ether into the residue, heating to 40-45 ℃, and stirring for about 1-2 hr; cooling to 0-5 deg.C and maintaining for about 1-2 hr. Filtering, collecting solid, drying to obtain about 130g (theoretical amount: 187.2g) of 109A4-00 dry product. Yield: 69.4 percent.
Example 52 Synthesis of allyl- [ (5-chloro-2-pyridine) amino ] -2-oxoacetate
Adding 1500g of ethyl acetate into a reaction bottle, adding 300g (2.334mol) of 2-amino-5-chloropyridine, cooling to 0-5 ℃ by using brine ice, dropwise adding 360g (2.423mol) of oxalyl chloride monoallyl ester, and controlling the temperature not to exceed 10 ℃ in the dropwise adding process; after the dropwise addition, the deicing salt bath is removed, the temperature is naturally returned to the room temperature, and the mixture is stirred overnight. After the reaction is finished, filtering, leaching with water, and collecting solid; dispersing the obtained solid in a mixed solution of 600g of ethyl acetate and 600g of water, controlling the temperature to be 20-25 ℃, dropwise adding a solution prepared from 205g (2.440mol) of sodium bicarbonate and 2200g of water, and adjusting the pH value to be 8; cooling to 0-5 ℃, and carrying out heat preservation and crystallization for about 3-4 hr; filtering, rinsing with petroleum ether, collecting solid, and drying to obtain about 431g (theoretical amount: 561.6g) of dried 109A 4-10. The yield thereof was found to be 76.7%.
Example Synthesis of 62- [ (5-chloro-2-pyridine) amino ] -2-oxoacetic acid allyl ester hydrochloride
Adding 500g of ethyl acetate into a reaction bottle, adding 100g (415.5mmol) of 109A4-00, cooling to 5-10 ℃, dropwise adding 45g (444.3mmol) of concentrated hydrochloric acid, and controlling the temperature not to exceed 15 ℃ in the dropwise adding process; after the dropwise addition, stirring at room temperature for about 6-8 hr. Cooling to 5-15 deg.C and keeping the temperature for about 1 hr. Filtration, rinsing with water, collection of the solid and drying gave about 96g (theoretical amount: 115.2g) of 109A4-10 as a dry product. The yield thereof was found to be 83.3%.
EXAMPLE 7 Synthesis of (1S) -3-cyclohexene-1-carboxylic acid- (. alpha.R) -a-methylbenzylamine salt
Adding 2300g of ethyl acetate and 70g of water into a reaction bottle, adding 500g (3.963mol) of 3-cyclohexene-1-formic acid, heating to 50-55 ℃, controlling the temperature not to exceed 65 ℃, and dropwise adding 480g (3.961mol) of (alpha R) -alpha-methylbenzylamine; after the dropwise addition, heating to 65-70 ℃ to completely dissolve the solid, stirring for 1hr, stirring overnight at room temperature, cooling to 0-5 ℃ and preserving heat for about 2-3 hr; filtering, collecting solid, and continuously separating the obtained wet product for 5-7 times by using ethyl acetate with the water content of about 3% (the dosage is about 2400 g-1500 g each time, and the dosage is correspondingly adjusted according to the quantity obtained after each separation and refining). The resolution is carried out until the specific rotation value of the product is about-40 degrees. The dried product was dried to obtain about 273g (theoretical amount: 490.1g) of 109B1-11 dried product. Yield: 55.7 percent.
(c=1,in methanol)。
Example 8 Synthesis of (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one
500g of acetonitrile is added into a reaction bottle, 250g (1.011mol) of 109B1-11 is added, the mixture is cooled to 0-5 ℃ by an ice salt bath, the temperature is controlled below 10 ℃, and 305g (1.067mol) of 5, 5-dimethyl dibromo hydantoin is added into the reaction system in batches. After the addition, the reaction is carried out for 1-2 hr at the temperature below 10 ℃, and then the mixture is stirred at room temperature overnight. After the reaction is finished, adding 500g of ethyl acetate into the reaction solution, then adding a solution prepared from 20g of anhydrous sodium thiosulfate and 500g of water, stirring, extracting, washing, standing, and separating liquid; the aqueous phase is extracted with 300g of ethyl acetate; the organic phases were combined and washed twice with saturated brine; concentrating the dry solvent under reduced pressure, adding 500g isopropanol into the residue, heating to 45-50 deg.C for dispersing, cooling to below 0 deg.C for crystallizing for 2-3 hr. Filtration was carried out, and the solid was collected and dried to obtain about 158g (theoretical amount: 207.3g) of a dried product of 109B 2-01. Yield: 76.2 percent.
Example 9 Synthesis of (1S, 3S, 4S) -4-bromo-3-hydroxy-N, N-dimethylcyclohexylformamide
Adding 660g of ethyl acetate into a reaction bottle, adding 150g (731.5mmol) of 109B2-01, cooling to 0-5 ℃ by using an ice salt bath, adding 330g (-2.93 mol) of 40% dimethylamine aqueous solution, and reacting for 24 hours at 0-5 ℃. After the reaction is finished, adding a solution prepared from 150g (713.8mmol) of citric acid monohydrate and 150g of water into the reaction solution; fully stirring, extracting, standing and separating liquid; the aqueous phase was extracted with further ethyl acetate (180g +90 g). Combining the organic phases; after concentration under reduced pressure, the residue 109B3-01 was fed in a theoretical amount (183.0g) without further purification.
EXAMPLE 10 Synthesis of (1S, 3S, 6R) -N, N-dimethyl-7-oxabicyclo [4.1.0] heptane-3-carboxamide
750g of methylene chloride was added to the residue of 109B3-01 (theoretical amount: 183.0g, 731.5mmol) obtained in example 9, and after stirring and dissolving completely, a solution of 41g of sodium hydroxide and 164g of water was added dropwise, and after completion of the addition, the mixture was reacted at 20 to 25 ℃ for 4 to 6 hours. After the reaction is finished, adding 90g of water into the reaction system, fully stirring, standing and separating liquid; the aqueous phase was extracted with additional dichloromethane (180g +90 g). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the dry dichloromethane was concentrated under reduced pressure to give about 113g (theoretical amount: 123.8g) of a residue 109B 4-01. Yield: 91.3 percent.
EXAMPLE 11 Synthesis of (1S, 3R, 4R) -3-amino-4-hydroxy-N, N-dimethylcyclohexylformamide
103.0g (608.7mmol) of 109B4-01 is added into a reaction bottle, 515g (-7.55 mol) of 25-28% concentrated ammonia water is added, and the mixture is heated to 40 ℃ for reaction for 10-12 hours. After the reaction was completed, the reaction mixture was directly concentrated to dryness under reduced pressure, and the residue 109B5-01 obtained was fed back in the theoretical amount (113.4g, 608.7mmol) without purification.
