CN111170893B - Lefamulin intermediate compound and application thereof in preparation of Lefamulin - Google Patents

Lefamulin intermediate compound and application thereof in preparation of Lefamulin Download PDF

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CN111170893B
CN111170893B CN202010057204.4A CN202010057204A CN111170893B CN 111170893 B CN111170893 B CN 111170893B CN 202010057204 A CN202010057204 A CN 202010057204A CN 111170893 B CN111170893 B CN 111170893B
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lefamulin
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张俊杰
白晓光
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Zhengzhou Yimihua Chiral Medicine Research Co ltd
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
    • C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
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Abstract

The invention discloses an intermediate compound of Lefamulin and application thereof in Lefamulin preparation, aiming at solving the technical problems of high Lefamulin preparation cost and low yield in the prior art. The invention provides an intermediate compound
Figure DEST_PATH_IMAGE002
And a preparation method thereof, and an application of the intermediate compound in the preparation of Lefamulin or Lefamulin-related medical intermediates. The invention overcomes the defects of low conversion rate of the target compound, high cost and difficult industrial production caused by the lack of chiral induction of chiral oxidation in the production process in the prior art; the production cost can be effectively reduced during industrial application, the generation of three wastes can be effectively controlled, and the method has obvious economic benefit and social benefit.

Description

Lefamulin intermediate compound and application thereof in preparation of Lefamulin
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to an intermediate compound of Lefamulin and application of the intermediate compound in Lefamulin preparation.
Background
Lefamulin (acetate) was developed by Nabriva Therapeutics and obtained as a commercial antibiotic approved by the U.S. Food and Drug Administration (FDA) on 19.8.2019 under the trade name Xenleta. Lefamulin is a pleuromutilin antibacterial agent used for treating community-acquired pneumonia (CABP) caused by susceptible microorganisms in adults. The antibacterial mechanism of Lefamulin is: bacterial protein synthesis is inhibited by interaction with the A-and P-positions of the Peptidyl Transferase Center (PTC) in the 23S RNA domain of the bacterial ribosomal 50S subunit. This makes it less prone to drug resistance development. Compared with beta-lactam antibiotics, quinolones, glycopeptides, macrolides and tetracycline antibiotics, Lefamulin has no cross resistance and has wide development and popularization prospects.
Chinese patent document CN104211624A and other related crystal form preparation patent documents describe the following Lefamulin preparation synthetic route:
Figure DEST_PATH_IMAGE001
；
however, in production practice, the preparation method has a long reaction route, wherein when a chiral functional group is constructed, epoxidation is performed to achiral induced oxidation, the selectivity is very low, the chiral purity requirement can be met through repeated recrystallization, and the industrial production of Lefamulin is severely restricted.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel intermediate compound capable of being used for preparing Lefamulin, and to open up a new synthetic preparation way for Lefamulin; so as to solve the technical problems of high preparation cost and low yield of Lefamulin in the prior art.
The inventor researches and discovers that: in the existing preparation route of Lefamulin, when double bond epoxidation is carried out from a cyclohexene structure to cyclohexene oxide, only conventional oxidant reaction is used, chiral induction is not carried out, and the obtained product has a chiral structure: the diastereoisomer is 85:15, and the content of the target product is 85%; the method needs repeated recrystallization in the purification process, the molar yield is sharply reduced to 30 percent, and the industrial production of Lefamulin is severely restricted.
In order to solve the technical problems, the invention specifically adopts the following technical scheme:
designing an intermediate compound, wherein the structural formula of the intermediate compound is as follows:
Figure 563732DEST_PATH_IMAGE002
；
in the formula, the R1Selected from: hydrogen, trifluoroacetyl radicalOr alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the X is selected from: any one of fluorine, chlorine, bromine and iodine;
the R is3Selected from: hydrogen, or any one of a silane group, an alkyl ether, and an acyl protecting group; wherein the content of the first and second substances,
the silyl protecting group is any one of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;
the alkyl ether protecting group is any one of benzyl, p-methoxybenzyl, methoxymethyl, 2-tetrahydropyran, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl and allyl;
the acyl protecting group is any one of acetyl, propionyl, benzoyl and pivaloyl.
