KR20010038312A - Method for the preparation of 2',3'-Didehydro-2',3'-dideoxycytidine derivatives - Google Patents

Abstract

PURPOSE: A method for producing 2',3'-didehydro-2'.3'-dideoxycytidine is provided, therefore the titled compound can be easily mass produced with low costs by simple reaction, separation and purification processes. CONSTITUTION: The method for producing 2',3'-didehydro-2'.3'-dideoxycytidine comprises the steps of: reacting the compound of formula (2) with R2SO2X, wherein R2 is lower alkyl or aryl and X is halogen atom, and amine organic base in organic solvents to produce the compound of formula (3); reacting the compound of formula (3) with alkali in aqueous solution to produce the compound of formula (4); reacting the compound of formula (4) with R3SO2X, wherein R3 is alkyl, aryl and X is halogen atom, in organic solvents containing K2CO3 or tertiary amine to produce the compound of formula (5); reacting the compound of formula (5) with ammonia, primary amine or secondary amine in organic solvents to produce the compound of formula (6); and reacting the compound of formula (6) with organic or inorganic base in organic solvents.

Description

Method for the preparation of 2 ', 3'-Didehydro-2', 3'-dideoxycytidine derivatives}

The present invention is to prepare a 2 ', 3'-didihydro-2', 3'-dideoxycytidine (2 ', 3'-Didehydro-2', 3'-dideoxycytidine) derivative of the formula (1) In detail, the present invention relates to a method for synthesizing the compound of formula (1), which can be synthesized on a large scale by using a deoxyuridine derivative as a raw material, and having low cost and excellent economic efficiency, and easy reaction, separation, and purification processes. will be.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ⁴ = H, alkyl group, aryl group: R ⁵ = H, alkyl group, aryl group]

Hepatitis B virus (HBV) is a virus that causes acute and chronic hepatitis and is a major cause of health and hygiene problems worldwide. Currently, more than 200 million people with chronic hepatitis caused by HBV are known.

HBV is a double-chain DNA virus whose DNA polymerase can synthesize DNA using both DNA and RNA as a template. Due to these characteristics, effective drugs against HBV infection have not been developed, and it is known that the best alternative is to vaccinate only to prevent infection.

Currently, HBV infected people are prescribed a nucleoside analogue such as interferon-α, adenine arabinoside, or ara-AMP thereof, but have no effect. Furthermore, drugs such as 3'-azido-3'-deoxythymidine, acyclovir, and foscarnet have been used, but they have no significant effect. Is being reported.

Recently, it has been found that 2 ', 3'-dideoxyneutelioside analogs act effectively against HBV in culture, particularly 2', 3'-dideoxy-3'-thiacytidine (2 ', 3). '-dideoxy-3'-thiacytidine) and 2', 3'-dideoxycytidine derivatives are known to have a very good effect on the inhibition of HBV proliferation while being less toxic.

On the other hand, human immunodeficiency virus (HIV), which causes AIDS, also has 2 ', 3'-didihydro-3'-deoxythymidine (2', 3'-dehydro-3). '-deoxythimidine), 2', 3'-didihydro-2 ', 3'-dideoxyguanosine (2', 3'-dehydro-3'-deoxyguanosine), 3'-azido-2 ', 3' 3'-azido-3'-deoxyguanosine, 2 ', 3'-dideoxyinosine, 3'-fluorine-2', 3'-dideoxyadenosine Nucleoside derivatives such as (3'-fluoro-2 ', 3'-dideoxyadenosine), 2', 3'-didihydro-2 ', 3'-dideoxycytidine (hereinafter referred to as "DDC"), and the like. It has also been found that its proliferation is inhibited. Some of these derivatives, including DDCs, are currently used to treat HIV.

Conventional 2 ', 3'-didihydro-2', 3'-dideoxycytidine derivative is a method using ① cytidine or 2'-dioxycytidine derivative as a raw material, ② lye depending on the starting material and the reaction intermediate A method by coupling a rib derivative with a base, a method of synthesizing from a uridine or a 2'-dioxyuridine derivative, and the like are known.

(1) First, as a case of using cytidine or 2'-dioxycytidine as a raw material, there are the following production examples.