EXAMPLE 12 Synthesis of (1S, 3R, 4R) -3-amino-4-hydroxy-N, N-dimethylcyclohexylformamide hydrochloride
Referring to the preparation methods of examples 9 to 11, 242g (1.180mol) of 109B2-01 were charged to obtain 109B5-01 residue. Adding 500-600 g of toluene into the residue, heating, refluxing and water separating, concentrating dry toluene under reduced pressure after water separation is finished, cooling to 15-25 ℃, and adding 900g of ethyl acetate; stirring evenly, cooling to 0-5 ℃, dripping 190g (1.30 mol) of 25% hydrogen chloride ethanol solution, keeping the temperature at 0-5 ℃ after dripping, and stirring for crystallization for 2-3 hr. Filtration, rinsing with ethyl acetate, collection of the solid and drying gave about 233g (theoretical amount: 262.8g) of 109B5-11 as a dry product. Yield: 88.7 percent.
Example 13 Synthesis of (1S) -3-cyclohexene-1-carboxylic acid
Adding 3000g of methyl tert-butyl ether and 1000g of water into a reaction bottle, adding 500g (2.022mol) of 109B1-11 obtained by the preparation method of reference example 7, cooling to 10-20 ℃, controlling the temperature to be not more than 25 ℃, and dropwise adding 250g (-2.47 mol) of hydrochloric acid (-36%); after the dropwise addition is finished, keeping the temperature at 15-25 ℃ and stirring for about 3-5 hours; standing, separating, and washing the organic phase once by using 1000g (-1.37 mol) of 5% diluted hydrochloric acid aqueous solution; the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and methyl t-butyl ether was concentrated under reduced pressure to give about 258g (theoretical amount: 255.0g) of residue 109B 1-01. The yield is more than 100%.
Example 14 Synthesis of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one
1000g of dichloromethane are added into the residue 109B1-01 (theoretical amount: 255.0g, 2.022mol) obtained in example 13, after stirring and complete dissolution, a solution prepared by 135g (1.274mol) of sodium carbonate and 1350g of water is dripped, after dripping is finished, the temperature is reduced to 10-20 ℃, the temperature is controlled not to exceed 20 ℃, 540g (2.128mol) of elemental iodine is added in batches, and after finishing dripping, the temperature is kept for reaction for 3-5 hours. After the reaction is finished, adding a solution prepared from 500g (3.163mol) of sodium thiosulfate and 1500g of water into the reaction system, and fully stirring for about 1-2 hr; controlling the temperature to be not more than 45 ℃, and concentrating the dichloromethane in the system under reduced pressure until the dichloromethane is concentrated and dried; after the concentration is finished, cooling to 15-20 ℃, and carrying out heat preservation and crystallization for 2-3 hr. Filtration, washing of the filter cake with water, collection of the solid and drying gave about 473g (theoretical amount: 509.5g) of a dried 109B 2-L3. Yield: 92.8 percent.
Example 15 Synthesis of (1S, 3S, 4S) -4-iodo-3-hydroxy-N, N-dimethylcyclohexylformamide
With reference to the preparation of example 9, 120g (476.1mmol) of 109B2-L3 were charged; about 135g (theoretical amount: 141.5g) of 109B3-L3 was obtained. Yield: 95.4 percent.
EXAMPLE 16 Synthesis of (1S, 3S, 6R) -N, N-dimethyl-7-oxabicyclo [4.1.0] heptane-3-carboxamide
Referring to the preparation method of example 10, 130g (437.5mmol) of 109B3-L3 was charged; about 65g (theoretical amount: 74.0g) of 109B4-01 oil was obtained. Yield: 87.8 percent.
Example 17 Synthesis of N- [ [ [ (benzyloxy) carbonyl ] amino ] sulfonyl ] -N, N-diethylethanaminium inner salt (109E2-00)
Adding 400g of acetonitrile into a reaction bottle, adding 73g (675.1mmol) of benzyl alcohol, and cooling to-5-0 ℃ by using ice brine; dropwise adding 95g (671.2mmol) of chlorosulfonyl isocyanate, and controlling the temperature to be 0-5 ℃ in the dropwise adding process; after the dropwise addition, stirring for about 30-40 min under heat preservation (at the moment, the product is 109E 1-00); controlling the temperature to be not more than 5 ℃, dropwise adding 143g (1.413mol) of triethylamine, and after dropwise adding, keeping the temperature and stirring for about 30-40 min; and preserving the heat for later use. The resulting suspension of 109E 2-00/acetonitrile (Burgess-type reagent) was used in the next reaction in stoichiometric amounts (211.0g, 671.2mmol) without further work-up.
Example 18 Synthesis of benzyl N- [ [ [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2-hydroxycyclohexyl ] amino ] sulfonyl ] carbamate
400g of water are added to the residue 109B5-01 (theoretical amount: 113.4g, 608.7mmol) obtained in example 11, the mixture is cooled to-5 to 0 ℃, the temperature is controlled not to exceed 10 ℃, and a solution prepared from 36g (900.0mmol) of sodium hydroxide and 144g of water is added; after the addition is finished, cooling to 0-5 ℃; the Burgess-type reagent prepared in example 17 (109E 2-00/acetonitrile suspension) (theoretical amount: 211.0g, 671.2mmol) was then added in its entirety to the cooled 109B5-01 aqueous sodium hydroxide solution. After the addition, the temperature is kept at 0-5 ℃, and the stirring reaction is carried out for 2-4 hours. After the reaction is finished, adding a solution prepared from 165g (about 1.63mol) of 36% hydrochloric acid and 165g of water, and adjusting the pH value of the reaction solution to 2-3; after the adjustment is finished, adding 500g of ethyl acetate into the reaction system, and fully stirring and extracting; standing and separating liquid; the aqueous phase was extracted twice more with ethyl acetate (360g +240 g). Combining the organic phases; washing once with saturated brine; separating out an organic phase, drying with anhydrous sodium sulfate, filtering, collecting filtrate, and concentrating dry ethyl acetate under reduced pressure; to the residue obtained 1000g of dichloromethane were added, dried over anhydrous sodium sulfate, filtered and the filtrate was collected to give a 109E 3-01/dichloromethane solution which was dosed backwards in theoretical amounts (243.2g, 608.7mmol) without further treatment.
Example 19 Synthesis of benzyl N- [ [ [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2- [ (methylsulfonyl) oxy ] cyclohexyl ] amino ] sulfonyl ] carbamate
85g (840.0mmol) of triethylamine is added to the 109E 3-01/dichloromethane solution (theoretical amount: 243.2g, 608.7mmol) obtained in example 18, the mixture is cooled to-5-0 ℃ with brine ice, the temperature is controlled not to exceed 10 ℃, and 83g (724.6mmol) of methanesulfonyl chloride is added dropwise; after the dropwise addition, the temperature is kept at 5-10 ℃ for reaction for 2-3 hr. After the reaction is finished, adding 750g of water into the reaction system; cooling to-5-0 deg.c with ice salt water, maintaining the temperature and stirring for crystallization for 3-5 hr; filtration, rinsing with water, collection of the solid and drying gave about 223g (theoretical amount: 290.7g) of dried 109E 4-01. Yield: 76.7 percent.
Example 20 Synthesis of benzyl N- [ [ [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2-hydroxycyclohexyl ] amino ] sulfonyl ] carbamate
According to the preparation method in example 17, 154g (1.424mol) of benzyl alcohol was charged to obtain a 109E 2-00/acetonitrile suspension (Burgess-type reagent).