The preparation method of the intermediate compound comprises the following steps:
(1) a radical R3Introducing the compound with the structure of the formula (II) to obtain a compound with the structure of the formula (III):
Figure DEST_PATH_IMAGE003
→
Figure 667823DEST_PATH_IMAGE004
；
the R is3Selected from: hydrogen, or any one of a silane group, an alkyl ether, and an acyl protecting group; wherein the content of the first and second substances,
the silyl protecting group is any one of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;
the alkyl ether protecting group is any one of benzyl, p-methoxybenzyl, methoxymethyl, 2-tetrahydropyran, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl and allyl;
the acyl protecting group is any one of acetyl, propionyl, benzoyl and pivaloyl;
the X is selected from: any one of fluorine, chlorine, bromine and iodine;
(2) adding a compound with a structure shown in a formula (III) into a protecting group R1 for derivatization to carry out Hofmann degradation reaction, thus obtaining the compound with the structure shown in the formula (I):
Figure 447561DEST_PATH_IMAGE004
→
Figure DEST_PATH_IMAGE005
；
the R is1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the X is selected from: any one of fluorine, chlorine, bromine and iodine;
the derivatization reagent is any one of tert-butyl alcohol, benzyl alcohol, allyl alcohol, methanol, ethanol and trifluoroacetic acid;
the R is3Selected from: hydrogen, or any one of a silane group, an alkyl ether, and an acyl protecting group; wherein the content of the first and second substances,
the silyl protecting group is any one of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;
the alkyl ether protecting group is any one of benzyl, p-methoxybenzyl, methoxymethyl, 2-tetrahydropyran, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl and allyl;
the acyl protecting group is any one of acetyl, propionyl, benzoyl and pivaloyl.
The intermediate compound is applied to the preparation of Lefamolin or Lefamolin related medical intermediates.
Further provides a preparation method of a Lefamulin-related medical intermediate, which comprises the following steps:
(1) de-R the intermediate compound3And (3) treating a protecting group to obtain a compound with a structure shown in a formula (IV):
Figure 780453DEST_PATH_IMAGE006
；
in the formula (IV), R is1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the X is selected from: any one of fluorine, chlorine, bromine and iodine;
(2) taking a compound with a structure shown in a formula (IV), and carrying out epoxidation reaction to obtain a compound with a structure shown in a formula (V):
Figure DEST_PATH_IMAGE007
；
in the formula (V), R1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
(3) taking a compound with a structure shown in a formula (V), and adding a sulfur-containing nucleophilic reagent to obtain a compound with a structure shown in a formula (VI):
Figure 594825DEST_PATH_IMAGE008
；
in the formula (VI), R is1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the R is2Selected from: any one of hydrogen, benzoyl, triphenyl, acetyl and propionyl;
(4) taking a compound with a structure of formula (VI), removing R2Treating with a protecting group to obtain a compound havingA compound with a structure shown in a formula (VII) is a Lefamulin-related medical intermediate:
Figure 604238DEST_PATH_IMAGE009
；
in the formula (VII), the R1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl.
In addition, the preparation method of Lefamulin comprises the following steps:
(1) de-R the intermediate compound3And (3) treating a protecting group to obtain a compound with a structure shown in a formula (IV):
Figure 871272DEST_PATH_IMAGE006
；
in the formula (IV), R is1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the X is selected from: any one of fluorine, chlorine, bromine and iodine;
(2) taking a compound with a structure shown in a formula (IV), and carrying out epoxidation reaction to obtain a compound with a structure shown in a formula (V):
Figure 70172DEST_PATH_IMAGE007
；
in the formula (V), R1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
(3) taking a compound with a structure shown in a formula (V), and adding a sulfur-containing nucleophilic reagent to obtain a compound with a structure shown in a formula (VI):
Figure 676734DEST_PATH_IMAGE008
；
in the formula (VI), R is1Selected from: hydrogen, trifluoroacetyl, or alkoxycarbonyl; the alkoxycarbonyl is selected from any one of tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl;
the R is2Is a pleuromutilin group;
(4) taking a compound with a structure of formula (VI), removing R1Protecting group to obtain a compound with a structure shown in a formula (VIII), namely Lefamulin;
Figure DEST_PATH_IMAGE010
。
preferably, in the step (3): the sulfur-containing nucleophile is a compound comprising a pleuromutilin parent nucleus.
