CN109942600B

CN109942600B - Preparation method of edoxaban

Info

Publication number: CN109942600B
Application number: CN201910298424.3A
Authority: CN
Inventors: 吕关锋; 肖江; 郭荣耀
Original assignee: Beijing Sihuan Kebao Pharmaceutical Co ltd; Inner Mongolia Jingdong Pharmaceutical Co ltd
Current assignee: Beijing Sihuan Kebao Pharmaceutical Co ltd; Inner Mongolia Jingdong Pharmaceutical Co ltd
Priority date: 2019-04-15
Filing date: 2019-04-15
Publication date: 2021-08-20
Anticipated expiration: 2039-04-15
Also published as: CN109942600A

Abstract

The invention relates to a new route and a new method for preparing an edoxaban p-toluenesulfonate hydrate and an intermediate thereof. The method comprises the following steps: compound 109A4x with high reactivity is prepared; compound 109C6x was prepared using a novel synthetic method; preparing novel compounds 109E8-01, 109E9x and 109T 7-01; and the intermediate is used for preparing the edoxaban p-toluenesulfonate hydrate. The new process and the new route avoid the need for a cryogenic reaction step and avoid the use of hazardous elemental sulfur and high risk n-butyllithium, high risk azide compounds. In a word, the method is more beneficial to the safe, simple and convenient industrial scale preparation of the edoxaban p-toluenesulfonate hydrate and the key intermediate thereof with effectively reduced cost.

Description

Preparation method of edoxaban

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a novel preparation method of an edoxaban hydrate p-toluenesulfonate and a key intermediate thereof. The structure of the p-toluenesulfonic acid edoxaban hydrate is as follows:

part of the key intermediate structures that have been reported at present are as follows:

the partial intermediate structure related to the invention is as follows:

background

Edoxaban p-toluenesulfonate hydrate, developed by Daiichi Sankyo corporation, was approved by the japan pharmaceutical and medical instruments integrated agency (PMDA) for sale on 2011, 4-22; 1 month 8 days 2015, approved by the U.S. Food and Drug Administration (FDA) for marketing; 6.19.2015, approved by the European drug administration (EMA) to market. Sold in Japan by the first Sanko corporation under the trade name of

Edoxaban p-toluenesulfonate is a direct anticoagulant factor Xa inhibitor. Can be used for treating venous thromboembolism of patients after total knee joint replacement, total hip joint replacement or hip joint fracture surgery.

For oral tablets, each tablet contains 15mg or 30mg edoxaban. The recommended dosage is 30mg per adult, 1 time per day. The indications include: stroke; stroke and systemic embolism; venous thromboembolism; deep vein thrombosis; ischemic stroke; pulmonary vascular obstruction.

The current main route for the preparation of Edoxaban tosylate hydrate is as follows:

109TM-11 route one (US2005119486A 1):

in the route, chiral amine compound 109B9-01 and lithium salt 109A3-10 of oxamide derivative are used for generating amide under the action of a condensing agent; removing Boc-protecting group under acidic condition; then the intermediate and 2-thiazole formic acid derivative lithium salt 109C6-10 are reacted to form amide under the condition of a condensing agent to prepare the edoxaban. Wherein chiral amine compound 109B9-01 requires the use of high-risk sodium azide, see the synthesis of route one, 109B9x, infra.

109TM-11 route two (US2005119486A 1):

in the method, chiral azide 109B8-01 is used as a starting material, Boc protection is removed, the chiral azide and 2-thiazole formic acid derivative lithium salt 109C6-10 form amide under the condition of a condensing agent, azido is reduced to form amino, and the amide and lithium salt 109A3-10 of oxamide derivative form amide under the action of the condensing agent, so that the edoxaban is prepared. Wherein chiral azide 109B8-01 requires the use of high-risk sodium azide, see the synthesis of route one, 109B9x, infra.