500g of water was added to a reaction flask, and 225g (1.006mol) of 109B5-11 obtained in example 12 was added; cooling to-5-0 ℃, controlling the temperature to be not more than 10 ℃, and adding a solution prepared from 115g (2.875mol) of sodium hydroxide and 230g of water; after the addition, the temperature was controlled not to exceed 5 ℃ and the 109E 2-00/acetonitrile suspension (Burgess-type reagent) prepared above was added in its entirety to 109B5-01 aqueous sodium hydroxide solution (109B5-11 was free as 109B 5-01); after the addition, the temperature is kept at 0-5 ℃, and the stirring reaction is carried out for 2-4 hours. After the reaction is finished, adding a solution prepared from 300g (about 2.96mol) of 36% hydrochloric acid and 300g of water, and adjusting the pH of the reaction solution to 2-4; after the adjustment is finished, adding 800g of ethyl acetate into the reaction system, and fully stirring and extracting; standing and separating liquid; the aqueous phase was extracted twice more with ethyl acetate (600g +400 g). Combining the organic phases; washing once with saturated brine; separating out an organic phase, drying with anhydrous sodium sulfate, filtering, collecting filtrate, and concentrating the dry solvent under reduced pressure; the residue 109E3-01 was obtained in an amount of about 524g (theoretical amount: 401.9 g). Yield: more than 100 percent, and feeding the materials backwards according to the theoretical amount.
Example 21 Synthesis of benzyl N- [ [ [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2- [ (methylsulfonyl) oxy ] cyclohexyl ] amino ] sulfonyl ] carbamate
Dissolving 109E3-01 (theoretical amount: 401.9g, 1.006mol) obtained in example 20 in 1200g of dichloromethane, adding anhydrous sodium sulfate, drying, filtering, collecting filtrate, adding 125g (1.235mol) of triethylamine, cooling to-5-0 ℃ with brine ice, controlling the temperature to be not more than 10 ℃, and dropwise adding 120g (1.048mol) of methanesulfonyl chloride; after the dropwise addition, the temperature is kept at 5-10 ℃ for reaction for 2-3 hr. After the reaction is finished, 1200g of water is added into the reaction system; cooling to-5-0 deg.c with ice salt water, maintaining the temperature and stirring for crystallization for 3-5 hr; filtration, rinsing with water, collection of the solid and drying gave about 438g (theoretical amount: 480.4g) of a dried 109E4-01 product. Yield: 91.2 percent.
EXAMPLE 22 Synthesis of benzyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate (109E7-01)
380g of acetonitrile was charged into a reaction flask, 190g (397.9mmol) of 109E4-01 obtained in example 19 was added, and 44.5g (439.8mmol) of triethylamine was added. Heating the reaction system to 58-62 ℃, and carrying out heat preservation reaction for 4-5 hr (after the intermediate state 109E5-01 is passed through 109E4-01, the intermediate state is converted into 109E 6-01); adding 160g (2.023mol) of pyridine/80 g (4.440mol) of water to prepare a solution, continuously heating to 80-85 ℃, and reacting for 4-5 hr (the ring opening of the intermediate state 109E6-01 is carried out through the intermediate state 109E7-X1, and part of the intermediate state 109E7-X2 is converted into the target product 109E 7-01); after the reaction is finished, cooling the reaction solution to room temperature, and adding a solution (with the concentration of about 50%) prepared by 48g (1.200mol) of sodium hydroxide and 48g of water while stirring; fully stirring to separate out solid; filtering, leaching a filter cake with acetonitrile, and collecting filtrate; concentrating the collected filtrate under reduced pressure to obtain residue, adding 500g of acetonitrile, heating to 30-40 ℃, and obtaining insoluble substances; then 100g of anhydrous sodium sulfate is added, and the mixture is stirred for about 1 hour at the temperature of 30-40 ℃; filtering with diatomite, leaching the filter cake with acetonitrile, and collecting the filtrate; the filtrate was concentrated to dryness to give an oil of about 135g (theoretical amount: 127.1 g). Yield: is greater than 100%.
Example 23 Synthesis of tert-butyl N- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- [ [ (benzyloxy) carbonyl ] amino ] cyclohexyl ] carbamate
Adding 720g tetrahydrofuran to the residue 109E7-01 (theoretical amount: 127.1g, 397.9mmol) obtained in example 22, cooling to 10-20 deg.C, controlling the temperature not to exceed 30 deg.C, adding 87g (398.6mmol) Boc anhydride, keeping the temperature at 20-30 deg.C, and stirring for reaction for about 1-2 hr; after the reaction is finished, concentrating tetrahydrofuran under reduced pressure; 800g of water were added to the residue, and the mixture was extracted twice with dichloromethane (500g +160 g); the dichloromethane phases are combined, washed once with 400g of water and dried over anhydrous sodium sulfate, filtered, the filter cake is rinsed with dichloromethane, the filtrates are combined and concentrated to dryness under reduced pressure, giving about 180g of oil (theoretical amount: 166.9 g). Yield: is greater than 100%.
Example 24 Synthesis of tert-butyl N- [ (1S, 2R, 4S) -2-amino-4- [ [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
To the residue 109E8-01 (theoretical amount: 166.9g, 397.9mmol) obtained in example 23 was added 800g of methanol, and stirred to dissolve, 18g of 10% Pd/C (water content: about 54.3%) was added; adding 52g (824.6mmol) of ammonium formate, stirring at room temperature for about 1hr, and heating to 50-55 deg.C until the reaction is completed; filtering, and leaching filter residues with a proper amount of methanol; the filtrate was collected and concentrated to dryness under reduced pressure to give about 135g (theoretical amount: 113.6g) of an oil. Yield: is greater than 100%.
Example 25 Synthesis of tert-butyl N- [ (1S, 2R, 4S) -2-amino-4- [ [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate monohydrate
600g of acetonitrile was added to the residue 109E9-01 (theoretical amount: 113.6g, 397.9mmol) obtained in example 24, and the mixture was stirred and heated to 30 to 40 ℃ to remove insoluble matter by filtration; collecting filtrate, and cooling to 15-25 ℃; controlling the temperature to be not more than 30 ℃, adding a solution prepared by 50.5g (400.6mmol) of oxalic acid dihydrate, 320g of acetonitrile and 50g of water into the collected and cooled filtrate, cooling to 5-10 ℃, preserving heat and stirring for about 2-3 hours; filtering, leaching a filter cake with acetonitrile/water, and collecting solid; the dried product 109E9-11 was obtained in an amount of about 128g (theoretical amount: 156.5 g). Yield: 81.8 percent.
Example 26 Synthesis of t-butyl N- [ (1S, 2R, 4S) -2-amino-4- [ [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate
90g (228.8mmol) of 109E9-11 prepared in example 25 were taken, the temperature was controlled at 80 to 90 ℃ and air-blast drying was carried out until the weight was constant, and about 86.1g (theoretical amount: 85.9g) of 109E9-21 as a dry product was obtained. Yield: -100%.