Further, the sulfur-containing nucleophile is a thio-pleuromutilin.
Compared with the prior art, the invention has the main beneficial technical effects that:
1. the product of the invention is produced by adopting a mature medical intermediate, and overcomes the defects of low conversion rate of a target compound, high cost and difficult industrial production caused by lack of chiral induction of double bond epoxidation in the production process in the prior art.
2. The preparation method is suitable for industrialization, can effectively reduce the production cost, can effectively control the generation of three wastes, and has remarkable economic benefit and social benefit.
3. The Lefamulin and the pharmaceutical intermediate thereof can be prepared by combining different substituent groups during production through corresponding ways.
Drawings
FIG. 1 shows Lefamulin compounds obtained in example 11HNMR Spectroscopy (CDCl)3400M) diagram.
FIG. 2 is an HPLC chromatogram of Lefamulin-related substance obtained in example 1.
Detailed Description
The following examples are intended to illustrate the present invention in detail and should not be construed as limiting the scope of the present invention in any way.
The instruments and devices referred to in the following examples are conventional instruments and devices unless otherwise specified; the related reagents are all conventional reagents in the market, if not specifically indicated; the chemical reactions involved are conventional reactions unless otherwise specified.
Example 1: preparation method of compound Lefamulin
Lefamulin is prepared by adopting commercially available (1R,3R,4R) -4-bromo-3-hydroxy-cyclohexanecarboxylic acid as a starting material, and the process flow is as follows:
Figure 857048DEST_PATH_IMAGE011
；
the method comprises the following specific steps:
(1) preparation of ((1R,3R,4R) -4-bromo-3-hydroxy-cyclohexyl) tert-butoxycarbonylamide
Adding 4.8kg of (1R,3R,4R) -4-bromo-3-hydroxycyclohexyl formic acid (commercially available, preparation technology is shown in Organic Process Research and Development, 2019, vol.23, # 4, p.524-534) and 50L of toluene into a 100L reaction kettle, adding 1.3eq of triethylamine under stirring, adding 1.1eq of azido diphenyl phosphate, heating and refluxing, cooling to 80 ℃ after the reaction is finished, dropwise adding 5L of tert-butyl alcohol, adding 5g of catalyst cuprous halide, and continuing the reaction for 2 hours. Purification yielded the target compound preparation ((1R,3R,4R) -4-bromo-3-hydroxy-cyclohexyl) tert-butoxycarbonylamide (i.e., formula A) 3.1 kg.
Similarly, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetamide analogs of formula a can be obtained by hofmann rearrangement with benzyl alcohol, allyl alcohol, methanol, ethanol, trifluoroacetic acid, and the like, respectively.
(2) Preparation of thiapleuromutilins
The preparation process comprises the following steps:
Figure DEST_PATH_IMAGE012
；
adding 50L of dichloromethane, 30L of water, 15kg of pleuromutilin, 5.0kg of potassium thioacetate, 1kg of sodium hydroxide and 50g of tetrabutylammonium bromide into a 100L reaction kettle, heating to 40 ℃, reacting under the stirring condition until the pleuromutilin is completely consumed, washing for 3 times, after washing, adding 1.8eq of hydrazine hydrate into the reaction kettle, stirring for 4 hours at normal temperature until no raw materials are left, after the reaction is finished, washing with water and a 5% citric acid aqueous solution, concentrating to be nearly dry, then adding 50L of absolute ethyl alcohol into the reaction kettle, recrystallizing to obtain a light yellow solid, and drying to obtain 12.8 kg of the thiapleuromutilin.