1) Bromoacetate intermediate ( Reduction with zinc (Zn) as catalyst (USP 4900828; J. Org. Chem. 1992, 57, 3473; Synthesis 1993, 303; J. Org. Chem. 1995, 60, 7902; Collect) Czech Chem Commun. 1996, 61, 645; J. Org. Chem. 1992, 44, 1404; USP 3817982).

2) using Barton Deoxygenation (USP 5,455,339)

3) using Corey-Winter Reaction (EP 342,422; J. Org. Chem. 1992, 57, 3473)

4) Synthesis via Sulfonate Intermediate (J. Org. Chem. 1967, 32, 817; EP 409,227; Chem. Pharm. Bull. 1989, 37, 2547; Nucleosides & Nucelotides 1990, 9, 1061)

However, when the cytidine or 2'-dioxycytidine derivative is used as a starting material, the price of the cytidine derivative or the 2'-dioxycytidine derivative is more expensive than the uridine derivative or the 2'-dioxyuridine derivative, The process of protecting and deprotecting the -NH ₂ group of cytidine during the process is essential, and in some processes, there are limitations in mass production such as using heavy metals or toxic compounds.

(2) The method by coupling the ribose derivative and the base (WO 96/22778; USP 5905070; USP 5703058; USP 5220003) forms a mixture of the α and β isomers as a result of the coupling, which causes problems in the selectivity and purification of the product. have.

(3) The following example is known as a method of synthesizing from uridine or 2'-deoxyuridine.

1) Amination of uracil rings after synthesis of 2 ', 3'-didehydro-2', 3'-dideoxyuridine (D4U) derivatives (Biochemical Pharmacology 1987, 36, 311; EP 261595; Org. Prep. Proc. 1990, 22, 265; J. Med. Chem. 1990, 33, 1833; J. Pharm. Sci. 1994, 83, 339; Tetrahedron Lett. 1994, 35, 3477)

According to this method, 5'-OH should be shielded and unshielded. In general, D4U compounds are unstable in acid, base, and heat, and thus the base portion and 2 ', 3'-didehydro-2', 3'- The disadvantage is that the dideoxyribose part is easily separated. In addition, after the preparation of the unstable derivative D4U, the reaction conditions are complicated and the yield is low.

2) Synthesis of D4C derivatives from intermediates of D4U derivatives (Org. Prep. Proc. Int. 1990, 22, 265; J. Med. Chem. 1996, 39, 1758; USP 5627160; USP 583088; USP 5631239; WO 93/23413 ; EP 204264)

This method takes about 70 hours when converting from uraciling to cytosine ring, and because the reaction reagents are expensive, the reaction intermediate and the final product are separated and purified by chromatography, which is difficult to use for large scale synthesis. do.

Accordingly, it is an object of the present invention to provide a process for preparing the compound of formula (1), which is economical, easy to react and purify, and which is capable of mass production.

In order to achieve the object of the present invention as described above, the present invention, the compound of formula (1) through a five-step reaction, such as sulfonylation step, oxetane ring formation step, 4C activation step, amination step and double bond formation step It provides a method of manufacturing.

Each step will be described below.

(1) sulfonylation step

The compound of formula (2) is reacted with R ² SO ₂ X and amine organic base under organic solvent to replace the 3 'and 5'-OH groups of the compound of formula (2) with sulfonyl group to prepare the compound of formula (3). Step where X is a halogen element.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ² SO ₂ = organosulfonyl group: R ² = ilkyl group, aryl group]

R ² represents a lower alkyl group or an aryl group. R ² SO ₂ Cl is lower alkylsulfonylchloride with R ² of C1-4, for example methanesulfonylchloride, trifluoromethanesulfonylchloride or arylsulfonylchloride, for example toluenesulfonylchloride, benzenesul Polyvinyl chloride and the like.

Bases used in this step are bases such as pyridine, triethylenamine (TEA), N-methylmorpholine and the like.

In this step, the organic solvent is preferably an aprotic organic solvent such as chloroform, methylene chloride, acetone, acetonitrile and the like.

In this step, the compound of formula (2): R ² SO ₂ X: Organic base is 1: (2 to 10): (2 to 20) to the equivalent, but 1: (2 to 4): (2 to 10) desirable.