Example 27 Synthesis of benzyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate monohydrate
With reference to the procedure of example 22, 425g (890.0mmol) of 109E4-01 obtained in example 21 were charged, and the residue 109E7-01 (based on a theoretical amount: 284.3 g) was dissolved in 1500g of acetonitrile and cooled to 15 to 25 ℃; controlling the temperature to be not more than 30 ℃, and slowly adding a solution prepared by 115g (912.2mmol) of oxalic acid dihydrate, 750g of acetonitrile and 115g of water into the 109E 4-01/acetonitrile solution; cooling to 5-10 ℃, and stirring for 2-3 hr under heat preservation; filtering, leaching a filter cake with acetonitrile/water, and collecting solid; air-drying to obtain about 330g (theoretical amount: 380.4g) of 109E7-11 dry product. Yield: 86.8 percent.
EXAMPLE 28 Synthesis of benzyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate
280g (655.0mmol) of 109E7-11 prepared in example 27 were taken, temperature was controlled at 80-90 ℃ and air-blast dried to constant weight, yielding 109E7-21 as a dry product of about 265g (theoretical amount: 268.2 g). Yield: 98.8 percent.
EXAMPLE 29 Synthesis of (1S, 3R, 4R) -3-amino-4-hydroxy-N, N-dimethylcyclohexylformamide hydrochloride
Adding 80kg of ethyl acetate into a reaction kettle, adding 18.3kg (89.25mol) of 109B2-01, cooling to 0-5 ℃ by using an ice salt bath, adding 40kg (357.5 mol) of 40% dimethylamine aqueous solution, and reacting for 24 hours at 0-5 ℃. After the reaction is finished, adding a solution prepared from 18.3g (87.08mmol) of citric acid monohydrate and 20kg of water into the reaction solution; fully stirring, extracting, standing and separating liquid; the aqueous phase was extracted with a further 40kg of ethyl acetate. Combining the organic phases; controlling the temperature to be not more than 60 ℃, concentrating under reduced pressure, adding 36kg of toluene into the obtained residue, controlling the temperature to be not more than 65 ℃, and concentrating under reduced pressure to be dry. 75kg of dichloromethane is added into the residue, and after stirring and full dissolution, a solution prepared by 3.8kg (95.00mol) of sodium hydroxide and 15.2kg of water is added; keeping the temperature to be 20-25 ℃ and reacting for 4-6 hr. After the reaction, adding 12kg of water into the reaction system, fully stirring, standing and separating liquid; the aqueous phase is extracted with a further 36kg of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was collected and the dry dichloromethane was concentrated under reduced pressure. To the resulting residue was added 35kg (. about. 513.8mol) of aqueous ammonia (. about.25%); heating to 40-45 ℃, and stirring for reaction for about 4-5 hr; after the reaction is finished, controlling the temperature to be not more than 60 ℃, reducing the pressure by using a roots pump, and basically concentrating and drying the water; about 90kg of isopropanol was added to the resulting residue; controlling the temperature to be not more than 60 ℃, and concentrating the dry isopropanol under reduced pressure; adding about 45kg of toluene into the residue, controlling the temperature to be not more than 70 ℃, concentrating the dry toluene under reduced pressure, cooling the obtained residue to 0-10 ℃, and adding 60kg of ethyl acetate; stirring uniformly, filtering and collecting filtrate; cooling the collected filtrate to 0-5 ℃, dropwise adding 13.5kg (92.57 mol) of 25% hydrogen chloride ethanol solution, and controlling the temperature not to exceed 10 ℃ in the dropwise adding process; after the dropwise addition, cooling to 0-5 ℃, and carrying out heat preservation, stirring and crystallization for about 3-4 hr. And (3) performing spin-filtration, rinsing with a proper amount of ethyl acetate, collecting the solid, and drying to obtain about 16.89kg (theoretical amount: 19.88g) of a dried product 109B 5-11. Yield: 85.0 percent.
Example 30 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate monohydrate
The first process step: adding 18kg of acetonitrile into a reaction kettle, adding 3.2kg (43.17mol) of tert-butyl alcohol, and cooling to-5-0 ℃ by using brine ice; 6.1kg (43.10mol) of chlorosulfonyl isocyanate is dripped, and the temperature is controlled between 0 and 5 ℃ in the dripping process; after the dropwise addition, stirring for about 1hr under heat preservation; controlling the temperature to be less than or equal to 5 ℃, dropwise adding 9.2kg (90.92mol) of triethylamine, and after dropwise adding, keeping the temperature and stirring for about 1-2 hr; and preserving the heat for later use.
And a second step: adding 18kg of water into a reaction kettle, adding 4kg (100.0mol) of sodium hydroxide, stirring to completely dissolve, and cooling to-5-0 ℃; controlling the temperature to be not more than 5 ℃, and adding 8kg (35.92mol) of 109B5-11 obtained in example 29 in batches; after the addition, stirring for about 30 min; controlling the temperature to be not more than 5 ℃, and adding all Burgess-type reagents obtained in the first procedure into the reaction liquid; after the addition, the temperature is kept at 0-5 ℃, and the stirring reaction is carried out for 3-5 hours. After the reaction is finished, adjusting the pH value of the system to 3-4 by using 6N hydrochloric acid; after the adjustment is finished, adding 30kg of ethyl acetate into the reaction system, and fully stirring and extracting; standing and separating liquid; the aqueous phase was extracted with a further 30kg of ethyl acetate. Combining the organic phases; washed once with 20kg of saturated brine; the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate collected, and the dry solvent concentrated under reduced pressure to give a residue.
And a third step of: adding 40kg of dichloromethane into the residue obtained in the second step, adding 4.0kg (39.53mol) of triethylamine, cooling to-5-0 ℃ with brine ice, controlling the temperature to be not more than 10 ℃, and dropwise adding 4.3kg (37.54mol) of methanesulfonyl chloride; after the dropwise addition, the temperature is kept at 5-10 ℃ for reaction for 3-5 hr. After the reaction is finished, 50kg of water is added into the reaction system; cooling to-5-0 deg.c with ice salt water, maintaining the temperature and stirring for crystallization for 3-5 hr; filtering, rinsing with water, collecting solid, and drying to obtain about 9.16kg (theoretical amount: 15.93kg based on 8kg of intermediate 109B 5-11) of 109D4-01 dry product. Yield: 57.5 percent.
Step four: adding 20kg of acetonitrile and 9.15kg (20.63mol) of 109D4-01 obtained in the third step into a reaction kettle, and adding 2.3kg (22.73mol) of triethylamine; heating the reaction system to 58-62 ℃, and reacting for 4-5 hr under heat preservation; then 8.2kg (103.7mol) of pyridine is added, 4kg of water is added; continuously heating to 80-85 ℃, and reacting for 4-5 hr; after the reaction is finished, cooling the reaction liquid by 10-20 ℃, and adding a solution prepared from 2.5kg (62.50mol) of sodium hydroxide and 2.5kg of water under stirring; fully stirring to separate out solid; filtering, leaching a filter cake with acetonitrile, and collecting filtrate; concentrating the collected filtrate under reduced pressure to obtain residue, adding 52kg of acetonitrile, heating to 30-40 ℃, and keeping insoluble substances; filtering with diatomite, leaching the filter cake with acetonitrile, and collecting the filtrate; adding 2.65kg of water into the filtrate, and cooling to 10-15 ℃; 2.65kg (21.02mol) oxalic acid dihydrate are added; cooling to 0-5 ℃, and stirring for 3-5 hr; filtering and collecting solid; air-drying to obtain about 6.82kg of 109B9-11 dry product (theoretical amount: 8.12kg, calculated by feeding 9.15kg of intermediate 109D 4-01). Yield: 84.0 percent.