(3) Preparation of Boc protected Lefamulin
Adding 20kg of ethanol and water into a 100L reaction kettle respectively, then adding 2.94 kg of ((1R,3R,4R) -4-bromo-3-hydroxy-cyclohexyl) tert-butyloxycarbonylamide and 4.0 kg of thio-pleuromutilin, then adding a mixed solution of 0.4kg of sodium hydroxide and 3kg of water, and reacting until no raw material is left after the addition is finished; the reaction solution was concentrated to remove ethanol, washed with 20L × 3 dichloromethane, and concentrated to give a foamy crude product, which was then added with 40L n-butanol, recrystallized, and dried to give 6.1kg of a white solid protected with Boc-Lefamulin (i.e., formula 4).
(4) Preparation of Lefamulin
40L of dichloromethane, 2kg of methanesulfonic acid and 6.0kg of Boc-protected Lefamulin were added to a 100L reaction vessel, and the mixture was stirred until the reaction was completed, and then washed with 20L of a 10% citric acid aqueous solution, 5% sodium bicarbonate, water and a saturated brine in this order. Concentrating to obtain waxy solid, and recrystallizing twice to obtain final product white solid 3.3 kg. The resulting final product structure1HNMR verified, as shown in FIG. 1, as Lefamulin.
As shown in FIG. 2, the product Lefamulin obtained has a purity of 99.215% by HPLC.
Similarly, when the protecting group is benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetylamide analogs, the deprotection regime chosen is that of the common organic-reactive alkoxycarbonyl deprotection methods of chemical methods.
Example 2: preparation method of compound Lefamulin
Lefamulin is prepared from commercially available (1R,3R,4R) -4-bromo-3-hydroxy-cyclohexanecarboxylic acid by the following scheme:
Figure 611378DEST_PATH_IMAGE013
；
the method comprises the following specific steps:
(1) preparation of (1R,3R,4R) -4-bromo-3- ((tert-butyldimethylsilyl) oxy) cyclohexanecarboxylic acid
60L of dichloromethane, (1R,3R,4R) -4-bromo-3-hydroxycyclohexyl formic acid 4.8kg (commercially available, preparation Process is shown in Organic Process Research and Development, 2019, vol.23, # 4, p.524-534) and tert-butyldimethylsilyl chloride 1.2eq are added into a 100L reaction kettle, triethylamine 1.3eq is added dropwise under stirring, the reaction system is stirred to the end point after the addition is finished, the reaction system is washed with water, and dichloromethane is concentrated to obtain 6.4 kg (namely formula 1) of (1R,3R,4R) -4-bromo-3- ((tert-butyldimethylsilyl) oxy) cyclohexyl formic acid. The yield thereof was found to be 98%.
Similarly, other silyl-protected analogs of formula 1 can be obtained by reaction with trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, etc., respectively.
(2) Preparation of ((1R,3R,4R) -4-bromo-3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) tert-butoxycarbonylamide
Adding 6.0kg of (1R,3R,4R) -4-bromo-3- ((tert-butyl dimethyl silicon base) oxygen) cyclohexanecarboxylic acid and 50L of toluene into a 100L reaction kettle, adding 1.3eq of triethylamine under stirring, adding 1.1eq of azido diphenyl phosphate, heating for refluxing, cooling to 80 ℃ after the reaction is finished, dropwise adding 5L of tert-butyl alcohol, adding 5g of catalyst cuprous halide, and continuing to react for 2 hours. Purification yielded 6.1kg of the target compound ((1R,3R,4R) -4-bromo-3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) tert-butoxycarbonylamide (i.e., formula A).
Similarly, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetamide analogs of formula A can be obtained by Hofmann rearrangement with benzyl alcohol, allyl alcohol, methanol, ethanol, trifluoroacetic acid, and the like, respectively.