First, an organic base and an organic solvent are added to the compound of formula (2), followed by cooling to 0-5 ° C. After R ² SO ₂ X was slowly added dropwise to the solution, the mixture was warmed to room temperature and stirred for 3 to 6 hours to react, whereby the 3 'and 5'-OH groups of the compound of formula (2) were substituted with an organicsulfonyl group. (3) A compound is formed. To this, 3-20 times of water is added to agglomerate the compound of formula (3) and filtered to obtain a mass of the compound of formula (3).

(2) oxetane ring forming step

In the aqueous solution, the compound of formula (3) is reacted with an alkaline component to form an oxetane ring having 3'C, 4'C and 5'C as members.

The alkali component may be any inorganic substance, but is preferably NaOH, KOH, or the like. In the case of applying the inorganic alkali in the present invention, the reaction proceeds at 20 to 50 ° C. without reflux as compared to the case where ethanol, which is reflux at the conventional 78 ° C., is required.

First, the alkali component is added to the water, and the compound of formula (3) or the compound of formula (3) and the alkali component are added 1 to 10 times at a rate of 30 to 60 minutes by 10 to 50%. In this process, the temperature is maintained at 20-50 ° C. and stirring is continued. After the reaction was completed, the mixture was cooled to 0-10 ° C., adjusted to pH 5.5-7.5, stirred for 2-5 hours, and filtered to form 3'C, 4'C and 5'C of the compound of formula (3). The compound of formula (4) in which an oxetane ring is formed is obtained.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ² SO ² = organosulfonyl group: R ² = alkyl group, aryl group]

(3) 4C activation step

The compound of formula (5) is substituted by reacting the compound of formula (4) with R ³ SO ₂ X in an organic solvent containing NaH, K ₂ CO _3, or a tertiary amine to replace the carbonyl group of C 4 with an organicsulfonyl group. This is the obtaining step, where X is a halogen group element.

As the tertiary amine, TEA, DIEA (diisopropylethylamine) and the like can be used, and these serve as a base. In the above, R ³ represents an aryl group such as benzene and toluene.

At this stage, the organic solvent can be any kind of acetonitrile (AN), dichloroethane (DCE), methyl isobutyl ketone (MIBK), but in terms of solubility of the reactants, It is preferable that it is an organic solvent.

In this step, the compound of formula (4): R ³ SO ₂ X: K ₂ CO ₃ or tertiary amine 1: 1 (1 ~ 10): (1 ~ 10) to the equivalent, but 1: (1 ~ 4): (1 It is preferable that it is -4).

This process is a compound of formula (4), R ³ SO ₂ X: K ₂ CO ₃ or tertiary amine is mixed with an organic solvent and reacted at 0 ~ 150 ℃ for 0.5 to 10 hours, the carbonyl group of 4C sulfonyl Reaction with the compound produces a compound of formula (5) which is activated with an organosulfonyl group.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ³ = alkyl group, aryl group]

(4) amination step

The compound of formula (5) is reacted with ammonia, primary amine or secondary amine under an organic solvent to replace the organic sulfonyl group of 4C with an amine group. Methylamine, ethylamine, benzylamine, etc. can be used as a primary amine, and dimethylamine, diisopropylamine, methylethylamine, methylbenzylamine, etc. can be used as a secondary amine. R ⁴ and R ⁵ in the compound of formula (6) may be the same or different and represent H, an alkyl group, or an aryl group, respectively.

In this step, the organic solvent may be any type such as AN, DCE, MIBK. Ammonia can be used in the gas phase or dissolved in a solvent, and primary or secondary amines can be dissolved in a solvent and used.

Ammonia, primary amine or secondary amine was added to the reaction solution after the 4C activation step while maintaining 0 to 150 ° C., and stirred for 0.5 to 3 hours. When the reaction solution was completed, the resultant was filtered at 0 to 100 ° C. to obtain a compound of formula (6) in which the 4th C sulfonyl group of the compound of formula (5) was substituted with an amine group.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ⁴ = H, alkyl group, aryl group: R ⁵ = H, alkyl group, aryl group]

(5) double bond formation step

In the organic solvent, the compound of formula (6) is reacted with an organic or inorganic base to decompose the oxetane ring and form a double bond to obtain a DDC derivative, which is the final product of the present invention.