The total yield is as follows: 48.3% (calculated by feeding 8kg of intermediate 109B5-11, 109B9-11 theoretical amount: 14.13kg)
Example 31 Synthesis of benzyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate oxalate monohydrate
The first process step: adding 18kg of acetonitrile into a reaction kettle, adding 4.67kg (43.18mol) of benzyl alcohol, and cooling to-5-0 ℃ by using brine ice; 6.1kg (43.10mol) of chlorosulfonyl isocyanate is dripped, and the temperature is controlled between 0 and 5 ℃ in the dripping process; after the dropwise addition, stirring for about 1hr under heat preservation; controlling the temperature to be less than or equal to 5 ℃, dropwise adding 9.2kg (90.92mol) of triethylamine, and after dropwise adding, keeping the temperature and stirring for about 1-2 hr; and preserving the heat for later use.
And a second step: adding 18kg of water into a reaction kettle, adding 4kg (100.0mol) of sodium hydroxide, stirring to completely dissolve, and cooling to-5-0 ℃; controlling the temperature to be not more than 5 ℃, and adding 8kg (35.92mol) of 109B5-11 obtained in example 29 in batches; after the addition, stirring for about 30 min; controlling the temperature to be not more than 5 ℃, and adding all Burgess-type reagents obtained in the first procedure into the reaction liquid; after the addition, the temperature is kept at 0-5 ℃, and the stirring reaction is carried out for 3-5 hours. After the reaction is finished, adjusting the pH value of the system to 3-4 by using 6N hydrochloric acid; after the adjustment is finished, adding 30kg of ethyl acetate into the reaction system, and fully stirring and extracting; standing and separating liquid; the aqueous phase was extracted with a further 30kg of ethyl acetate. Combining the organic phases; washed once with 20kg of saturated brine; the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate collected, and the dry solvent concentrated under reduced pressure to give a residue.
And a third step of: adding 40kg of dichloromethane into the residue obtained in the second step, adding 4.0kg (39.53mol) of triethylamine, cooling to-5-0 ℃ with brine ice, controlling the temperature to be not more than 10 ℃, and dropwise adding 4.3kg (37.54mol) of methanesulfonyl chloride; after the dropwise addition, the temperature is kept at 5-10 ℃ for reaction for 3-5 hr. After the reaction is finished, 50kg of water is added into the reaction system; cooling to-5-0 deg.c with ice salt water, maintaining the temperature and stirring for crystallization for 3-5 hr; filtering, rinsing with water, collecting solid, and drying to obtain about 15.02kg (theoretical amount: 17.15kg, calculated by feeding 8kg of intermediate 109B 5-11) of 109E4-01 dry product. Yield: 87.6 percent.
Step four: adding 30kg of acetonitrile and 15.0kg (31.41mol) of 109E4-01 obtained in the third step into a reaction kettle, and adding 3.5kg (34.59mol) of triethylamine; heating the reaction system to 58-62 ℃, and reacting for 4-5 hr under heat preservation; then 12.5kg (158.0mol) of pyridine is added, and 6.3kg of water is added; continuously heating to 80-85 ℃, and reacting for 4-5 hr; after the reaction is finished, cooling the reaction liquid by 10-20 ℃, and adding a solution prepared from 3.81kg (95.25mol) of sodium hydroxide and 4.0kg of water under stirring; fully stirring to separate out solid; filtering, leaching a filter cake with acetonitrile, and collecting filtrate; concentrating the collected filtrate under reduced pressure to obtain residue, adding 80kg of acetonitrile, heating to 30-40 ℃, and obtaining insoluble substances; filtering with diatomite, leaching the filter cake with acetonitrile, and collecting the filtrate; adding 4.00kg of water into the filtrate, and cooling to 10-15 ℃; 4.00kg (31.73mol) oxalic acid dihydrate is added; cooling to 0-5 ℃, and stirring for 3-5 hr; filtering and collecting solid; air-drying to obtain about 11.13kg of 109E7-11 dry product (theoretical amount: 13.43kg based on 15kg of the intermediate 109E 4-01). Yield: 82.9 percent.
The total yield is as follows: 72.6% (calculated by feeding 8kg of intermediate 109B5-11, 109E7-11 theoretical amount: 15.35kg)
EXAMPLE 323 Synthesis of bromo-1-methyl-4-piperidone hydrobromide
Adding 40g of glacial acetic acid into a reaction bottle, controlling the temperature to be not more than 30 ℃, dropwise adding 22.6g (199.7mmol) of 1-methyl-4-piperidone, adding 18g of water, uniformly stirring, controlling the temperature to be not more than 25 ℃, dropwise adding a solution prepared from 32g (200.2mmol) of liquid bromine and 30g of glacial acetic acid, and after dropwise adding, keeping the temperature at 20-30 ℃ and stirring for reaction overnight; filtering, leaching a filter cake with ethyl acetate, and collecting a solid; drying to obtain about 29.2g (theoretical amount: 54.5g) of 109C1-10 dry product. Yield: 53.6 percent.
Example 333-Synthesis of bromo-1-methyl-4-piperidone hydrobromide
Adding 40g of glacial acetic acid into a reaction bottle, controlling the temperature to be not more than 25 ℃, dropwise adding 22.6g (199.7mmol) of 1-methyl-4-piperidone, and dropwise adding a solution prepared from 34g (201.7 mmol) of 48% hydrobromic acid aqueous solution and 40g of glacial acetic acid; controlling the temperature to be not more than 20 ℃, dropwise adding a solution prepared from 32g (200.2mmol) of liquid bromine and 30g of glacial acetic acid, and keeping the temperature at 20-25 ℃ to stir for reaction overnight after dropwise adding; filtering, leaching a filter cake with ethyl acetate, and collecting a solid; drying to obtain about 51.3g (theoretical amount: 54.5g) of dried 109C 1-10. Yield: 94.1 percent.
Example Synthesis of 344, 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridin-2-amine dihydrobromide salt
Adding 720g of n-propanol into a reaction bottle, adding 180g (659.4mmol) of 109C1-10, adding 53g (696.3mmol) of thiourea, heating the reaction solution to 95-100 ℃, and carrying out reflux reaction for about 30-36 hours; after the reaction is finished, cooling the reaction liquid to 5-10 ℃, and stirring for crystallization overnight; filtering, leaching a filter cake with n-propanol, and collecting a solid; drying to obtain about 159g (theoretical amount: 218.3g) of 109C2-10 dry product. Yield: 72.8 percent.
Example Synthesis of 354, 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridin-2-amine dihydrobromide salt
Adding 1600g of absolute ethyl alcohol into a reaction bottle, adding 409.5g (1.500mol) of 109C1-10, adding 125.6g (1.650mol) of thiourea, heating the reaction solution to 75-80 ℃, and carrying out reflux reaction for 42-48 hours; after the reaction is finished, cooling the reaction liquid to 5-10 ℃, and stirring for crystallization for 3-4 hr; filtering, leaching a filter cake with absolute ethyl alcohol, and collecting a solid; drying to obtain about 413g (theoretical amount: 496.6g) of dried 109C 2-10. Yield: 83.2 percent.