109TM-11 route III (US2009105491A 1):

this route is similar to the 109TM-11 route one, using three key intermediate classes 109B9x, 109Ax, 109C6x as corresponding more easily purified and higher quality derivative forms. Wherein, the 109B9-11 adopts oxalate hydrate, which greatly reduces the content of various diastereoisomers and enantiomers in the free alkali 109B9-01 and the content of chloro compounds and enamine derivatives in the free alkali; 109A1-10, the hydrochloride of the ethyl ester derivative is selected, compared with the lithium salt, the relatively expensive condensing agent (such as EDCI and HOBt) can be omitted, and the quality of the ethyl ester hydrochloride can be very high; the choice of 109C6-20, which is inherently well controlled in quality, is also easier and more accurate to stoichiometrically dose than the lithium salt. Therefore, various quality indexes of the final target product can be better controlled in the process of preparing edoxaban.

The main route of some key intermediates is as follows:

109Ax (US2005119486a 1):

the method uses 5-chloro-2-aminopyridine to react with oxalyl chloride monoethyl ester to obtain 109A1-10, obtains 109A1-00 through dissociation, obtains 109A2-00 through ester exchange, and obtains a corresponding lithium salt 109A3-10 form through lithium hydroxide hydrolysis; the above references to either the ethyl ester, methyl ester (or their corresponding hydrochloride salt forms), or lithium carboxylate salt forms are directly applicable to the preparation of edoxaban intermediates. Compared with the synthetic route of edoxaban shown above, the selection of the active ester form is more favorable for saving cost.

109B9x route one (US2005119486a 1):

the route takes racemic 3-cyclohexene-1-formic acid as a starting material, and after the resolution, separating (1S) -3-cyclohexene-1-formic acid, iodinating to obtain 109F1-01, under the alkaline condition, the lactone ring is opened through ester exchange and then the ring is closed to obtain an epoxy compound 109F3-01, the corresponding azide 109F4-01 is obtained after the ring is opened through sodium azide, the corresponding Boc-protected amino derivative 109F6-01 is obtained through Pd/C catalytic hydrogenation in the presence of Boc anhydride, the azide 109F8-01 is obtained through sulfonic acid esterification and sodium azide substitution, the corresponding carboxylic acid compound 109F9-01 is obtained through hydrolysis, the corresponding amide 109B8-01 is obtained by the reaction of dimethylamine hydrochloride and a condensing agent, and the corresponding amino compound 109B9-01 is obtained by the reduction of azide. The route realizes the synthesis of the epoxy compound 109F3-01 by adding expensive elementary iodine, wherein iodine only serves as a leaving group to achieve the function of chiral selection of an intermediate, is not irreplaceable, and is not suitable from the aspect of cost control; the azide intermediate obtained by the route by using high-risk sodium azide twice needs expensive Pd/C for catalytic reduction; and the introduction of the N, N-dimethylamide group takes place in a very subsequent step; for the above reasons, the route is very disadvantageous in terms of production safety control and cost reduction, and is not suitable for industrial-scale production.

109B9x route two (US2005119486a 1):

the route is a derivative of route one of 109B9 x; the deficiency of the first route of 109B9x is inherited, and the number of times of Pd/C catalytic hydrogenation is increased; for the above reasons, the route is very disadvantageous in terms of production safety control and cost reduction, and is not suitable for industrial-scale production.