In this step, it is preferable to use a solvent having a boiling point of 100 ° C. or less, for example, isopropyl alcohol, t-butanol, and the like for the convenience of the organic solvent. T-butoxy potassium, potassium hydroxide and the like can be used as the organic or inorganic base.

In this process, the equivalent ratio of the compound of formula (6): base is 1: (1-10), but is preferably 1: (1-4).

When the compound of formula (6) is dissolved in a solvent and refluxed for 4 to 6 hours by adding a base, the compound of formula (1), which is the target substance of the present invention, is produced.

After cooling the reaction solution in which the compound of formula (1) is produced to 5 ~ 10 ℃ to adjust the pH to 6 ~ 8 and stirred for 1 to 3 hours at room temperature. The reaction mixture was filtered, the filtrate was distilled under reduced pressure, decolorized with methanol, and recrystallized to obtain a compound of formula (1) purified with high purity.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ⁴ = H, alkyl group, aryl group: R ⁵ = H, alkyl group, aryl group]

The reaction scheme of the entire process is as follows.

[R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ² SO ² = organosulfonyl group: R ² = alkyl group, aryl group: R ³ = alkyl group, aryl group: R ⁴ = H, alkyl group, aryl group : R ⁵ = H, alkyl group, aryl group]

The production method of the present invention as described above is inexpensive and easy to purchase reagents used in the entire manufacturing process, not only do not use toxic substances like heavy metals, but also within a short reaction time without pressure in the easily reachable temperature range The compound of formula (1) can be obtained.

In addition, since the amine group is introduced into the second half of the process in the entire reaction process, the reaction is easier and the intermediate is easy to crystallize, and the product is easily separated and purified at each stage, compared to the conventional technique of introducing the amine group in the first half of the reaction. This becomes possible. Furthermore, according to the conventional manufacturing method, the final material is separated and purified by chromatography, but according to the method of the present invention, the compound of formula (1) can be purified by simple recrystallization.

The present invention will be described in more detail with reference to the following Examples. The following examples are examples for clearly explaining the manufacturing method of the present invention, and the scope of the present invention is not limited or changed by this. In addition, it is easy for those skilled in the art to change and apply various conditions of the following examples within a reasonable range, and such modifications will be included in the technical scope of the present invention.

Example 1

(1) Synthesis of 2'-deoxy-3 ', 5'-dimethanesulfonyluridine

To 50 g of 2'-deoxyuridine, 60 mL of pyridine and 40 mL of dichloromethane were added, followed by cooling to 5 ° C. 39 mL of methanesulfonylchloride was slowly added dropwise while stirring at room temperature. 50 L of water was added to the reaction solution to remove additional methylene chloride, and the resulting mass was filtered to obtain 2'-deoxy-3 ', 5'-dimethanesulfonyluridine (2'-deoxy-3'). , 5'-dimethanesulfonyluridine) was obtained 78.3g (93%).

(2) Synthesis of 3 ', 5'-anhydro-2'-deoxyuridine

After dissolving 27 g of sodium hydroxide in 160 L of water, 71 g of 2'-deoxy-3 ', 5'-dimethanesulfonyluridine was dissolved in three times. Dividing was added every 30 minutes. After completion of the reaction by stirring at 35 ° C. for 2 to 3 hours, the mixture was cooled and adjusted to pH 6.7 using AcOH. Subsequently, the mixture was stirred at 5 ° C. for 3 hours and then filtered to give 3 ′, 5′-anhydro-2′-deoxyuridine (33.5 g, 86%).

(3) Synthesis of 2 ', 3'-didihydro-2', 3'-dideoxycytidine

To 18 g of 3 ', 5'-anhydro-2'-deoxyuridine, 32 g of p-toluenesulfonylchloride and anhydrous potassium carbonate (K ₂ CO ₃ ) 34 g of acetonitrile was added thereto, and the mixture was refluxed for 4 to 5 hours, followed by 3 ', 5'-anhydro-2'-deoxy-4-Op-toluenesulfonyluridine (3', 5'-anhydro -2'-deoxy-4- Op-toluenesulfonyluridine) was prepared.