(3) Preparation of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide
50L of tetrahydrofuran is added into a 100L reaction kettle, 6.0kg of ((1R,3R,4R) -4-bromo-3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) tert-butoxycarbonyl amide is added under the stirring condition, 1.1eq of tetrabutylammonium fluoride is added, the temperature is increased and the reflux reaction is carried out until no raw material is left, the temperature is reduced, and 4.2kg of the target compound ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonyl amide (namely the formula 3) is obtained after purification.
Similarly, when the protecting group is a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, or the like, the deprotection method is a common organic reactive silyl group deprotection method in chemical methods.
(4) Preparation of Boc protected Lefamulin
20kg of each of ethanol and water was added to a 100L reactor, 6.3kg of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide and 7.9kg of thiapleuromutilin prepared in example 1 were then added, and a mixed solution of 0.9kg of potassium hydroxide and 5kg of water was added and the reaction was carried out until no raw material remained; the reaction solution was concentrated to remove ethanol, washed with 20L × 3 dichloromethane, and concentrated to give a foamy crude product, which was then added with 40L n-butanol, recrystallized, and dried to give 8.4 kg of a white solid protected with Boc-Lefamulin (i.e., formula 4) with a yield of 81%.
(6) Preparation of Lefamulin
40L of dichloromethane, 2kg of methanesulfonic acid and 8.0 kg of Boc-protected Lefamulin were added to a 100L reaction vessel, and the mixture was stirred until the reaction was completed, and then washed with 20L of a 10% citric acid aqueous solution, 5% sodium bicarbonate, water and a saturated brine in this order. Concentrating to obtain waxy solid, and recrystallizing twice to obtain final product white solid 5.1 kg with yield 76.1%.
Similarly, when the protecting group is benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetylamide analogs, the deprotection regime chosen is that of the common organic-reactive alkoxycarbonyl deprotection methods of chemical methods.
Example 3: preparation method of compound Lefamulin
Lefamulin is prepared from commercially available (1R,3R,4R) -4-bromo-3-hydroxy-cyclohexanecarboxylic acid by the following scheme:
Figure DEST_PATH_IMAGE014
；
(1) preparation of (1R,3R,4R) -4-bromo-3- (benzyloxy) cyclohexanecarboxylic acid
100ml of DMF (1R,3R,4R) -4-bromo-3-hydroxycyclohexyl formic acid (30 g), benzyl bromide (1.2 eq) and sodium hydride (1.3 eq) are added into a 250ml three-neck flask, after the addition is finished, the mixture is stirred, heated and reacted to the end point, a reaction system is quenched by water, and dichloromethane is used for extraction to obtain 21.4 g of the target compound (namely the formula 1).
Similarly, other alkyl ether protected analogs of formula 1' can be obtained by reaction with p-methoxy benzyl chloride, methoxy chloromethyl or methoxy bromomethyl ether, 3, 4-dihydro-2H-pyran, 2- (trimethylsilyl) ethoxymethyl chloride, allyl chloride, and the like, respectively. And the like to obtain other alkyl ether protected analogs of formula 1, respectively.
(2) Preparation of ((1R,3R,4R) -4-bromo-3- ((benzyloxy) cyclohexyl) tert-butoxycarbonylamide
Adding 20g of (1R,3R,4R) -4-bromo-3- (benzyloxy) cyclohexanecarboxylic acid and 100ml of toluene into a 250ml three-neck flask, adding 1.3eq of triethylamine under stirring, adding 1.1eq of azido diphenyl phosphate, heating and refluxing, cooling to 80 ℃ after the reaction is finished, dropwise adding 10 ml of tert-butyl alcohol, adding 0.1g of cuprous halide serving as a catalyst, and continuing the reaction for 2 hours. Purification gave 19.4g of the title compound ((1R,3R,4R) -4-bromo-3- (benzyloxy) cyclohexyl) tert-butoxycarbonylamide (i.e., formula A).