109B9x route three (US2016016974a 1):

in the method, a Burgess-type reagent reacts with an amino compound 109B5-01 to obtain a sulfuryl diamide derivative 109D3-01, hydroxyl at the ortho position of the sulfamide is converted into sulfonic ester, the sulfonic acid ester is ingeniously converted into a ternary nitrogen heterocyclic derivative intermediate state, then rearrangement and ring expansion are carried out to obtain a compound 109D6-01, an intermediate 109B9-01 is obtained through hydrolysis, and the compound is purified through oxalate forming (including a hydrate thereof) to obtain a high-purity intermediate. The route adopts tert-butyl alcohol to prepare Burgess-type reagent, and we find out when studying the process that: in the preparation of 109D3-01, when the charging amount is on the scale of 5 kg-10 kg, the product 109D3-01 is easy to decompose in the post-treatment process, and the yield is greatly reduced, and the subsequent research shows that the result is caused because the tert-butyl sulfonylcarbamate group in the structure of the compound 109D3-01 is not very stable; therefore, the route needs much more detailed research in the process of realizing industrial mass production in order to achieve better effect.

109C6x route one (US2005119486a 1):

the method comprises the steps of reacting 4-aminopyridine serving as a starting material with Boc-anhydride to obtain 109H1-00, preparing a compound 109H2-00 by using combination of n-butyl lithium and elemental sulfur under a cryogenic condition, reacting with formic acid to obtain a thiazolopyridine compound 109H3-00, reacting with iodomethane to obtain a corresponding pyridine quaternary ammonium salt compound 109H4-10, reducing by sodium borohydride to obtain a corresponding reduction product 109C4-00, preparing a corresponding lithium carboxylate salt by using n-butyl lithium and carbon dioxide gas under the cryogenic condition again, neutralizing by hydrochloric acid and salifying to obtain the compound 109C 6-20. The route uses cryogenic conditions twice, uses expensive and easily ignited n-butyl lithium twice, needs flammable and explosive elemental sulfur, and needs to introduce carbon dioxide as a carboxylation source; during the process, the methyl iodide with extremely low boiling point and high cost is used as an N-alkylating reagent; the method has many hidden troubles from the perspective of production safety, is not beneficial to controlling the cost, and is not suitable for industrial scale production.

109C6x route two (US2005119486a 1):

the method comprises the steps of cyclizing N-Boc-4-piperidone serving as a starting material with cyanamide aqueous solution and elemental sulfur to obtain corresponding thiazolamine 109J1-00, converting amino into a corresponding bromide 109J2-00 through diazotization reaction by using tert-butyl nitrite and bromide, removing a Boc protecting group to obtain 109J3-00, reacting with iodomethane to obtain 109C3-00, preparing corresponding lithium carboxylate salt by using N-butyl lithium and carbon dioxide gas under a cryogenic condition, and neutralizing and salifying by using hydrochloric acid to obtain a compound 109C 6-20. In the route, due to the existence of Boc-protecting groups, relatively expensive tert-butyl nitrite is required to be used as a diazotization reagent, iodomethane with extremely low boiling point and high price is required to be used as an N-alkylation reagent, flammable and explosive elemental sulfur is required to be used, deep cooling conditions are required, expensive N-butyl lithium which is easy to catch fire is required, and the route has the defects of more hidden dangers from the aspect of production safety, is not beneficial to control cost and is not suitable for industrial scale production.

109C6x route three (US9233980B 2):

the method comprises the steps of cyclizing N-methyl-4-piperidone serving as a starting material with a cyanamide aqueous solution and elemental sulfur to obtain corresponding thiazolylamine 109C2-00, salifying with hydrobromic acid to obtain 109C2-10, converting amino into a corresponding bromide 109C3-00 through diazotization with sodium nitrite hydrobromic acid, preparing a corresponding lithium carboxylate salt from N-butyl lithium and carbon dioxide gas under a cryogenic condition, neutralizing with hydrochloric acid, and salifying to obtain a compound 109C 6-20. The route needs flammable and explosive elemental sulfur, needs cryogenic conditions and expensive and easily ignited n-butyllithium, has more hidden dangers from the viewpoint of production safety, is not beneficial to controlling the cost, and is not suitable for industrial scale production.