(4) Synthesis of 3 ', 5'-anhydro-2'-deoxycytidine

Insoluble materials were removed by filtration from the reaction solution, NH ₃ gas was added thereto while maintaining 70 ° C., and the mixture was stirred for 1 hour. Concentrate the reaction solution, add 600 mL of acetone, stir for 1 hour, reflux, cool, filter, and dry to obtain 3 ', 5'-anhydro-2'-deoxycytidine (3', 5'-anhydro-2 ' -deoxycytidine).

(5) Synthesis of 2 ', 3'-didihydro-2', 3'-dideoxycytidine

11.6 g of t-butoxy potassium (t-BuOK) and the cake were added to 350 mL of isopropyl alcohol and refluxed for 5 to 6 hours. After cooling the reaction solution, the pH was adjusted to 7.0 with 2N methanolic HCl. After stirring for 2 hours at room temperature, the filtrate was distilled under reduced pressure. 35 mL of methanol was added to the concentrated residue, and the mixture was cooled to 4 ° C. and filtered. Then decolorized with methanol and recrystallized to give 2 ', 3'-didihydro-2', 3'-dideoxycytidine (2 ', 3'-didehydro-2', 3'-dideoxycytidine) (8 g, 44%). Got it.

Example 2

(1) Synthesis of 2'-deoxy-3 ', 5'-dimethanesulfonyl-5-fluorouridine

To 100 g of 2'-deoxy-5-fluorouridine, 125 mL of pyridine and 25 mL of dichloromethane were added and mixed, followed by cooling to 3 ° C. 75 mL of methanesulfonyl chloride was slowly added dropwise, followed by stirring at room temperature for 4 hours. 350 mL of water was then added to remove methylene chloride, and the resulting cake was filtered to obtain wet 2'-deoxy-3 ', 5'-dimethanesulfonyl-5-fluorouridine (2'-deoxy-3). ', 5'-dimethanesulfonyl-5-fluorouridine) (236 g) was obtained. It was used for the next step reaction without drying or purification.

(2) Synthesis of 3 ', 5'-anhydro-2'-deoxy-5-fluorouridine

Sodium hydroxide solution was prepared by dissolving 50 g of sodium hydroxide in 56 mL of water. 4 mL of sodium hydroxide solution was added to 86 mL of water, and the temperature was raised to 50 ° C., followed by wet 2'-deoxy-3 ', 5'-dimethanesulfonyl-5-fluorouridine (2'-deoxy-). 23.7 g of 3 ', 5'-dimethanesulfonyl-5-fluorouridine) was added thereto. After 30 minutes of stirring at 50 ° C, 4 mL of sodium hydroxide solution and 23.7 g of 2'-deoxy-3 ', 5'-dimethanesulfonyl-5-fluorouridine in wet state were added at 30 minute intervals. Repeated times. After stirring for 30 minutes while maintaining 50 ℃, the remaining sodium hydroxide solution was all added and stirred for an additional 1 hour. The reaction solution was cooled and the pH was adjusted to 6.7 with AcOH. The mixture was stirred at 5 ° C. for 2 hours and then filtered. The dried cake was purified by recrystallization in methanol to obtain 3 ', 5'-anhydro-2'-deoxy-5-fluorouridine (3', 5'-anhydro-2'-deoxy-5-fluorouridine) ( 79 g, 85%).

(3) Synthesis of 2 ', 3'-didihydro-2', 3'-dideoxy-5-fluorocytidine

71 g of p-toluenesulfonylchloride in 40 g of 3 ', 5'-anhydro-2'-deoxy-5-fluorouridine (3', 5'-anhydro-2'-deoxy-5-fluorouridine) Add 37 g of anhydrous potassium carbonate, add 475 mL of acetonitrile, and reflux for 2 hours to obtain 3 ', 5'-anhydro-2'-deoxy-5-fluoro-4-Op-toluenesulfonyluridine (3 ', 5'-anhydro-2'-deoxy-5-fluoro-4- Op-toluenesulfonyluridine) was prepared. NH ₃ gas was added while maintaining the temperature at 60 ° C., followed by stirring for 2 hours to obtain 3 ′, 5′-anhydro-2′-deoxy-5-fluorocytidine (3 ′, 5′-anhydro-2′-deoxy- 5-fluorocytidine) was prepared. The reaction solution was cooled to room temperature and filtered. 400 mL of isopropyl alcohol was added to the concentrated residue, and the filtrate was dissolved in 38.8 g of t-butoxy potassium and refluxed for 6 hours. After cooling the reaction solution, the pH was adjusted to 7.0 with 2N methanolic HCl, stirred at room temperature, filtered and the filtrate was distilled under reduced pressure. 100 mL of methanol was added to the concentrated residue, and the mixture was cooled to 4 ° C. and filtered. Bleached with methanol and recrystallized to give 2 ', 3'-didihydro-dideoxy-5-fluorocytidine (2', 3'-didehydro-2 ', 3'-dideoxy-5-fluorocytidine) (15 g, 38% )