Example 364, Synthesis of 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridin-2-amine sulfate
625g of absolute ethyl alcohol is added into the reaction bottle; adding 125g (1.105mol) of 1-methyl-4-piperidone, and heating to 45-50 ℃; 93g (1.106mol) of 50% chloramine aqueous solution are added dropwise, and after the addition, 35.5g (1.107mol) of elemental sulfur are added. Dropwise adding a solution prepared from 8g (112.5mmol) of pyrrolidine and 80g of absolute ethyl alcohol; after the dropwise addition, the temperature is kept at 55-60 ℃ for reaction for 2-4 hr. After the reaction is finished, cooling the reaction liquid to 35-45 ℃, controlling the temperature to be not more than 60 ℃, and slowly dripping solution prepared by 120g (1.199mol) of concentrated sulfuric acid and 120g of water; after the dropwise addition is finished, heating the reaction solution to 70-75 ℃, and stirring for 1-2 hr under heat preservation; cooling to 0-5 deg.C, and maintaining the temperature for crystallization for about 2-4 hr. Filtering, leaching a filter cake with absolute ethyl alcohol, and collecting a solid; drying to obtain about 263g (theoretical amount: 295.3g) of dried 109C 2-20. Yield: 89.1 percent.
EXAMPLE 372 Synthesis of bromo-4, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine
2500g of water was charged into a reaction flask, 1275g (. about. 7.576mol) of a 48% aqueous hydrobromic acid solution was added, 500g (1.510mol) of 109C2-10 was added, and after stirring, 17.5g (78.35mmol) of copper bromide was added. Controlling the temperature to be less than 10 ℃, dropwise adding a solution prepared from 156g (2.266mol) of sodium nitrite/750 g of water, and after the dropwise adding is finished, keeping the temperature to be 20-25 ℃ for reaction for 3 hours. After the reaction is finished, controlling the temperature to be not more than 20 ℃, preparing a solution by using 410g (10.25mol) of sodium hydroxide and 820g of water, and adjusting the pH value of the system to be more than or equal to 13; extracted three times with toluene (1500 g.times.3); all organic phases are combined, dried by anhydrous sodium sulfate, filtered, filter residue is rinsed by toluene, filtrate is collected, and toluene is concentrated under reduced pressure to obtain about 247g of brown oily residue 109C3-00 (containing about 5-10% of 109C4-00, theoretical amount: 352.1 g). The yield thereof was found to be 70.2%.
Example Synthesis of 384, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine
Adding 245g (1.051mol)109C3-00 into a reaction bottle, adding 630g ethanol, and heating to 50-55 ℃ under stirring; controlling the temperature to be not more than 65 ℃, and dropwise adding a solution prepared from 376g (2.159mol) of sodium hydrosulfite and 1500g of water; after the dropwise addition, the temperature is kept at 65-70 ℃ for reaction for about 16-20 hr. After the reaction is finished, concentrating the ethanol under reduced pressure; cooling the obtained residue to 20-25 ℃, and adjusting the pH of a system to be 14 by using a solution prepared from 88g (2.200mol) of sodium hydroxide and 175g of water; extracted four times with toluene (750g × 4); the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filter residue rinsed with toluene, the filtrate was collected and the toluene was concentrated under reduced pressure to give an oily residue 109C4-00 of about 145g (theoretical amount: 162.1 g; the residue obtained can be used in the subsequent reaction without purification). The yield thereof was found to be 89.5%.
Example Synthesis of 394, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine
Adding 1350g of water into a reaction bottle, cooling by using brine ice, controlling the temperature to be not more than 30 ℃, and slowly dropwise adding 575g (5.746mol) of 98% sulfuric acid; after the dropwise addition, cooling to 15-20 ℃, and adding 252g (1.909mol) of 50% hypophosphorous acid aqueous solution; cooling to 10-15 ℃, and then adding 256g (957.7mmol) of 109C2-20 obtained in example 36; continuously cooling to-5-0 ℃, controlling the temperature not to exceed 5 ℃, and dropwise adding a solution prepared from 99g (1.435mmol) of sodium nitrite and 300g of water; after the dropwise addition, the temperature is kept at 5-10 ℃, and the stirring reaction is carried out for about 2-3 hours. After the reaction is finished, adjusting the pH of the system to 14 by using a solution prepared from 680g of sodium hydroxide and 1020g of water; after the adjustment is finished, adding toluene for extraction (800g multiplied by 2+600g +400 g); combining the organic phases, drying with anhydrous sodium sulfate, filtering, leaching with toluene, and collecting the filtrate; toluene was concentrated under reduced pressure to give an oily residue 109C4-00 of about 104.6g (theoretical amount: 147.7 g). The yield thereof was found to be 70.8%.
Example Synthesis of 404, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine p-toluenesulfonate
To a reaction flask was added 500g of isopropanol, 100g (648.4mmol) of 109C4-00 prepared in example 39; 125g (657.2mmol) of p-toluenesulfonic acid monohydrate were added; after the addition, heating to 40-50 ℃ to completely dissolve the materials, and keeping the temperature for about 1 hr; cooling to 0-5 ℃, and keeping the temperature for crystallization overnight. Filtering, leaching a filter cake with isopropanol, and collecting solid; drying to obtain about 126g (theoretical amount: 211.7g) of 109C4-10 dry product. Yield: and 59.5 percent.
100g of the 109C4-10 thus obtained was freed by alkalinization with sodium hydroxide, extracted with toluene and concentrated to dryness to give about 39.2g of 109C4-00 (theoretical amount: 47.25 g). Free yield: 83.0 percent.
Example Synthesis of 412, 2, 2-trichloro-1- (4, 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridin-2-yl) ethanone
Into a reaction flask, 700g of toluene was charged, and 140g (907.7mmol) of 109C4-00 obtained in example 38 was added; then 138g (1.364mol) of triethylamine is added, the temperature is controlled to be not more than 25 ℃, and 230g (1.265mol) of trichloroacetyl chloride is added dropwise; after the dropwise addition, the internal temperature is kept at 30-35 ℃ for reaction for about 2-4 hr. After the reaction is finished, cooling to 10-15 ℃, adding 700g of water into the reaction system, adding 140g (1.666mol) of sodium bicarbonate in batches, and stirring for about 20-30 min; standing and separating liquid; the aqueous phase was extracted with 300g of toluene, the organic phases were combined and washed with 2% aqueous sodium bicarbonate solution (300 g. times.2); drying with anhydrous sodium sulfate, filtering, leaching the filter residue with toluene, and collecting the filtrate; the toluene was concentrated under reduced pressure to give a residue 109C5-00 of about 259g (theoretical amount: 272.0 g). The yield thereof was found to be 95.2%.