Similarly, the analogue of the carbobenzoxy, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and trifluoroacetyl amide in the formula A can be respectively obtained by Hofmann rearrangement with benzyl alcohol, allyl alcohol, methanol, ethanol, trifluoroacetic acid and the like.
(3) Preparation of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide
30ml of methanol was charged into a 100ml autoclave, 10.0 g of ((1R,3R,4R) -4-bromo-3-benzyloxy) cyclohexyl) tert-butoxycarbonylamide was added, 1g of palladium on carbon was further added, hydrogen was introduced into the autoclave to 0.3 MP, the reaction was terminated at room temperature, palladium on carbon was filtered, and 6.7g of the objective compound ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide (i.e., formula 2) was obtained after concentration and purification.
Similarly, when the protecting group is p-methoxybenzyl, methoxymethylether, 3, 4-dihydro-2H-pyranyl, 2- (trimethylsilyl) ethoxymethyl, allyl, 2- (trimethylsilyl) ethoxymethyl chloride, allyl, etc., the deprotection is a chemically common organic reactive alkoxy deprotection method.
(4) Preparation of Boc protected Lefamulin
30g of each of ethanol and water was put into a 100ml three-necked flask, and then 6.3 g of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) t-butoxycarbonylamide and 7.2g of thiapleuromutilin prepared in example 1 were added, and then a mixed solution of 0.8g of potassium hydroxide and 5 ml of water was added, and after the addition was completed, the reaction was carried out until no raw material remained; the reaction solution was concentrated to remove ethanol, washed with 100ml of dichloromethane, concentrated to give a foamy crude product, and then 20ml of n-butanol was added to the crude product, recrystallized, and dried to give 8.0g of a white solid protected with Boc-Lefamulin (i.e., formula 4).
(5) Preparation of Lefamulin
A100 ml three-necked flask was charged with 40ml of methylene chloride, 2g of methanesulfonic acid and 7.0g of Boc protection Lefamulin, and the mixture was stirred until the reaction was terminated, and then washed with 100ml of a 10% citric acid aqueous solution, 5% sodium hydrogencarbonate, water and saturated brine in this order. The mixture was concentrated to give a waxy solid which was recrystallized to give 6.4 g of a white solid as the final product.
Similarly, when the protecting group is benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetylamide analogs, the deprotection regime chosen is that of the common organic-reactive alkoxycarbonyl deprotection methods of chemical methods.
Example 4: preparation method of compound Lefamulin
Lefamulin is prepared by adopting commercially available (1R,3R,4R) -4-bromo-3-hydroxy-cyclohexanecarboxylic acid as a starting material, and the process flow is as follows:
Figure 286072DEST_PATH_IMAGE015
；
the method comprises the following specific steps:
(1) preparation of (1R,3R,4R) -3- (acetoxy) -4-bromo-cyclohexanecarboxylic acid
100ml of ethyl acetate, (1R,3R,4R) -4-bromo-3-hydroxycyclohexyl formic acid 10 g and acetyl chloride 1.2eq are added into a 250ml three-necked flask, the temperature is reduced to 0 ℃, triethylamine is 1.3eq is added, after the addition is finished, the temperature is raised to the end point, reaction liquid is washed, and the target compound 11.4 g (namely formula 1) is obtained through concentration and purification.
Similarly, reaction with acetic anhydride, propionyl chloride, benzoyl chloride, pivaloyl chloride, etc. gives similar ester-protected analogs.
(2) Preparation of (1R,3R,4R) -3- (Acetyloxy) -4-bromo-cyclohexyl-tert-butyloxycarbonylamide
Adding 10 g of (1R,3R,4R) -4-bromo-3- (acetoxyl) cyclohexanecarboxylic acid and 50ml of toluene into a 250ml three-neck flask, adding 1.3eq of triethylamine under stirring, adding 1.1eq of azido diphenyl phosphate, heating and refluxing, cooling to 80 ℃ after the reaction is finished, dropwise adding 5 ml of tert-butyl alcohol, adding 0.1g of catalyst cuprous halide, and continuing the reaction for 2 hours. Purification yielded 7.4 g of the title compound ((1R,3R,4R) -4-bromo-3- (acetoxy) cyclohexyl) tert-butoxycarbonylamide (i.e., formula A).