The present invention relates to a method for preparing the compound of formula (1), the reaction and purification conditions are easy and the yield is high, mass production is possible, as well as the starting material, uracil derivatives, which are cheaper than cytosine derivatives as starting materials, cheap and toxic Since it is used as a reagent, it is superior and economical compared to the conventional manufacturing method in terms of device cost, raw material cost and operating cost, it is possible to supply hepatitis B and AIDS treatment at a low price.

Claims (7)

The compound of formula (2) is reacted with R ² SO ₂ X [R2 is a lower alkyl group or an aryl group: X is a halogen group element] and an amine organic base under an organic solvent. A sulfonylation step of preparing a compound of formula (3) by substituting the group for an organic sulfonyl group; A ring forming step of preparing the compound of formula (4) by reacting the compound of formula (3) with an alkali component in an aqueous solution to form an oxetane ring having 3 ', C', 4 ', and 5'C as a member; In the organic solvent containing K ₂ CO ₃ or tertiary amine, the compound of formula (4) is reacted with R ₃ SO ₂ X [where R 3 is an alkyl group and an aryl group: X is a halogen group] to form a carbonyl group of 4 C. A 4C activation step of preparing a compound of formula (5) by substitution with a sulfonyl group; An amination step of preparing the compound of formula (6) by reacting the compound of formula (5) with ammonia, primary amine or secondary amine in an organic solvent to replace the sulfonyl group of C 4 with an amine; 2 ', 3'-didihydro-2', 3'-dide, characterized in that it is prepared by a double bond step of reacting the compound of formula (6) with an organic or inorganic base to form a double bond in an organic solvent. Method for preparing oxycytidine derivatives. [R ¹ = H, lower alkyl, F, Cl, I, CF 3: R ² SO ² = organosulfonyl group: R ² = alkyl group, aryl group: R ³ = alkyl group, aryl group: R ⁴ = H, alkyl group, aryl group : R ⁵ = H, alkyl group, aryl group] The method of claim 1, The alkali component in the ring forming step is NaOH, the reaction is a method for producing a 2 ', 3'-didihydro-2', 3'-dideoxycytidine derivative, characterized in that in an aqueous solution of 70 ℃ or less. The method of claim 1, In the sulfonylation step, R ³ SO ₂ X is arylsulfonyl chloride, characterized in that 2 ', 3'-didihydro-2', 3'-dideoxycytidine derivatives. The method according to claim 1 or 3, In the sulfonylation step, the organic solvent is an aprotic organic solvent such as acetonitrile, chloroform, methylene chloride, acetone, dichloroethane, etc., characterized in that 2 ', 3'-didihydro-2', 3'-dideoxycytidine Process for the preparation of derivatives. The method according to claim 1 or 3 or 4, The base used in the sulfonylation step is NaH, K ₂ CO ₃ or tertiary amine, characterized in that the preparation of 2 ', 3'-didihydro-2', 3'-dideoxycytidine derivative. The method according to any one of claims 1 to 5, 2 ', 3'-didihydro-2', 3'-dideoxycytidine derivative, characterized in that ammonia, primary amine or secondary amine dissolved in gaseous ammonia or organic solvent in the amine substitution step Manufacturing method. The method according to any one of claims 1 to 6, In the double bond forming step, an organic solvent has a boiling point of 100 ° C. or less and uses t-BuOK or KOH to prepare 2 ′, 3′-didihydro-2 ′, 3′-dideoxycytidine derivatives. Way.