Example 424 Synthesis of lithium salt of 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine-2-carboxylic acid
Into a reaction vessel were charged 200g (667.6mmol) of 109C5-00 obtained in example 41; and (3) under stirring, controlling the temperature to be not more than 25 ℃, adding a solution prepared from 70g (1.668mol) of lithium hydroxide monohydrate and 420g of water, keeping the temperature at 20-30 ℃, and stirring for reacting overnight. After the reaction is finished, adding toluene to extract impurities (200g multiplied by 3), and keeping a water phase; concentrating the aqueous phase under reduced pressure to obtain a residue; adding 400g of absolute ethyl alcohol into the residue, stirring and heating to 40-50 ℃ to completely dissolve the material; concentrating the ethanol under reduced pressure to obtain a residue; to the resulting residue was added 150g of tetrahydrofuran, and after dispersion with stirring, the mixture was concentrated to dryness under reduced pressure to give about 142g (theoretical amount: 136.3g) of residue 109C 6-10. Yield: > 100% (with part of the lithium hydroxide).
Example 434 Synthesis of hydrochloride salt of, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine-2-carboxylic acid
96g (451.3mmol, calculated from the theoretical yield) of 109C6-10 obtained in example 42 was charged into a reaction flask; adding 400g of absolute ethyl alcohol, stirring and heating to 40-50 ℃ under stirring to completely dissolve the materials; adding 12g of active carbon, stirring and decoloring for about 20min, carrying out hot filtration, leaching filter residues with absolute ethyl alcohol, and collecting filtrate; cooling the collected filtrate to 0-5 ℃, controlling the temperature not to exceed 5 ℃, and dropwise adding 96g (947.9 mmol) of 36% concentrated hydrochloric acid; keeping the temperature at 0-5 ℃ for crystallization for 2-3 hr. Filtering, leaching a filter cake with absolute ethyl alcohol, and collecting a solid; the dried product 109C6-20 (theoretical amount: 105.6g, calculated according to the theoretical yield) was obtained in an amount of about 73 g. Yield: 69.1 percent.
Example Synthesis of 444, 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridine-2-carboxylic acid hydrochloride
275g (1.783mol) of 109C4-00 obtained by the method described in example 38 was charged in a reaction flask, followed by 1350g of toluene; under stirring, 275g (2.718mol) of triethylamine is added, and 450g (2.475mol) of trichloroacetyl chloride is dropwise added at the temperature of 20-30 ℃; after the dropwise addition, the internal temperature is maintained at 30-40 ℃ for reaction for about 2-4 hr. After 109C4-00 is converted into 109C5-00, controlling the temperature not to exceed 30 ℃, and dropwise adding a solution prepared from 215g (5.124mol) of lithium hydroxide monohydrate and 1300g of water; after the dropwise addition, the temperature is kept at 20-25 ℃ for reaction overnight. Filtering, filtering to remove insoluble substances, collecting filtrate, standing, and separating; the separated aqueous phase was extracted with toluene to extract impurities (300 g. times.2); collecting the water phase, concentrating under reduced pressure to dryness, adding 1500g of absolute ethyl alcohol into the obtained residue, heating to 40-45 ℃ to completely dissolve the residue, and adding 50g of activated carbon to decolor; filtering, leaching the filter residue with about 300g of absolute ethyl alcohol, and combining the filtrates; cooling the filtrate to 0-5 ℃, controlling the temperature not to exceed 5 ℃, dripping 580g (about 5.727mol) of 36% concentrated hydrochloric acid, separating out solids, and carrying out heat preservation at-5-0 ℃ for crystallization for 2-3 hours; filtering, leaching a filter cake with absolute ethyl alcohol, and collecting a solid; air-drying to obtain about 303g (theoretical amount: 418.5g) of 109C6-20 dry product. Yield: 72.4 percent.
Example Synthesis of sodium salt of 454, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine-2-carboxylic acid
60g of water was added to the reaction flask, and 30g (100.1mmol) of 109C5-00 obtained in example 41 was added; and (3) under stirring, controlling the temperature to be not more than 25 ℃, adding a solution prepared from 10g (250.0mmol) of sodium hydroxide and 90g of water, keeping the temperature at 20-30 ℃, and stirring for reacting overnight. After the reaction is finished, adding toluene to extract impurities (400g multiplied by 3), and keeping a water phase; adding 13.5g (133.3mmol) of hydrochloric acid (36% aq.) into the water phase, and adjusting the pH value of the system to 12-13; the aqueous phase was concentrated under reduced pressure to give a residue, 300g of anhydrous ethanol was added to the residue, heated under reflux for about 20min, filtered hot to remove insoluble matter, the filtrate was collected, and the filtrate was concentrated to dryness to give a residue of 109C6-30 (theoretical amount: 22.0g) of about 19 g. Yield: 86.4% (wherein there may be a portion of the inorganic salt).
Example 46 Synthesis of tert-butyl [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- [ [ (4, 5, 6, 7-tetrahydro-5-methylthiazol [5, 4-c ] opyridin-2-yl) carbonyl ] amino ] cyclohexyl ] carbamate
Adding 32g (85.24mmol) of 109E9-21 into a reaction bottle, adding 160g of dichloromethane, adding 80g of water, cooling to 5-15 ℃, slowly adding a solution prepared from 25g (180.9mmol) of anhydrous potassium carbonate and 100g of water, stirring, extracting, standing and separating; the aqueous phase was extracted with more dichloromethane (80 g.times.2); mixing dichloromethane phases, adding anhydrous sodium sulfate, stirring and drying; filtering, leaching filter residues with dichloromethane, and collecting filtrate; adding 22g (217.4mmol) of triethylamine into the filtrate, stirring and cooling to 0-5 ℃; then 22g (93.74mmol) of 109C6-20, 14g (103.6mmol) of HOBt and 22g (114.8mmol) of EDCI.HCl are added; the temperature is returned to 20 to 25 ℃, and the stirring reaction is carried out for about 16 to 20 hours. After the reaction is finished, adding 10g (98.82mmol) of triethylamine into the reaction system, and adding 240g of water; stirring uniformly, standing and separating liquid; the aqueous phase was extracted with more dichloromethane (160g × 2); the organic phases were combined and dried over anhydrous sodium sulfate; filtration and collection of the filtrate gave a 109T 5-01/dichloromethane solution (without further treatment, 39.69g of theoretical amount charged further).
EXAMPLE 47 Synthesis of N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] -4, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride
250g (685.7 mmol) of 10% ethyl acetate hydrochloride solution is slowly dropped into the 109T 5-01/dichloromethane solution (theoretical amount: 85.24mmol) obtained in the example 46, and after dropping, the temperature is controlled to be 20-30 ℃ to react for about 30-60 min; controlling the temperature to be not more than 30 ℃, and concentrating excessive hydrogen chloride in the system under reduced pressure; filtering, leaching a filter cake with ethyl acetate, and collecting a solid; drying to obtain about 35.2g (theoretical amount: 37.37g) of dried 109T 6-21. Yield: 94.2 percent.