Similarly, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetamide analogs of formula a can be obtained by hofmann rearrangement with benzyl alcohol, allyl alcohol, methanol, ethanol, trifluoroacetic acid, and the like, respectively.
(3) Preparation of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide
30ml of tetrahydrofuran and 30ml of water are added into a 100ml three-necked flask, 6.0 g of (1R,3R,4R) -3- (acetoxy) -4-bromo-cyclohexyl-tert-butoxycarbonylamide and 0.4 g of lithium hydroxide are added, the temperature is raised to 30 ℃ to react until the end, and 4.7g of the target compound ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide (namely formula 2) is obtained after concentration and purification.
The reaction can also be carried out as described in step (3) of example 1, and the type and amount of base can be adjusted according to conventional methods in the art to prepare boc-protected Lefumalin by a one-pot method, and such reactions are also within the scope of the present invention.
(4) Preparation of Lefamulin
20ml of methylene chloride, 1g of methanesulfonic acid and 4.0 g of Boc-protected Lefamulin were put into a 100ml three-necked flask, and the mixture was stirred until the reaction was completed, and then washed with 50ml of a 10% citric acid aqueous solution, 5% sodium hydrogencarbonate, water and saturated brine in this order. The concentrate was taken to give a waxy solid which was recrystallised to give the final product as a white solid, 1.9 g.
Similarly, when the protecting group is benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetylamide analogs, the deprotection regime chosen is that of the common organic-reactive alkoxycarbonyl deprotection methods of chemical methods.
Example 5: preparation of Lefamulin pharmaceutical intermediate compound
(1) ((1R,2R,4R) -4-tert-butoxycarbonylamide-2-hydroxy) cyclohexylthiobenzoate was prepared using ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide prepared in example 1.
The process is as follows:
Figure DEST_PATH_IMAGE016
；
adding 200ml of ethanol and water into a 1L three-necked bottle, adding 30g of ((1R,3R,4R) -4-bromo-3-hydroxycyclohexyl) tert-butoxycarbonylamide, adding a mixed solution of 5.4g of potassium hydroxide and 20g of water, reacting until no raw material remains after the addition is finished, concentrating a solvent, extracting with dichloromethane to obtain a semi-solid, dissolving with 300 ml of toluene, dropwise adding 1.2eq of thiobenzoic acid at 40-50 ℃, reacting, and purifying to obtain 43 g of a target compound after the reaction is finished.
(2) Preparation of (1R,3R,4R) -3-hydroxy-4-mercapto-cyclohexyl) -carbamic acid tert-butyl ester
200ml of dichloromethane is added into a 500ml three-necked flask, 30g of the compound ((1R,2R,4R) -4-tert-butoxycarbonylamide-2-hydroxy) cyclohexyl thiobenzoate obtained in the previous step is taken, 6g of hydrazine hydrate is dropwise added, and after the reaction is finished, 19.7 g of the target compound (1R,3R,4R) -3-hydroxy-4-mercapto-cyclohexyl) -carbamic acid tert-butyl ester (namely Lefamulin medical intermediate compound) is obtained through purification.
The lefamolin pharmaceutical intermediate compound can be further prepared into lefamolin according to the preparation method of lefamolin described in chinese patent document CN 104211624A.
While the invention has been described in detail with reference to the drawings and examples, it will be understood by those skilled in the art that various changes in the form and details may be made therein without departing from the spirit and scope of the invention.

Claims (7)

1. An intermediate compound having the formula:
Figure 266842DEST_PATH_IMAGE001
；
in the formula, the R1Is tert-butyloxycarbonyl;
the R is3Selected from: hydrogen, or any one of tert-butyl dimethyl silicon base and benzyl;
and X is bromine.