Disclosure of Invention

The invention provides a new synthetic route of p-toluenesulfonic acid edoxaban hydrate, and a corresponding intermediate is prepared; and the new intermediate is used for preparing the edoxaban p-toluenesulfonate hydrate. The method is characterized by comprising the following steps:

1) the preparation of a novel compound 109A4x (comprising 109A4-10 and free base 109A4-00) which has high reactivity as the compounds 109A1-00, 109A2-00 and 109A 3-10;

2) 3-cyclohexene-1-formic acid is used as an initial material, and subjected to salification resolution, halogenation, urethane exchange, dehydrohalogen acid and aminolysis ring-opening by (alpha R) -alpha-methylbenzylamine to obtain amino alcohol (or salification and purification by hydrogen chloride to obtain a corresponding hydrochloride) 109B5 x; wherein X represents halogen;

3) reacting benzyl alcohol, chlorosulfonyl isocyanate and triethylamine to prepare a Burgess-type reagent;

4) carrying out sulfonylation amination, sulfonylation esterification, ternary nitrogen hybridization, rearrangement into five-membered ring, hydrolysis and Boc-protection on a Burgess-type reagent and 109B5x to obtain a compound 109E8-01, removing Cbz-protection to obtain 109E9-01, and carrying out salt formation and purification with oxalic acid to obtain 109E9 x; wherein R2 represents C1-C4 straight or branched chain alkyl, phenyl or substituted phenyl;

5) taking a compound 1-methyl-4-piperidone as a raw material, and performing bromination, cyclization with thiourea, diazotization bromination, reduction debromination, Friedel-crafts acylation and trihaloketone hydrolysis reaction to obtain a corresponding carboxylic acid derivative 109C6 x;

6) taking a compound 109E9x (comprising free alkali and oxalate or oxalate hydrate thereof) as a raw material, condensing with a compound 109C6x, removing Boc-protection, carrying out amidation reaction with a compound 109A4x to obtain Edoxaban free alkali, and salifying with p-toluenesulfonic acid monohydrate in the presence of water to prepare p-toluenesulfonic acid Edoxaban hydrate;

7) taking 109E7x (including free alkali and oxalate or oxalate hydrate thereof) as a raw material, carrying out amidation reaction with a compound 109A4x, removing a Cbz-protecting group, carrying out condensation reaction with a compound 109C6x to obtain edoxaban free alkali, and salifying with p-toluenesulfonic acid monohydrate in the presence of water to prepare p-toluenesulfonic acid edoxaban hydrate;

wherein:

the method for preparing the compound 109A4x in the step 1) has the reaction temperature of 0-60 ℃, and preferably 0-10 ℃.

The method for preparing the compound 109B5x and the salt thereof in the step 2) is to remove the residual water out of the system, preferably toluene, in an azeotropic manner by adding a solvent such as toluene, acetonitrile, ethanol, isopropanol, butanol or any ratio combination thereof after obtaining the compound 109B 5-01; dissolving the residue with ethyl acetate, and adding hydrogen chloride/lower alcohol solution, preferably hydrogen chloride/ethanol solution; salifying to obtain the high-purity compound 109B 5-11.

The method for preparing the compound 109E2x in the step 3) comprises the steps of reacting benzyl chlorosulfonylaminocarboxylate with fatty tertiary amine to obtain inner salt, namely a Burgess-type reagent; wherein R is₂₁，R₂₂，R₂₃Represents a C1-C4 linear or branched alkyl group, preferably ethyl, i.e. triethylamine; the reaction solvent is selected from acetonitrile, dichloromethane and ethyl acetate, preferably acetonitrile.

In the method for preparing the compound 109E4x, the compound 109E7x, and the compound 109E9x in the step 4), the sulfonylation reagent used for preparing the compound 109E4x is C1-C4 low-carbon alkyl sulfonyl chloride, benzene sulfonyl chloride or substituted benzene sulfonyl chloride (such as o-chlorobenzene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, and p-toluene sulfonyl chloride), preferably methyl sulfonyl chloride, that is, R is R₂Preferably methyl; salifying and purifying the compound 109E7x and the compound 109E9x, and selecting oxalic acid to obtain corresponding oxalate or oxalate hydrate; the catalyst for removing Cbz-protection is Pd/C, Pd (OH)₂/C、PdCl₂Etc., preferably Pd/C; ammonium formate and H are selected as hydrogen source₂Formic acid, etc., preferably ammonium formate.