Example 48N1- (5-chloro-2-pyridyl) -N2- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- [ [ (4, 5, 6, 7-tetrahydro-5-methylthiazole [5, 4-c)]And pyridin-2-yl) carbonyl]Amino group]Cyclohexyl radical]Synthesis of oxalamide (Edoxaban)
Adding 360g of acetonitrile into a reaction bottle, adding 30g (68.43mmol) of 109T6-21, adding 21g (75.78mmol) of 109A4-10, controlling the temperature to be not more than 40 ℃, and dropwise adding 35g (345.9mmol) of triethylamine; after the dropwise adding is finished, heating to 65-75 ℃ and reacting for 6-8 hours; after the reaction is finished, cooling to 10-20 ℃, adding 720g of water into the reaction system, stirring uniformly, filtering, and leaching filter residues with 500g of dichloromethane; collecting the filtrate, adding 1000g of dichloromethane, and fully stirring and extracting; the aqueous phase was extracted once more with 600g of dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate; filtering, leaching filter residues with dichloromethane, collecting filtrate, and concentrating under reduced pressure to obtain residue; adding 40g of methanol into the residue, heating to 40-50 ℃ to uniformly disperse the methanol, cooling to 5-10 ℃, and carrying out heat preservation and crystallization for about 2-3 hours; filtering, leaching a filter cake with methanol, and collecting solid; drying to obtain about 33.3g (theoretical amount: 37.50g) of 109TM-01 dry product. Yield: 88.8 percent.
Example 49 Synthesis of benzyl N- [ (1R, 2S, 5S) -2- [ [2- [ (5-chloro-2-pyridinyl) amino ] -2-oxoacetyl ] amino ] -5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
900g of acetonitrile is added into a reaction bottle, 82g (200.3mmol) of 109E7-21 prepared in example 28 is added, 60g (249.3mmol) of 109A4-00 is added, the temperature is controlled not to exceed 40 ℃, and 65g (642.3mmol) of triethylamine is added dropwise; after the dropwise adding is finished, heating to 65-75 ℃ and reacting for 8-10 hr; after the reaction is finished, cooling to 10-20 ℃, adding 2000g of water into the reaction system, stirring uniformly, cooling to 5-10 ℃, and carrying out heat preservation and crystallization for about 2-3 hr; filtering, leaching a filter cake with water, and collecting solid; drying to obtain about 74.7g (theoretical amount: 100.5g) of a dried 109T7-01 product. Yield: 74.3 percent.
Example 50N1- [ (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl]Cyclohexyl radical]-N2Synthesis of (5-chloro-2-pyridyl) ethanediamide
To a reaction flask was added 200g of tetrahydrofuran, and 25g (49.80mmol) of 109T7-01 obtained in example 49 was added; stirring to dissolve, adding 3.0g of 5% Pd/C (water content about 59.1%); preserving the temperature at 20-30 ℃, dropwise adding 7.0g (129.3mmol) of 85% formic acid, and stirring at room temperature until the reaction is finished; filtering, leaching the filter residue with a proper amount of tetrahydrofuran; collecting the filtrate, adding a solution prepared from 10g of anhydrous potassium carbonate, 20g of sodium chloride and 70g of water into the filtrate, and stirring and washing; the organic phase was washed once more with 80g of saturated brine; dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated to dryness under reduced pressure to give 109T2-01 (theoretical amount: 18.32g) of about 18 g. Yield: 98.3 percent.
Example 51N1- [ (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl]Cyclohexyl radical]-N2Synthesis of (5-chloro-2-pyridyl) oxalamide hydrobromide
Add 15g (249.8mmol) glacial acetic acid to the flask, add 40g (237.3mmol) hydrobromic acid (. about.48% aq.), add 5g (9.961mmol)109T7-01 from example 49; heating to 40-50 ℃ until the reaction is finished; controlling the temperature to be not more than 50 ℃, concentrating the dry ice acetic acid and the hydrobromic acid in high vacuum to obtain a residue, adding ethyl acetate into the residue, and stirring and dispersing; filtration, rinsing of the filter cake with ethyl acetate and air drying gave about 4.7g of 109T 2-51.
Example 52N1- [ (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl]Cyclohexyl radical]-N2Synthesis of (5-chloro-2-pyridyl) oxalamide trifluoroacetate
75g (657.8mmol) of trifluoroacetic acid were added to a reaction flask, and 5g (9.961mmol) of 109T7-01 obtained in example 49 was added; heating to 60-70 ℃ until the reaction is finished; after the reaction is finished, cooling, controlling the temperature to be not more than 60 ℃, concentrating the dry trifluoroacetic acid under reduced pressure to obtain a residue, adding ethyl acetate into the residue, and stirring and dispersing; filtration, rinsing of the filter cake with ethyl acetate and air drying gave about 5.2g of 109T 2-61.
Example 53N1- (5-chloro-2-pyridyl) -N2- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2-[[(4,5,67-tetrahydro-5-methylthiazole [5, 4-c ]]And pyridin-2-yl) carbonyl]Amino group]Cyclohexyl radical]Synthesis of oxalamide (Edoxaban)
To 18g (48.93mmol) of the residue 109T2-01 obtained in example 50 was added 270g of acetonitrile, and the mixture was dissolved by stirring, added 12g (118.6mmol) of triethylamine, and cooled to 0 to 5 ℃ by stirring; then 12.6g (53.69mmol) of 109C6-20 and 10.5g (68.56mmol) of HOBt. H were added2O, 13.0g (67.81mmol) EDCI. HCl; stirring and reacting for about 20-24 hr at room temperature. After the reaction is finished, adding 180g of water into the reaction system; after stirring uniformly, filtering, removing insoluble substances, and leaching filter residues with 120g of dichloromethane; collecting the filtrate, adding 300g of dichloromethane, and fully stirring and extracting; the aqueous phase was extracted once more with 200g of dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate; filtering, leaching filter residues with dichloromethane, collecting filtrate, and concentrating under reduced pressure to obtain residue; adding 25g of methanol into the residue, heating to 40-50 ℃ to uniformly disperse the methanol, cooling to 5-10 ℃, and carrying out heat preservation and crystallization for about 2-3 hours; filtering, leaching a filter cake with methanol, and collecting solid; drying to obtain about 20.7g (theoretical amount: 26.82g) of dried 109TM-01 product. Yield: 77.2 percent.
Example 54N1- (5-chloro-2-pyridyl) -N2- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- [ [ (4, 5, 6, 7-tetrahydro-5-methylthiazole [5, 4-c)]And pyridin-2-yl) carbonyl]Amino group]Cyclohexyl radical]Synthesis of oxalamide tosylate monohydrate (Edoxaban tosylate hydrate)
Adding 120g of absolute ethyl alcohol into a reaction bottle, adding 60g of purified water, adding 28g (51.09mmol) of 109TM-01 obtained in example 48, stirring and dispersing uniformly, adding 10.2g (53.62mmol) of p-toluenesulfonic acid monohydrate, heating to 75-80 ℃ for complete dissolution, adding 3g of activated carbon, preserving heat, stirring and decoloring for about 20-30 min; filtering while hot, leaching filter residues with absolute ethyl alcohol, collecting filtrate, cooling to 0-5 ℃, and carrying out heat preservation and crystallization for about 2-3 hours; filtering, leaching a filter cake with 75% ethanol, and collecting a solid; the dried product was air-dried at about 40 ℃ to obtain about 34.2g (theoretical amount: 37.72g) of 109TM-11 dried product. Yield: 90.7 percent.