2. A process for the preparation of an intermediate compound as claimed in claim 1, comprising the steps of:
(1) a radical R3Introducing the compound with the structure of the formula (II) to obtain a compound with the structure of the formula (III):
Figure 940269DEST_PATH_IMAGE002
Figure 700415DEST_PATH_IMAGE003
；
the X is bromine;
(2) adding a compound with a structure of formula (III) into a protecting group R1And (2) derivatization, specifically adding triethylamine under the stirring condition, adding diphenyl phosphorazide, cooling to 80 ℃ after the reaction is finished, dropwise adding tert-butyl alcohol, adding a catalyst, and continuing to react for 2 hours to obtain the compound with the structure of formula (I):
Figure 233027DEST_PATH_IMAGE003
Figure 642315DEST_PATH_IMAGE004
；
the R is1Is tert-butyloxycarbonyl;
the derivatization reagent is tert-butyl alcohol;
the R is3Selected from: hydrogen, or any one of tert-butyl dimethyl silicon base and benzyl;
and X is bromine.
3. Use of an intermediate compound according to claim 1 for the preparation of lefamolin or a lefamolin-related pharmaceutical intermediate.
4. A preparation method of a Lefamulin-related medical intermediate is characterized by comprising the following steps:
(1) de-R the intermediate compound of claim 13And (3) treating a protecting group to obtain a compound with a structure shown in a formula (IV):
Figure 701407DEST_PATH_IMAGE005
；
in the formula (IV), R is1Is tert-butyloxycarbonyl;
the X is bromine;
(2) taking a compound with a structure shown in a formula (IV), and carrying out epoxidation reaction to obtain a compound with a structure shown in a formula (V):
Figure 553825DEST_PATH_IMAGE006
；
in the formula (V), R1Is tert-butyloxycarbonyl;
(3) taking a compound with a structure shown in a formula (V), and adding a sulfur-containing nucleophilic reagent to obtain a compound with a structure shown in a formula (VI):
Figure 167209DEST_PATH_IMAGE007
；
in the formula (VI), R is1Is tert-butyloxycarbonyl;
the R is2Selected from: any one of hydrogen, benzoyl, triphenyl, acetyl and propionyl;
(4) taking a compound with a structure of formula (VI), removing R2And (3) treating the protecting group to obtain a compound with a structure shown in a formula (VII), namely a Lefamulin-related medical intermediate:
Figure 841904DEST_PATH_IMAGE008
；
in the formula (VII), the R1Is tert-butyloxycarbonyl.
5. A preparation method of Lefamulin is characterized by comprising the following steps:
(1) de-R the intermediate compound of claim 13And (3) treating a protecting group to obtain a compound with a structure shown in a formula (IV):
Figure 286661DEST_PATH_IMAGE005
；
in the formula (IV), R is1Is tert-butyloxycarbonyl;
the X is bromine;
(2) taking a compound with a structure shown in a formula (IV), and carrying out epoxidation reaction to obtain a compound with a structure shown in a formula (V):
Figure 654189DEST_PATH_IMAGE006
；
in the formula (V), R1Is tert-butyloxycarbonyl;
(3) taking a compound with a structure shown in a formula (V), and adding a sulfur-containing nucleophilic reagent to obtain a compound with a structure shown in a formula (VI):
Figure 82765DEST_PATH_IMAGE009
；
in the formula (VI), R is1Is tert-butyloxycarbonyl;
the R is2Is a pleuromutilin group:
Figure 92309DEST_PATH_IMAGE010
；
(4) taking a compound with a structure of formula (VI), removing R1Protecting group to obtain a compound with a structure shown in a formula (VIII), namely Lefamulin;
Figure 922731DEST_PATH_IMAGE011
。
6. the method for producing Lefamulin according to claim 5, wherein in the step (3): the sulfur-containing nucleophile is a compound comprising a pleuromutilin parent nucleus.
7. The method of Lefamulin according to claim 6, wherein the sulfur-containing nucleophile is thiopleuromutilin.
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