In the method for preparing the compound 109C2-10, the compound 109C4-00 and the compound 109C6x in the step 5), the alpha-bromocarbonyl compound 109C1-10 and thiourea are heated and cyclized in methanol, ethanol, n-propanol, isopropanol and butanol to obtain the compound 109C2-10, preferably ethanol; the debromination preparation compound 109C4 is selected from reducing sulfite or reducing for catalytic hydrogenation, preferably sodium hydrosulfite (sodium hydrosulfite); compound 109C5-00 can be isolated or the corresponding 109C6x can be prepared directly afterwards without isolation.

The method for preparing the compound of the hydrate of the compound of the paratoluene sulfonic acid edoxaban in the step 6) comprises the step of carrying out condensation reaction on 109E9x serving as a raw material and 109C6x to obtain a compound 109T5-01, wherein the compound represented by the general formula 109E9x is preferably a free base thereof, namely 109E9-01, and the compound represented by the general formula 109C6x is preferably a hydrochloride thereof, namely 109C 6-20; after de-Boc-protection, amidation reaction with 109A4x (i.e. 109A4-00 or its hydrochloride salt 109A4-10) gives Edoxaban free base.

The method for preparing the compound of the hydrate of the compound of the paratoluene sulfonic acid of step 7) comprises the steps of carrying out amidation reaction on 109E7x serving as a raw material and 109A4x (namely 109A4-00 or hydrochloride thereof 109A4-10) to obtain a compound 109T7-01, and then removing a Cbz-protecting group to obtain 109T2 x; then amidation reaction is carried out with compound 109C6x to obtain the edoxaban free base. The method for removing Cbz-protection comprises the following steps:

firstly, heterogeneous catalytic deprotection: the noble metal catalyst is Pd/C, Pd (OH)₂/C、PdCl₂Etc. the hydrogen source is formic acid, ammonium formate or H₂Etc., preferably a Pd/C + formic acid combination;

secondly, homogeneous deprotection: trifluoroacetic acid, a combination of palladium chloride, triethylsilane and dichloromethane, a combination of hydrobromic acid and glacial acetic acid, and a combination of iodotrimethylsilane, triethylamine and acetonitrile, preferably trifluoroacetic acid; 109T2x wherein HB represents the acid that forms a salt after Cbz-deprotection, as follows: hydrobromic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid; r is 1 or 2.

In conclusion, the invention adopts a new synthetic route and a new method to prepare the new intermediate of edoxaban and uses the intermediate to prepare the edoxaban p-toluenesulfonate hydrate.

Firstly, preparing a high-reactivity intermediate 109A4x for synthesizing a paratoluenesulfonic acid edoxaban hydrate; both in its free base form and its hydrochloride form, are highly reactive in subsequent urethane exchange reactions.

Secondly, preparing intermediates 109E7x and 109E9x for synthesizing the edoxaban p-toluenesulfonate hydrate; and the p-toluenesulfonic acid edoxaban hydrate is prepared by the method, 109A4x and 109C6x in different docking modes. Compared with the compound 109D3-01 involved in the third route of 109B9x, the intermediate 109E3-01 involved in the process of preparing the compound 109E7x and the compound 109E9x has more stable structure of 109E3-01 per se, is easier to implement in large-scale industrial production process, the yield can also be kept stable, and the obtained product has better quality, thereby influencing the yield and quality of the subsequent sulfonate 109D4-01 and the corresponding 109E 4-01: on a scale up to 5 kg-10 kg at 109B5-11, a molar yield of 57.5% of 109D4-01 was obtained by parallel control experiments (see examples 30 and 31), while the corresponding molar yield of 109E4-01 was 87.6%. In the post-treatment process of preparing 109E7-01, the invention adopts a simpler post-treatment method, avoids the method of thermally extracting the product by using toluene in the document US2016016974A1, because the reaction system contains pyridine, triethylamine, sodium hydroxide and other materials with malodor or high corrosivity, if the thermal extraction method in the document is adopted, safety accidents can easily happen without paying attention, and the volatile organic compounds are difficult to avoid being dissipated into the atmosphere to cause pollution in the thermal extraction process. By adopting the method for preparing the chiral amine intermediate, the use of high-risk sodium azide can be avoided, and the use of expensive Pd/C catalyst can be reduced as much as possible.

Thirdly, preparing an intermediate 109C6x for synthesizing the edoxaban p-toluenesulfonate hydrate by adopting a new route and a new method; in the invention, the alpha-bromoketone intermediate and thiourea are adopted to prepare corresponding thiazolamine 109C2-10 by cyclization, thereby avoiding using flammable and explosive elemental sulfur; in the preparation of 109C4-00, although the invention needs to be brominated and adopts a method of reduction debromination by sodium hydrosulfite, the high-purity 109C4-00 is directly obtained, and salt-forming purification and dissociation are not needed, so that the product can be directly used for the next reaction; the total yield of diazotization bromination and sodium hydrosulfite reduction reaches 62.8 percent; if the thiazolamine sulfate 109C2-20 is used for directly deaminating by using a hypophosphorous acid aqueous solution after diazotization, the purity of 109C4-00 directly obtained is not high enough, the salt is required to be dissociated again after purification, and the obtained product can be used, and the total yield of the three steps of deamination, salt formation and dissociation is 35.0 percent; the improved process of the present invention is more advantageous by comparison with the control (see comparative data for examples 37 to 38 and examples 39 to 40). In addition, the method of removing ammonia by using a hypophosphorous acid aqueous solution after diazotization needs a large amount of sulfuric acid as a reaction solution, and the reaction solution can generate a large amount of viscous oily substances, so that extraction and liquid separation are very difficult; greatly increases the waste water and the waste liquid, and is not friendly to the environment.

Abbreviations:

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 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.

Claims

1. A preparation method of an Edoxaban hydrate, namely 109TM-11, tosylate is characterized by comprising the following steps:

1) reacting oxalyl chloride monoallyl ester with 2-amino-5-chloropyridine through N-amidation reaction to obtain hydrochloride a-1 or free alkali a-0 of the corresponding amide;

2) 3-cyclohexene-1-formic acid is used as a starting material, 109B1-11 is obtained through a (alpha R) -alpha-methylbenzylamine salification resolution reaction, stereoselective addition and intramolecular esterification are carried out on the starting material and a halogenated reagent to obtain corresponding halogenated cyclized lactone 109B2x, urethane exchange reaction and ring opening are carried out on the corresponding halogenated cyclized lactone and a dimethylamine aqueous solution to obtain amide 108B3x, hydrohalic acid is removed in molecules under the action of alkali to obtain an epoxy compound 108B4-01, amino alcohol is obtained through ammonolysis ring opening, or salt is formed with hydrogen chloride to obtain a corresponding hydrochloride derivative 109B5 x; wherein X represents halogen bromine or iodine; wherein b is 0 or 1;

3) carrying out alcoholysis reaction on benzyl alcohol and chlorosulfonyl isocyanate to obtain 109E1-00, and reacting with fatty tertiary amine to obtain inner salt to obtain a corresponding Burgess-type reagent 109E2 x; wherein R is₂₁，R₂₂，R₂₃Represents a C1-C4 linear or branched alkyl group;

4) carrying out sulfonylation reaction on a Burgess-type reagent 109E2-00 and 109B5x to obtain 109E3-01, carrying out sulfonylation esterification reaction on the Bugess-type reagent and substituted sulfonyl chloride to obtain corresponding sulfonic ester 109E4x, rearranging the sulfonic ester and ortho-position sulfonamide into a five-membered ring 109E6-01 through a ternary nitrogen heterocyclic intermediate state 109E5-01 under the alkaline condition, carrying out hydrolysis reaction to obtain 109E7x, carrying out Boc protection to obtain 109E8-01, removing Cbz-protection to obtain 109E9-01, and carrying out salt formation and purification on the sulfonic ester and the oxalic acid to obtain 109E9 x; wherein R is₂Represents C1-C4 straight chain or branched chain alkyl, phenyl; compound 109E7x with compound 109E9x having the formula: m is 1; compound 109E7x with compound 109E9x having the formula: p is more than or equal to 0 and less than or equal to 2;

5) taking a compound 1-methyl-4-piperidone as a raw material, carrying out bromination reaction to obtain an alpha-bromo carbonyl compound 109C1-10, cyclizing the alpha-bromo carbonyl compound with thiourea to obtain a corresponding 2-aminothiazole derivative 109C2-10, carrying out diazotization bromination reaction to obtain 109C3-00, carrying out reduction reaction to remove bromine to obtain 109C4-00, carrying out Friedel-crafts acylation reaction to obtain 109C5-00, and hydrolyzing a trihaloketone compound by adopting a haloform reaction to obtain a corresponding carboxylic acid derivative 109C6 x; wherein, in the formula 109C6x, when R is₃When H, c is 1; when R3 is Li⁺Or Na⁺When c is 0;

6) carrying out condensation reaction on a compound 109E9x, including oxalate or oxalate hydrate thereof, serving as a raw material and a compound 109C6x to obtain a compound 109T5-01, removing a Boc-protecting group to obtain 109T6x free alkali or a corresponding salt form, carrying out amidation reaction on the free alkali and a compound 109A4x to obtain edoxaban free alkali, and salifying the free alkali and p-toluenesulfonic acid monohydrate in the presence of water to prepare p-toluenesulfonic acid edoxaban hydrate; wherein, m in the general formula of 109E9xEnclosing: m is 1; 109E9x formula wherein p ranges: p is more than or equal to 0 and less than or equal to 2; in the formula 109C6x, when R is₃When H, c is 1; when R3 is Li⁺Or Na⁺When c is 0; in the general formula 109T6x, HB represents hydrochloric acid and methanesulfonic acid used for removing Boc protection; q is 1 or 2;

7) or taking a compound 109E7x, including oxalate or oxalate hydrate thereof, as a raw material to perform amidation reaction with a compound 109A4x to obtain a compound 109T7-01, removing a Cbz-protecting group to obtain 109T2x, performing condensation reaction with the compound 109C6x to obtain edoxaban free base, and salifying the edoxaban free base and p-toluenesulfonic acid monohydrate in the presence of water to prepare the p-toluenesulfonic acid edoxaban hydrate; wherein m ranges in the formula 109E7 x: m is 1; 109E7x formula wherein p ranges: p is more than or equal to 0 and less than or equal to 2; in the formula 109C6x, when R is₃When H, c is 1; when R3 is Li⁺Or Na⁺When c is 0; in the general formula of 109T2x, HB represents hydrobromic acid, trifluoroacetic acid, hydrochloric acid and methanesulfonic acid which form salts after Cbz-protection removal; r is 1 or 2;

2. the process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 1): oxalyl chloride monoallyl ester and 2-amino-5-chloropyridine are subjected to N-amidation reaction to obtain hydrochloride or free alkali of corresponding amide; the reaction solvent is ethyl acetate, acetonitrile, tetrahydrofuran and toluene; the reaction temperature is 0-60 ℃.

3. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 2): compound 109B5x was obtained, B ═ 0, and residual water was removed azeotropically by addition of toluene, acetonitrile, ethanol, isopropanol, butanol, or any combination thereof; dissolving the residue with ethyl acetate, and adding hydrogen chloride/ethanol solution; salification gave compound 109B5x, B ═ 1.

4. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 3): after preparing benzyl chlorosulfonylaminocarboxylate, reacting the benzyl chlorosulfonylaminocarboxylate with fatty tertiary amine to obtain inner salt, namely Burgess-type reagent 109E2 x; wherein R is₂₁，R₂₂，R₂₃Represents a C1-C4 linear or branched alkyl group; the reaction solvent is acetonitrile, dichloromethane or ethyl acetate

5. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 4): the sulfonylating reagent used for preparing the compound 109E4x is C1-C4 straight-chain or branched alkyl sulfonyl chloride, benzene sulfonyl chloride; salifying and purifying compound 109E9x, and using oxalic acid to obtain the corresponding oxalate or oxalate hydrate, wherein m in the oxalate general formula of compound 109E9x is within the range: m is 1; the oxalate salt of compound 109E9x has the formula p range: p is more than or equal to 0 and less than or equal to 2; the catalyst for removing Cbz-protection is Pd/C, Pd (OH)₂/C、PdCl₂(ii) a The hydrogen source is ammonium formate, H₂Formic acid

6. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 5): heating and cyclizing the alpha-bromocarbonyl compound 109C1-10 and thiourea in methanol, ethanol, n-propanol, isopropanol and butanol to obtain a compound 109C 2-10; by havingPreparing a compound 109C4-00 by original sulfite or catalytic hydrogenation reduction debromination; the compound 109C5-00 can be separated, or the corresponding 109C6x can be prepared directly afterwards without separation; wherein, in the formula 109C6x, when R is₃When H, c is 1; when R3 is Li⁺Or Na⁺When c is 0

7. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 6): carrying out condensation reaction on 109E9x serving as a raw material and a compound 109C6x to obtain a compound 109T5-01, wherein the general formula 109E9x represents 109E 9-01; formula 109C6x represents the hydrochloride salt, i.e., 109C 6-20; removing Boc-protecting group, and performing amidation reaction with 109A4x to obtain edoxaban free base.

8. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 7): carrying out amidation reaction on 109E7x serving as a raw material and a compound 109A4x, free alkali 109A4-00 or hydrochloride 109A4-10 thereof to obtain a compound 109T7-01, and removing a Cbz-protecting group to obtain 109T2 x; the method for removing Cbz-protection comprises the following steps:

1) heterogeneous catalytic deprotection: the noble metal catalyst is Pd/C, Pd (OH)₂/C、PdCl₂The hydrogen source is formic acid, ammonium formate, H₂；

2) Homogeneous deprotection: trifluoroacetic acid, a combination of palladium chloride, triethylsilane and dichloromethane, a combination of hydrobromic acid and glacial acetic acid, and a combination of trimethyliodosilane, triethylamine and acetonitrile; in the general formula of 109T2x, HB represents hydrobromic acid, trifluoroacetic acid, hydrochloric acid and methanesulfonic acid which form salts after Cbz-protection removal; r is 1 or 2

9. The process for preparing edoxaban-p-toluenesulfonate hydrate 109TM-11 according to claim 1, characterized by step 6) or step 7): adding paratoluenesulfonic acid monohydrate into a mixed solution of ethanol and water, heating until the mixture is completely dissolved, adding activated carbon for decoloring, carrying out hot filtration, collecting filtrate, cooling and crystallizing to obtain the paratoluenesulfonic acid edoxaban hydrate; wherein the solvent used for salifying is a mixed solution of ethanol and water, and the ratio of ethanol to water is 0.5-3.0: 1.0; the total solvent amount is 3.0-10.0: 1.0; the dissolving temperature is 50-100 ℃ during salification.